Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome</title>
<author><name sortKey="Merico, Daniele" sort="Merico, Daniele" uniqKey="Merico D" first="Daniele" last="Merico">Daniele Merico</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zarrei, Mehdi" sort="Zarrei, Mehdi" uniqKey="Zarrei M" first="Mehdi" last="Zarrei">Mehdi Zarrei</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Costain, Gregory" sort="Costain, Gregory" uniqKey="Costain G" first="Gregory" last="Costain">Gregory Costain</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff3">Medical Genetics Residency Training Program, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ogura, Lucas" sort="Ogura, Lucas" uniqKey="Ogura L" first="Lucas" last="Ogura">Lucas Ogura</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alipanahi, Babak" sort="Alipanahi, Babak" uniqKey="Alipanahi B" first="Babak" last="Alipanahi">Babak Alipanahi</name>
<affiliation><nlm:aff id="aff4">Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gazzellone, Matthew J" sort="Gazzellone, Matthew J" uniqKey="Gazzellone M" first="Matthew J." last="Gazzellone">Matthew J. Gazzellone</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Butcher, Nancy J" sort="Butcher, Nancy J" uniqKey="Butcher N" first="Nancy J." last="Butcher">Nancy J. Butcher</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thiruvahindrapuram, Bhooma" sort="Thiruvahindrapuram, Bhooma" uniqKey="Thiruvahindrapuram B" first="Bhooma" last="Thiruvahindrapuram">Bhooma Thiruvahindrapuram</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nalpathamkalam, Thomas" sort="Nalpathamkalam, Thomas" uniqKey="Nalpathamkalam T" first="Thomas" last="Nalpathamkalam">Thomas Nalpathamkalam</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chow, Eva W C" sort="Chow, Eva W C" uniqKey="Chow E" first="Eva W. C." last="Chow">Eva W. C. Chow</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">Department of Psychiatry University of Toronto, Ontario, M5T 1R8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Andrade, Danielle M" sort="Andrade, Danielle M" uniqKey="Andrade D" first="Danielle M." last="Andrade">Danielle M. Andrade</name>
<affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff7">Epilepsy Genetics Program, Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Ontario, M5T 2S8 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Frey, Brendan J" sort="Frey, Brendan J" uniqKey="Frey B" first="Brendan J." last="Frey">Brendan J. Frey</name>
<affiliation><nlm:aff id="aff4">Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marshall, Christian R" sort="Marshall, Christian R" uniqKey="Marshall C" first="Christian R." last="Marshall">Christian R. Marshall</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scherer, Stephen W" sort="Scherer, Stephen W" uniqKey="Scherer S" first="Stephen W." last="Scherer">Stephen W. Scherer</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff8">McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bassett, Anne S" sort="Bassett, Anne S" uniqKey="Bassett A" first="Anne S." last="Bassett">Anne S. Bassett</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">Department of Psychiatry University of Toronto, Ontario, M5T 1R8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">Department of Psychiatry, and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff10">Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5S 2S1 Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff11">The Dalglish Family Hearts and Minds Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto, Ontario, M5G 2C4 Canada</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26384369</idno>
<idno type="pmc">4632064</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632064</idno>
<idno type="RBID">PMC:4632064</idno>
<idno type="doi">10.1534/g3.115.021345</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">000063</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000063</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome</title>
<author><name sortKey="Merico, Daniele" sort="Merico, Daniele" uniqKey="Merico D" first="Daniele" last="Merico">Daniele Merico</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zarrei, Mehdi" sort="Zarrei, Mehdi" uniqKey="Zarrei M" first="Mehdi" last="Zarrei">Mehdi Zarrei</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Costain, Gregory" sort="Costain, Gregory" uniqKey="Costain G" first="Gregory" last="Costain">Gregory Costain</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff3">Medical Genetics Residency Training Program, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ogura, Lucas" sort="Ogura, Lucas" uniqKey="Ogura L" first="Lucas" last="Ogura">Lucas Ogura</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alipanahi, Babak" sort="Alipanahi, Babak" uniqKey="Alipanahi B" first="Babak" last="Alipanahi">Babak Alipanahi</name>
<affiliation><nlm:aff id="aff4">Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gazzellone, Matthew J" sort="Gazzellone, Matthew J" uniqKey="Gazzellone M" first="Matthew J." last="Gazzellone">Matthew J. Gazzellone</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Butcher, Nancy J" sort="Butcher, Nancy J" uniqKey="Butcher N" first="Nancy J." last="Butcher">Nancy J. Butcher</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thiruvahindrapuram, Bhooma" sort="Thiruvahindrapuram, Bhooma" uniqKey="Thiruvahindrapuram B" first="Bhooma" last="Thiruvahindrapuram">Bhooma Thiruvahindrapuram</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nalpathamkalam, Thomas" sort="Nalpathamkalam, Thomas" uniqKey="Nalpathamkalam T" first="Thomas" last="Nalpathamkalam">Thomas Nalpathamkalam</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chow, Eva W C" sort="Chow, Eva W C" uniqKey="Chow E" first="Eva W. C." last="Chow">Eva W. C. Chow</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">Department of Psychiatry University of Toronto, Ontario, M5T 1R8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Andrade, Danielle M" sort="Andrade, Danielle M" uniqKey="Andrade D" first="Danielle M." last="Andrade">Danielle M. Andrade</name>
<affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff7">Epilepsy Genetics Program, Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Ontario, M5T 2S8 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Frey, Brendan J" sort="Frey, Brendan J" uniqKey="Frey B" first="Brendan J." last="Frey">Brendan J. Frey</name>
<affiliation><nlm:aff id="aff4">Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marshall, Christian R" sort="Marshall, Christian R" uniqKey="Marshall C" first="Christian R." last="Marshall">Christian R. Marshall</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scherer, Stephen W" sort="Scherer, Stephen W" uniqKey="Scherer S" first="Stephen W." last="Scherer">Stephen W. Scherer</name>
<affiliation><nlm:aff id="aff1">The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff8">McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5G 0A4 Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bassett, Anne S" sort="Bassett, Anne S" uniqKey="Bassett A" first="Anne S." last="Bassett">Anne S. Bassett</name>
<affiliation><nlm:aff id="aff2">Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">Department of Psychiatry University of Toronto, Ontario, M5T 1R8 Canada, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">Department of Psychiatry, and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff10">Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5S 2S1 Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff11">The Dalglish Family Hearts and Minds Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto, Ontario, M5G 2C4 Canada</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">G3: Genes|Genomes|Genetics</title>
<idno type="eISSN">2160-1836</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of <italic>DGCR8</italic>
haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal <italic>P</italic>
= 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a <italic>DGCR8</italic>
mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal <italic>P</italic>
= 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Andrade, D M" uniqKey="Andrade D">D. M. Andrade</name>
</author>
<author><name sortKey="Krings, T" uniqKey="Krings T">T. Krings</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
<author><name sortKey="Kiehl, T R" uniqKey="Kiehl T">T. R. Kiehl</name>
</author>
<author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Arinami, T" uniqKey="Arinami T">T. Arinami</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ascano, M" uniqKey="Ascano M">M. Ascano</name>
</author>
<author><name sortKey="Mukherjee, N" uniqKey="Mukherjee N">N. Mukherjee</name>
</author>
<author><name sortKey="Bandaru, P" uniqKey="Bandaru P">P. Bandaru</name>
</author>
<author><name sortKey="Miller, J B" uniqKey="Miller J">J. B. Miller</name>
</author>
<author><name sortKey="Nusbaum, J D" uniqKey="Nusbaum J">J. D. Nusbaum</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Balan, S" uniqKey="Balan S">S. Balan</name>
</author>
<author><name sortKey="Iwayama, Y" uniqKey="Iwayama Y">Y. Iwayama</name>
</author>
<author><name sortKey="Toyota, T" uniqKey="Toyota T">T. Toyota</name>
</author>
<author><name sortKey="Toyoshima, M" uniqKey="Toyoshima M">M. Toyoshima</name>
</author>
<author><name sortKey="Maekawa, M" uniqKey="Maekawa M">M. Maekawa</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Barry, G" uniqKey="Barry G">G. Barry</name>
</author>
<author><name sortKey="Briggs, J A" uniqKey="Briggs J">J. A. Briggs</name>
</author>
<author><name sortKey="Vanichkina, D P" uniqKey="Vanichkina D">D. P. Vanichkina</name>
</author>
<author><name sortKey="Poth, E M" uniqKey="Poth E">E. M. Poth</name>
</author>
<author><name sortKey="Beveridge, N J" uniqKey="Beveridge N">N. J. Beveridge</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
<author><name sortKey="Abdelmalik, P" uniqKey="Abdelmalik P">P. AbdelMalik</name>
</author>
<author><name sortKey="Gheorghiu, M" uniqKey="Gheorghiu M">M. Gheorghiu</name>
</author>
<author><name sortKey="Husted, J" uniqKey="Husted J">J. Husted</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
<author><name sortKey="Marshall, C R" uniqKey="Marshall C">C. R. Marshall</name>
</author>
<author><name sortKey="Lionel, A C" uniqKey="Lionel A">A. C. Lionel</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
<author><name sortKey="Scherer, S W" uniqKey="Scherer S">S. W. Scherer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
<author><name sortKey="Scherer, S W" uniqKey="Scherer S">S. W. Scherer</name>
</author>
<author><name sortKey="Brzustowicz, L M" uniqKey="Brzustowicz L">L. M. Brzustowicz</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bayes, A" uniqKey="Bayes A">A. Bayes</name>
</author>
<author><name sortKey="Van De Lagemaat, L N" uniqKey="Van De Lagemaat L">L. N. van de Lagemaat</name>
</author>
<author><name sortKey="Collins, M O" uniqKey="Collins M">M. O. Collins</name>
</author>
<author><name sortKey="Croning, M D" uniqKey="Croning M">M. D. Croning</name>
</author>
<author><name sortKey="Whittle, I R" uniqKey="Whittle I">I. R. Whittle</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Beveridge, N J" uniqKey="Beveridge N">N. J. Beveridge</name>
</author>
<author><name sortKey="Cairns, M J" uniqKey="Cairns M">M. J. Cairns</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Brzustowicz, L M" uniqKey="Brzustowicz L">L. M. Brzustowicz</name>
</author>
<author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Butcher, N J" uniqKey="Butcher N">N. J. Butcher</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
<author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Karas, D" uniqKey="Karas D">D. Karas</name>
</author>
<author><name sortKey="Ho, A" uniqKey="Ho A">A. Ho</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Butcher, N" uniqKey="Butcher N">N. Butcher</name>
</author>
<author><name sortKey="Kiehl, T" uniqKey="Kiehl T">T. Kiehl</name>
</author>
<author><name sortKey="Hazrati, L" uniqKey="Hazrati L">L. Hazrati</name>
</author>
<author><name sortKey="Chow, E" uniqKey="Chow E">E. Chow</name>
</author>
<author><name sortKey="Rogaeva, E" uniqKey="Rogaeva E">E. Rogaeva</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Butcher, N" uniqKey="Butcher N">N. Butcher</name>
</author>
<author><name sortKey="Marras, C" uniqKey="Marras C">C. Marras</name>
</author>
<author><name sortKey="Pondal, M" uniqKey="Pondal M">M. Pondal</name>
</author>
<author><name sortKey="Christopher, L" uniqKey="Christopher L">L. Christopher</name>
</author>
<author><name sortKey="Strafella, A" uniqKey="Strafella A">A. Strafella</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Butcher, N" uniqKey="Butcher N">N. Butcher</name>
</author>
<author><name sortKey="Fung, W" uniqKey="Fung W">W. Fung</name>
</author>
<author><name sortKey="Fitzpatrick, L" uniqKey="Fitzpatrick L">L. Fitzpatrick</name>
</author>
<author><name sortKey="Guna, A" uniqKey="Guna A">A. Guna</name>
</author>
<author><name sortKey="Andrade, D" uniqKey="Andrade D">D. Andrade</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cabili, M N" uniqKey="Cabili M">M. N. Cabili</name>
</author>
<author><name sortKey="Trapnell, C" uniqKey="Trapnell C">C. Trapnell</name>
</author>
<author><name sortKey="Goff, L" uniqKey="Goff L">L. Goff</name>
</author>
<author><name sortKey="Koziol, M" uniqKey="Koziol M">M. Koziol</name>
</author>
<author><name sortKey="Tazon Vega, B" uniqKey="Tazon Vega B">B. Tazon-Vega</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Carnevali, P" uniqKey="Carnevali P">P. Carnevali</name>
</author>
<author><name sortKey="Baccash, J" uniqKey="Baccash J">J. Baccash</name>
</author>
<author><name sortKey="Halpern, A L" uniqKey="Halpern A">A. L. Halpern</name>
</author>
<author><name sortKey="Nazarenko, I" uniqKey="Nazarenko I">I. Nazarenko</name>
</author>
<author><name sortKey="Nilsen, G B" uniqKey="Nilsen G">G. B. Nilsen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cheung, E N" uniqKey="Cheung E">E. N. Cheung</name>
</author>
<author><name sortKey="George, S R" uniqKey="George S">S. R. George</name>
</author>
<author><name sortKey="Costain, G A" uniqKey="Costain G">G. A. Costain</name>
</author>
<author><name sortKey="Andrade, D M" uniqKey="Andrade D">D. M. Andrade</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Lionel, A C" uniqKey="Lionel A">A. C. Lionel</name>
</author>
<author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
<author><name sortKey="Forsythe, P" uniqKey="Forsythe P">P. Forsythe</name>
</author>
<author><name sortKey="Russell, K" uniqKey="Russell K">K. Russell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Darnell, J C" uniqKey="Darnell J">J. C. Darnell</name>
</author>
<author><name sortKey="Van Driesche, S J" uniqKey="Van Driesche S">S. J. Van Driesche</name>
</author>
<author><name sortKey="Zhang, C" uniqKey="Zhang C">C. Zhang</name>
</author>
<author><name sortKey="Hung, K Y" uniqKey="Hung K">K. Y. Hung</name>
</author>
<author><name sortKey="Mele, A" uniqKey="Mele A">A. Mele</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Derrien, T" uniqKey="Derrien T">T. Derrien</name>
</author>
<author><name sortKey="Johnson, R" uniqKey="Johnson R">R. Johnson</name>
</author>
<author><name sortKey="Bussotti, G" uniqKey="Bussotti G">G. Bussotti</name>
</author>
<author><name sortKey="Tanzer, A" uniqKey="Tanzer A">A. Tanzer</name>
</author>
<author><name sortKey="Djebali, S" uniqKey="Djebali S">S. Djebali</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Drmanac, R" uniqKey="Drmanac R">R. Drmanac</name>
</author>
<author><name sortKey="Sparks, A B" uniqKey="Sparks A">A. B. Sparks</name>
</author>
<author><name sortKey="Callow, M J" uniqKey="Callow M">M. J. Callow</name>
</author>
<author><name sortKey="Halpern, A L" uniqKey="Halpern A">A. L. Halpern</name>
</author>
<author><name sortKey="Burns, N L" uniqKey="Burns N">N. L. Burns</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Forstner, A J" uniqKey="Forstner A">A. J. Forstner</name>
</author>
<author><name sortKey="Degenhardt, F" uniqKey="Degenhardt F">F. Degenhardt</name>
</author>
<author><name sortKey="Schratt, G" uniqKey="Schratt G">G. Schratt</name>
</author>
<author><name sortKey="Nothen, M M" uniqKey="Nothen M">M. M. Nothen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fromer, M" uniqKey="Fromer M">M. Fromer</name>
</author>
<author><name sortKey="Pocklington, A J" uniqKey="Pocklington A">A. J. Pocklington</name>
</author>
<author><name sortKey="Kavanagh, D H" uniqKey="Kavanagh D">D. H. Kavanagh</name>
</author>
<author><name sortKey="Williams, H J" uniqKey="Williams H">H. J. Williams</name>
</author>
<author><name sortKey="Dwyer, S" uniqKey="Dwyer S">S. Dwyer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fu, W" uniqKey="Fu W">W. Fu</name>
</author>
<author><name sortKey="O Onnor, T D" uniqKey="O Onnor T">T. D. O’Connor</name>
</author>
<author><name sortKey="Jun, G" uniqKey="Jun G">G. Jun</name>
</author>
<author><name sortKey="Kang, H M" uniqKey="Kang H">H. M. Kang</name>
</author>
<author><name sortKey="Abecasis, G" uniqKey="Abecasis G">G. Abecasis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fung, W L" uniqKey="Fung W">W. L. Fung</name>
</author>
<author><name sortKey="Mcevilly, R" uniqKey="Mcevilly R">R. McEvilly</name>
</author>
<author><name sortKey="Fong, J" uniqKey="Fong J">J. Fong</name>
</author>
<author><name sortKey="Silversides, C" uniqKey="Silversides C">C. Silversides</name>
</author>
<author><name sortKey="Chow, E" uniqKey="Chow E">E. Chow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fung, W L" uniqKey="Fung W">W. L. Fung</name>
</author>
<author><name sortKey="Butcher, N J" uniqKey="Butcher N">N. J. Butcher</name>
</author>
<author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Andrade, D M" uniqKey="Andrade D">D. M. Andrade</name>
</author>
<author><name sortKey="Boot, E" uniqKey="Boot E">E. Boot</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Geaghan, M" uniqKey="Geaghan M">M. Geaghan</name>
</author>
<author><name sortKey="Cairns, M J" uniqKey="Cairns M">M. J. Cairns</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Abecasis, G R" uniqKey="Abecasis G">G. R. Abecasis</name>
</author>
<author><name sortKey="Auton, A" uniqKey="Auton A">A. Auton</name>
</author>
<author><name sortKey="Brooks, L D" uniqKey="Brooks L">L. D. Brooks</name>
</author>
<author><name sortKey="Depristo, M A" uniqKey="Depristo M">M. A. DePristo</name>
</author>
<author><name sortKey="Durbin, R M" uniqKey="Durbin R">R. M. Durbin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Girard, S L" uniqKey="Girard S">S. L. Girard</name>
</author>
<author><name sortKey="Gauthier, J" uniqKey="Gauthier J">J. Gauthier</name>
</author>
<author><name sortKey="Noreau, A" uniqKey="Noreau A">A. Noreau</name>
</author>
<author><name sortKey="Xiong, L" uniqKey="Xiong L">L. Xiong</name>
</author>
<author><name sortKey="Zhou, S" uniqKey="Zhou S">S. Zhou</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Girirajan, S" uniqKey="Girirajan S">S. Girirajan</name>
</author>
<author><name sortKey="Rosenfeld, J A" uniqKey="Rosenfeld J">J. A. Rosenfeld</name>
</author>
<author><name sortKey="Coe, B P" uniqKey="Coe B">B. P. Coe</name>
</author>
<author><name sortKey="Parikh, S" uniqKey="Parikh S">S. Parikh</name>
</author>
<author><name sortKey="Friedman, N" uniqKey="Friedman N">N. Friedman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Griffiths Jones, S" uniqKey="Griffiths Jones S">S. Griffiths-Jones</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Guipponi, M" uniqKey="Guipponi M">M. Guipponi</name>
</author>
<author><name sortKey="Santoni, F A" uniqKey="Santoni F">F. A. Santoni</name>
</author>
<author><name sortKey="Setola, V" uniqKey="Setola V">V. Setola</name>
</author>
<author><name sortKey="Gehrig, C" uniqKey="Gehrig C">C. Gehrig</name>
</author>
<author><name sortKey="Rotharmel, M" uniqKey="Rotharmel M">M. Rotharmel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gulsuner, S" uniqKey="Gulsuner S">S. Gulsuner</name>
</author>
<author><name sortKey="Walsh, T" uniqKey="Walsh T">T. Walsh</name>
</author>
<author><name sortKey="Watts, A C" uniqKey="Watts A">A. C. Watts</name>
</author>
<author><name sortKey="Lee, M K" uniqKey="Lee M">M. K. Lee</name>
</author>
<author><name sortKey="Thornton, A M" uniqKey="Thornton A">A. M. Thornton</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hochstenbach, R" uniqKey="Hochstenbach R">R. Hochstenbach</name>
</author>
<author><name sortKey="Buizer Voskamp, J E" uniqKey="Buizer Voskamp J">J. E. Buizer-Voskamp</name>
</author>
<author><name sortKey="Vorstman, J A" uniqKey="Vorstman J">J. A. Vorstman</name>
</author>
<author><name sortKey="Ophoff, R A" uniqKey="Ophoff R">R. A. Ophoff</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hotelling, H" uniqKey="Hotelling H">H. Hotelling</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hu, P" uniqKey="Hu P">P. Hu</name>
</author>
<author><name sortKey="Greenwood, C M" uniqKey="Greenwood C">C. M. Greenwood</name>
</author>
<author><name sortKey="Beyene, J" uniqKey="Beyene J">J. Beyene</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Purcell, S M" uniqKey="Purcell S">S. M. Purcell</name>
</author>
<author><name sortKey="Wray, N R" uniqKey="Wray N">N. R. Wray</name>
</author>
<author><name sortKey="Stone, J L" uniqKey="Stone J">J. L. Stone</name>
</author>
<author><name sortKey="Visscher, P M" uniqKey="Visscher P">P. M. Visscher</name>
</author>
<author><name sortKey="O Onovan, M C" uniqKey="O Onovan M">M. C. O’Donovan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Karayiorgou, M" uniqKey="Karayiorgou M">M. Karayiorgou</name>
</author>
<author><name sortKey="Simon, T J" uniqKey="Simon T">T. J. Simon</name>
</author>
<author><name sortKey="Gogos, J A" uniqKey="Gogos J">J. A. Gogos</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kiehl, T R" uniqKey="Kiehl T">T. R. Kiehl</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
<author><name sortKey="Mikulis, D J" uniqKey="Mikulis D">D. J. Mikulis</name>
</author>
<author><name sortKey="George, S R" uniqKey="George S">S. R. George</name>
</author>
<author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kirov, G" uniqKey="Kirov G">G. Kirov</name>
</author>
<author><name sortKey="Pocklington, A J" uniqKey="Pocklington A">A. J. Pocklington</name>
</author>
<author><name sortKey="Holmans, P" uniqKey="Holmans P">P. Holmans</name>
</author>
<author><name sortKey="Ivanov, D" uniqKey="Ivanov D">D. Ivanov</name>
</author>
<author><name sortKey="Ikeda, M" uniqKey="Ikeda M">M. Ikeda</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lowther, C" uniqKey="Lowther C">C. Lowther</name>
</author>
<author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Stavropoulos, D J" uniqKey="Stavropoulos D">D. J. Stavropoulos</name>
</author>
<author><name sortKey="Melvin, R" uniqKey="Melvin R">R. Melvin</name>
</author>
<author><name sortKey="Silversides, C K" uniqKey="Silversides C">C. K. Silversides</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mccarthy, S E" uniqKey="Mccarthy S">S. E. McCarthy</name>
</author>
<author><name sortKey="Gillis, J" uniqKey="Gillis J">J. Gillis</name>
</author>
<author><name sortKey="Kramer, M" uniqKey="Kramer M">M. Kramer</name>
</author>
<author><name sortKey="Lihm, J" uniqKey="Lihm J">J. Lihm</name>
</author>
<author><name sortKey="Yoon, S" uniqKey="Yoon S">S. Yoon</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mcdonald Mcginn, D M" uniqKey="Mcdonald Mcginn D">D. M. McDonald-McGinn</name>
</author>
<author><name sortKey="Fahiminiya, S" uniqKey="Fahiminiya S">S. Fahiminiya</name>
</author>
<author><name sortKey="Revil, T" uniqKey="Revil T">T. Revil</name>
</author>
<author><name sortKey="Nowakowska, B A" uniqKey="Nowakowska B">B. A. Nowakowska</name>
</author>
<author><name sortKey="Suhl, J" uniqKey="Suhl J">J. Suhl</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
<author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Butcher, N J" uniqKey="Butcher N">N. J. Butcher</name>
</author>
<author><name sortKey="Warnica, W" uniqKey="Warnica W">W. Warnica</name>
</author>
<author><name sortKey="Ogura, L" uniqKey="Ogura L">L. Ogura</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Moran, V A" uniqKey="Moran V">V. A. Moran</name>
</author>
<author><name sortKey="Perera, R J" uniqKey="Perera R">R. J. Perera</name>
</author>
<author><name sortKey="Khalil, A M" uniqKey="Khalil A">A. M. Khalil</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Moreau, M P" uniqKey="Moreau M">M. P. Moreau</name>
</author>
<author><name sortKey="Bruse, S E" uniqKey="Bruse S">S. E. Bruse</name>
</author>
<author><name sortKey="David Rus, R" uniqKey="David Rus R">R. David-Rus</name>
</author>
<author><name sortKey="Buyske, S" uniqKey="Buyske S">S. Buyske</name>
</author>
<author><name sortKey="Brzustowicz, L M" uniqKey="Brzustowicz L">L. M. Brzustowicz</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Morrow, E M" uniqKey="Morrow E">E. M. Morrow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Need, A C" uniqKey="Need A">A. C. Need</name>
</author>
<author><name sortKey="Mcevoy, J P" uniqKey="Mcevoy J">J. P. McEvoy</name>
</author>
<author><name sortKey="Gennarelli, M" uniqKey="Gennarelli M">M. Gennarelli</name>
</author>
<author><name sortKey="Heinzen, E L" uniqKey="Heinzen E">E. L. Heinzen</name>
</author>
<author><name sortKey="Ge, D" uniqKey="Ge D">D. Ge</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Philip, N" uniqKey="Philip N">N. Philip</name>
</author>
<author><name sortKey="Bassett, A" uniqKey="Bassett A">A. Bassett</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Pinto, D" uniqKey="Pinto D">D. Pinto</name>
</author>
<author><name sortKey="Delaby, E" uniqKey="Delaby E">E. Delaby</name>
</author>
<author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
<author><name sortKey="Barbosa, M" uniqKey="Barbosa M">M. Barbosa</name>
</author>
<author><name sortKey="Merikangas, A" uniqKey="Merikangas A">A. Merikangas</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Piton, A" uniqKey="Piton A">A. Piton</name>
</author>
<author><name sortKey="Gauthier, J" uniqKey="Gauthier J">J. Gauthier</name>
</author>
<author><name sortKey="Hamdan, F F" uniqKey="Hamdan F">F. F. Hamdan</name>
</author>
<author><name sortKey="Lafreniere, R G" uniqKey="Lafreniere R">R. G. Lafreniere</name>
</author>
<author><name sortKey="Yang, Y" uniqKey="Yang Y">Y. Yang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Prasad, S E" uniqKey="Prasad S">S. E. Prasad</name>
</author>
<author><name sortKey="Howley, S" uniqKey="Howley S">S. Howley</name>
</author>
<author><name sortKey="Murphy, K C" uniqKey="Murphy K">K. C. Murphy</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Purcell, S M" uniqKey="Purcell S">S. M. Purcell</name>
</author>
<author><name sortKey="Moran, J L" uniqKey="Moran J">J. L. Moran</name>
</author>
<author><name sortKey="Fromer, M" uniqKey="Fromer M">M. Fromer</name>
</author>
<author><name sortKey="Ruderfer, D" uniqKey="Ruderfer D">D. Ruderfer</name>
</author>
<author><name sortKey="Solovieff, N" uniqKey="Solovieff N">N. Solovieff</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Quek, X C" uniqKey="Quek X">X. C. Quek</name>
</author>
<author><name sortKey="Thomson, D W" uniqKey="Thomson D">D. W. Thomson</name>
</author>
<author><name sortKey="Maag, J L" uniqKey="Maag J">J. L. Maag</name>
</author>
<author><name sortKey="Bartonicek, N" uniqKey="Bartonicek N">N. Bartonicek</name>
</author>
<author><name sortKey="Signal, B" uniqKey="Signal B">B. Signal</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rees, E" uniqKey="Rees E">E. Rees</name>
</author>
<author><name sortKey="Walters, J T" uniqKey="Walters J">J. T. Walters</name>
</author>
<author><name sortKey="Georgieva, L" uniqKey="Georgieva L">L. Georgieva</name>
</author>
<author><name sortKey="Isles, A R" uniqKey="Isles A">A. R. Isles</name>
</author>
<author><name sortKey="Chambert, K D" uniqKey="Chambert K">K. D. Chambert</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Schneider, M" uniqKey="Schneider M">M. Schneider</name>
</author>
<author><name sortKey="Debbane, M" uniqKey="Debbane M">M. Debbane</name>
</author>
<author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
<author><name sortKey="Fung, W L" uniqKey="Fung W">W. L. Fung</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schofield, C M" uniqKey="Schofield C">C. M. Schofield</name>
</author>
<author><name sortKey="Hsu, R" uniqKey="Hsu R">R. Hsu</name>
</author>
<author><name sortKey="Barker, A J" uniqKey="Barker A">A. J. Barker</name>
</author>
<author><name sortKey="Gertz, C C" uniqKey="Gertz C">C. C. Gertz</name>
</author>
<author><name sortKey="Blelloch, R" uniqKey="Blelloch R">R. Blelloch</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Silversides, C K" uniqKey="Silversides C">C. K. Silversides</name>
</author>
<author><name sortKey="Lionel, A C" uniqKey="Lionel A">A. C. Lionel</name>
</author>
<author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
<author><name sortKey="Migita, O" uniqKey="Migita O">O. Migita</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Stankiewicz, P" uniqKey="Stankiewicz P">P. Stankiewicz</name>
</author>
<author><name sortKey="Lupski, J R" uniqKey="Lupski J">J. R. Lupski</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Stark, K L" uniqKey="Stark K">K. L. Stark</name>
</author>
<author><name sortKey="Xu, B" uniqKey="Xu B">B. Xu</name>
</author>
<author><name sortKey="Bagchi, A" uniqKey="Bagchi A">A. Bagchi</name>
</author>
<author><name sortKey="Lai, W S" uniqKey="Lai W">W. S. Lai</name>
</author>
<author><name sortKey="Liu, H" uniqKey="Liu H">H. Liu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Suhl, J A" uniqKey="Suhl J">J. A. Suhl</name>
</author>
<author><name sortKey="Chopra, P" uniqKey="Chopra P">P. Chopra</name>
</author>
<author><name sortKey="Anderson, B R" uniqKey="Anderson B">B. R. Anderson</name>
</author>
<author><name sortKey="Bassell, G J" uniqKey="Bassell G">G. J. Bassell</name>
</author>
<author><name sortKey="Warren, S T" uniqKey="Warren S">S. T. Warren</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Swaby, J A" uniqKey="Swaby J">J. A. Swaby</name>
</author>
<author><name sortKey="Silversides, C K" uniqKey="Silversides C">C. K. Silversides</name>
</author>
<author><name sortKey="Bekeschus, S C" uniqKey="Bekeschus S">S. C. Bekeschus</name>
</author>
<author><name sortKey="Piran, S" uniqKey="Piran S">S. Piran</name>
</author>
<author><name sortKey="Oechslin, E N" uniqKey="Oechslin E">E. N. Oechslin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Timms, A E" uniqKey="Timms A">A. E. Timms</name>
</author>
<author><name sortKey="Dorschner, M O" uniqKey="Dorschner M">M. O. Dorschner</name>
</author>
<author><name sortKey="Wechsler, J" uniqKey="Wechsler J">J. Wechsler</name>
</author>
<author><name sortKey="Choi, K Y" uniqKey="Choi K">K. Y. Choi</name>
</author>
<author><name sortKey="Kirkwood, R" uniqKey="Kirkwood R">R. Kirkwood</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Vorstman, J A" uniqKey="Vorstman J">J. A. Vorstman</name>
</author>
<author><name sortKey="Breetvelt, E J" uniqKey="Breetvelt E">E. J. Breetvelt</name>
</author>
<author><name sortKey="Thode, K I" uniqKey="Thode K">K. I. Thode</name>
</author>
<author><name sortKey="Chow, E W" uniqKey="Chow E">E. W. Chow</name>
</author>
<author><name sortKey="Bassett, A S" uniqKey="Bassett A">A. S. Bassett</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wang, K" uniqKey="Wang K">K. Wang</name>
</author>
<author><name sortKey="Li, M" uniqKey="Li M">M. Li</name>
</author>
<author><name sortKey="Hakonarson, H" uniqKey="Hakonarson H">H. Hakonarson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Warnica, W" uniqKey="Warnica W">W. Warnica</name>
</author>
<author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
<author><name sortKey="Costain, G" uniqKey="Costain G">G. Costain</name>
</author>
<author><name sortKey="Alfred, S E" uniqKey="Alfred S">S. E. Alfred</name>
</author>
<author><name sortKey="Wei, J" uniqKey="Wei J">J. Wei</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Williams, H J" uniqKey="Williams H">H. J. Williams</name>
</author>
<author><name sortKey="Monks, S" uniqKey="Monks S">S. Monks</name>
</author>
<author><name sortKey="Murphy, K C" uniqKey="Murphy K">K. C. Murphy</name>
</author>
<author><name sortKey="Kirov, G" uniqKey="Kirov G">G. Kirov</name>
</author>
<author><name sortKey="O Onovan, M C" uniqKey="O Onovan M">M. C. O’Donovan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xiong, H Y" uniqKey="Xiong H">H. Y. Xiong</name>
</author>
<author><name sortKey="Alipanahi, B" uniqKey="Alipanahi B">B. Alipanahi</name>
</author>
<author><name sortKey="Lee, L J" uniqKey="Lee L">L. J. Lee</name>
</author>
<author><name sortKey="Bretschneider, H" uniqKey="Bretschneider H">H. Bretschneider</name>
</author>
<author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xu, B" uniqKey="Xu B">B. Xu</name>
</author>
<author><name sortKey="Karayiorgou, M" uniqKey="Karayiorgou M">M. Karayiorgou</name>
</author>
<author><name sortKey="Gogos, J A" uniqKey="Gogos J">J. A. Gogos</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xu, B" uniqKey="Xu B">B. Xu</name>
</author>
<author><name sortKey="Ionita Laza, I" uniqKey="Ionita Laza I">I. Ionita-Laza</name>
</author>
<author><name sortKey="Roos, J L" uniqKey="Roos J">J. L. Roos</name>
</author>
<author><name sortKey="Boone, B" uniqKey="Boone B">B. Boone</name>
</author>
<author><name sortKey="Woodrick, S" uniqKey="Woodrick S">S. Woodrick</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yuen, R K" uniqKey="Yuen R">R. K. Yuen</name>
</author>
<author><name sortKey="Thiruvahindrapuram, B" uniqKey="Thiruvahindrapuram B">B. Thiruvahindrapuram</name>
</author>
<author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
<author><name sortKey="Walker, S" uniqKey="Walker S">S. Walker</name>
</author>
<author><name sortKey="Tammimies, K" uniqKey="Tammimies K">K. Tammimies</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zarrei, M" uniqKey="Zarrei M">M. Zarrei</name>
</author>
<author><name sortKey="Macdonald, J R" uniqKey="Macdonald J">J. R. MacDonald</name>
</author>
<author><name sortKey="Merico, D" uniqKey="Merico D">D. Merico</name>
</author>
<author><name sortKey="Scherer, S W" uniqKey="Scherer S">S. W. Scherer</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">G3 (Bethesda)</journal-id>
<journal-id journal-id-type="iso-abbrev">Genetics</journal-id>
<journal-id journal-id-type="hwp">G3: Genes, Genomes, Genetics</journal-id>
<journal-id journal-id-type="pmc">G3: Genes, Genomes, Genetics</journal-id>
<journal-id journal-id-type="publisher-id">G3: Genes, Genomes, Genetics</journal-id>
<journal-title-group><journal-title>G3: Genes|Genomes|Genetics</journal-title>
</journal-title-group>
<issn pub-type="epub">2160-1836</issn>
<publisher><publisher-name>Genetics Society of America</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26384369</article-id>
<article-id pub-id-type="pmc">4632064</article-id>
<article-id pub-id-type="publisher-id">GGG_021345</article-id>
<article-id pub-id-type="doi">10.1534/g3.115.021345</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Investigations</subject>
</subj-group>
</article-categories>
<title-group><article-title>Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Merico</surname>
<given-names>Daniele</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="author-notes" rid="afn2"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zarrei</surname>
<given-names>Mehdi</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="author-notes" rid="afn2"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Costain</surname>
<given-names>Gregory</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>†</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ogura</surname>
<given-names>Lucas</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alipanahi</surname>
<given-names>Babak</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>§</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gazzellone</surname>
<given-names>Matthew J.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Butcher</surname>
<given-names>Nancy J.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Thiruvahindrapuram</surname>
<given-names>Bhooma</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nalpathamkalam</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chow</surname>
<given-names>Eva W. C.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>†</sup>
</xref>
<xref ref-type="aff" rid="aff5">**</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Andrade</surname>
<given-names>Danielle M.</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>††</sup>
</xref>
<xref ref-type="aff" rid="aff7"><sup>‡‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Frey</surname>
<given-names>Brendan J.</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>§</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marshall</surname>
<given-names>Christian R.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Scherer</surname>
<given-names>Stephen W.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="aff" rid="aff8"><sup>§§</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bassett</surname>
<given-names>Anne S.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>†</sup>
</xref>
<xref ref-type="aff" rid="aff5">**</xref>
<xref ref-type="aff" rid="aff9">***</xref>
<xref ref-type="aff" rid="aff10"><sup>†††</sup>
</xref>
<xref ref-type="aff" rid="aff11"><sup>‡‡‡</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>2</sup>
</xref>
</contrib>
<aff id="aff1"><label>*</label>
The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada</aff>
<aff id="aff2"><label>†</label>
Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</aff>
<aff id="aff3"><label>‡</label>
Medical Genetics Residency Training Program, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada</aff>
<aff id="aff4"><label>§</label>
Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada</aff>
<aff id="aff5"><label>**</label>
Department of Psychiatry University of Toronto, Ontario, M5T 1R8 Canada, University of Toronto, Toronto, Ontario, Canada</aff>
<aff id="aff6"><label>††</label>
Division of Neurology, Department of Medicine, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada</aff>
<aff id="aff7"><label>‡‡</label>
Epilepsy Genetics Program, Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Ontario, M5T 2S8 Canada</aff>
<aff id="aff8"><label>§§</label>
McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5G 0A4 Canada</aff>
<aff id="aff9"><label>***</label>
Department of Psychiatry, and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada</aff>
<aff id="aff10"><label>†††</label>
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5S 2S1 Canada</aff>
<aff id="aff11"><label>‡‡‡</label>
The Dalglish Family Hearts and Minds Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto, Ontario, M5G 2C4 Canada</aff>
</contrib-group>
<author-notes><fn id="afn2" fn-type="equal"><label>1</label>
<p>These authors contributed equally to this work.</p>
</fn>
<corresp id="cor1"><label>2</label>
Corresponding author: Centre for Addiction and Mental Health, 33 Russell Street, Room 1100, Toronto, Ontario, Canada M5S 2S1. E-mail: <email>anne.bassett@utoronto.ca</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>16</day>
<month>9</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><month>11</month>
<year>2015</year>
</pub-date>
<volume>5</volume>
<issue>11</issue>
<fpage>2453</fpage>
<lpage>2461</lpage>
<history><date date-type="received"><day>14</day>
<month>8</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>12</day>
<month>9</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015 Merico <italic>et al.</italic>
</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="2453.pdf"></self-uri>
<abstract><p>Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of <italic>DGCR8</italic>
haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal <italic>P</italic>
= 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a <italic>DGCR8</italic>
mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal <italic>P</italic>
= 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes.</p>
</abstract>
<kwd-group><kwd>22q11 deletion syndrome</kwd>
<kwd>next-generation sequencing</kwd>
<kwd>genetic architecture</kwd>
<kwd>copy number variation</kwd>
<kwd>microRNA</kwd>
<kwd><italic>DGCR8</italic>
</kwd>
<kwd>schizophrenia</kwd>
<kwd>noncoding RNA</kwd>
<kwd>lincRNA</kwd>
<kwd><italic>FMR1</italic>
</kwd>
<kwd>synapse</kwd>
<kwd>connectivity</kwd>
<kwd>postsynaptic density</kwd>
<kwd>polygenic risk score</kwd>
<kwd><italic>ABLIM1</italic>
</kwd>
<kwd><italic>BSN</italic>
</kwd>
<kwd><italic>DIP2A</italic>
</kwd>
<kwd><italic>EXOC4</italic>
</kwd>
<kwd><italic>ITM2C</italic>
</kwd>
<kwd><italic>MYH9</italic>
</kwd>
<kwd><italic>MYH10</italic>
</kwd>
<kwd><italic>PCNT</italic>
</kwd>
<kwd><italic>PTPRG</italic>
</kwd>
<kwd><italic>SLITRK2</italic>
</kwd>
<kwd><italic>ZDHHC5</italic>
</kwd>
</kwd-group>
<counts><page-count count="9"></page-count>
</counts>
</article-meta>
</front>
<body><p>Schizophrenia is a complex neuropsychiatric disease with prominent genetic heterogeneity. The established molecular genetic risk factors of largest effect are rare copy number variations (CNVs), especially 22q11.2 deletions (<xref rid="bib42" ref-type="bibr">Kirov <italic>et al.</italic>
2012</xref>
; <xref rid="bib20" ref-type="bibr">Costain <italic>et al.</italic>
2013</xref>
; <xref rid="bib63" ref-type="bibr">Stankiewicz and Lupski 2010</xref>
; <xref rid="bib43" ref-type="bibr">Lowther <italic>et al.</italic>
2015</xref>
; <xref rid="bib8" ref-type="bibr">Bassett <italic>et al.</italic>
2010</xref>
; <xref rid="bib36" ref-type="bibr">Hochstenbach <italic>et al.</italic>
2011</xref>
; <xref rid="bib19" ref-type="bibr">Costain and Bassett 2012</xref>
; <xref rid="bib58" ref-type="bibr">Rees <italic>et al.</italic>
2014</xref>
). Whole-exome sequencing (WES) studies indicate that rare coding sequence variants also contribute to schizophrenia (<xref rid="bib31" ref-type="bibr">Girard <italic>et al.</italic>
2011</xref>
; <xref rid="bib74" ref-type="bibr">Xu <italic>et al.</italic>
2012</xref>
; <xref rid="bib50" ref-type="bibr">Need <italic>et al.</italic>
2012</xref>
; <xref rid="bib35" ref-type="bibr">Gulsuner <italic>et al.</italic>
2013</xref>
; <xref rid="bib67" ref-type="bibr">Timms <italic>et al.</italic>
2013</xref>
; <xref rid="bib25" ref-type="bibr">Fromer <italic>et al.</italic>
2014</xref>
; <xref rid="bib56" ref-type="bibr">Purcell <italic>et al.</italic>
2014</xref>
; <xref rid="bib44" ref-type="bibr">McCarthy <italic>et al.</italic>
2014</xref>
; <xref rid="bib34" ref-type="bibr">Guipponi <italic>et al.</italic>
2014</xref>
). Rare variants that disrupt mechanisms regulating expression of protein-coding genes are likely to be part of the genetic architecture of schizophrenia as well (<xref rid="bib49" ref-type="bibr">Morrow 2015</xref>
; <xref rid="bib29" ref-type="bibr">Geaghan and Cairns 2014</xref>
; <xref rid="bib24" ref-type="bibr">Forstner <italic>et al.</italic>
2013</xref>
; <xref rid="bib10" ref-type="bibr">Beveridge and Cairns 2012</xref>
; <xref rid="bib48" ref-type="bibr">Moreau <italic>et al.</italic>
2011</xref>
; <xref rid="bib73" ref-type="bibr">Xu <italic>et al.</italic>
2010</xref>
; <xref rid="bib70" ref-type="bibr">Warnica <italic>et al.</italic>
2015</xref>
). These variants usually alter noncoding RNA gene exons or splicing and transcription regulatory motifs that typically reside outside of protein-coding exons. For this reason, the majority of these variants are detectable only by the use of whole-genome sequencing (WGS).</p>
<p>Extensive research efforts have focused on understanding the contribution of common variation to schizophrenia risk. The most recent large-scale study successfully identified more than 100 genome-wide significant loci, although with very modest effect size and often obscure molecular mechanisms (<xref rid="bib59" ref-type="bibr">Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014</xref>
). A polygenic risk score, based on the additive contribution of many weakly associated variants (<xref rid="bib39" ref-type="bibr">International Schizophrenia Consortium <italic>et al.</italic>
2009</xref>
), has been used successfully to maximize the fraction of schizophrenia risk explained by common variation (<xref rid="bib59" ref-type="bibr">Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014</xref>
). Pathway-level methods also have been investigated to identify commonalities among many different contributing variants, rare or common (<xref rid="bib42" ref-type="bibr">Kirov <italic>et al.</italic>
2012</xref>
; <xref rid="bib20" ref-type="bibr">Costain <italic>et al.</italic>
2013</xref>
; <xref rid="bib25" ref-type="bibr">Fromer <italic>et al.</italic>
2014</xref>
; <xref rid="bib56" ref-type="bibr">Purcell <italic>et al.</italic>
2014</xref>
; <xref rid="bib70" ref-type="bibr">Warnica <italic>et al.</italic>
2015</xref>
; <xref rid="bib51" ref-type="bibr">Pathway Analysis Subgroup of Psychiatric Genomics Consortium Network 2015</xref>
).</p>
<p>Even in 22q11.2 deletion syndrome (22q11.2DS), where the recurrent 22q11.2 deletion imparts a 25% risk of developing schizophrenia (<xref rid="bib27" ref-type="bibr">Fung <italic>et al.</italic>
2010</xref>
; <xref rid="bib60" ref-type="bibr">Schneider <italic>et al.</italic>
2014</xref>
), there remain undiscovered determinants of expression. One proposed mechanism involves genome-wide microRNA (miRNA) dysregulation related to haploinsufficiency of the <italic>DGCR8</italic>
gene that lies within the 22q11.2 deletion region (<xref rid="bib64" ref-type="bibr">Stark <italic>et al.</italic>
2008</xref>
; <xref rid="bib24" ref-type="bibr">Forstner <italic>et al.</italic>
2013</xref>
; <xref rid="bib61" ref-type="bibr">Schofield <italic>et al.</italic>
2011</xref>
; <xref rid="bib11" ref-type="bibr">Brzustowicz and Bassett 2012</xref>
; <xref rid="bib46" ref-type="bibr">Merico <italic>et al.</italic>
2014</xref>
). In individuals with 22q11.2 deletions this haploinsufficiency could increase susceptibility to the effects of protein-coding mutations that otherwise may be tolerated, including those in genes that are involved in schizophrenia in the general population (<xref rid="bib11" ref-type="bibr">Brzustowicz and Bassett 2012</xref>
).</p>
<p>In this initial proof-of-principle study, we hypothesized that the 22q11.2 deletion would provide enhanced power to investigate biologically plausible mechanisms for schizophrenia. We used high-quality, WGS of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years), followed by a comprehensive annotation and prioritization of rare variants impacting coding and non-coding sequence (<xref rid="bib75" ref-type="bibr">Yuen <italic>et al.</italic>
2015</xref>
). To maximize statistical power, we investigated rare variant burden for gene-sets with higher <italic>a priori</italic>
likelihood of contributing to schizophrenia risk. We additionally investigated common variant contribution using a polygenic risk score model.</p>
<p>We found evidence for rare variants outside the 22q11.2 region perturbing gene networks relevant to idiopathic schizophrenia, for a <italic>DGCR8</italic>
/miRNA-related mechanism, for other noncoding sequence variants, and for a polygenic risk contribution, and predicted that maximal statistical power can be achieved with attainable sample sizes of this genetic model.</p>
<sec sec-type="methods|materials" id="s1"><title>Methods and Materials</title>
<sec id="s2"><title>Subjects</title>
<p>From a cohort of Canadian adults with 22q11.2DS (<xref rid="bib6" ref-type="bibr">Bassett <italic>et al.</italic>
2003</xref>
, <xref rid="bib7" ref-type="bibr">2008</xref>
; <xref rid="bib11" ref-type="bibr">Brzustowicz and Bassett 2012</xref>
; <xref rid="bib18" ref-type="bibr">Cheung <italic>et al.</italic>
2014</xref>
; <xref rid="bib27" ref-type="bibr">Fung <italic>et al.</italic>
2010</xref>
; <xref rid="bib60" ref-type="bibr">Schneider <italic>et al.</italic>
2014</xref>
; <xref rid="bib68" ref-type="bibr">Vorstman <italic>et al.</italic>
2013</xref>
; <xref rid="bib66" ref-type="bibr">Swaby <italic>et al.</italic>
2011</xref>
; <xref rid="bib12" ref-type="bibr">Butcher <italic>et al.</italic>
2012</xref>
, <xref rid="bib13" ref-type="bibr">2013</xref>
, <xref rid="bib15" ref-type="bibr">2015</xref>
), we selected nine unrelated individuals of European descent (<xref ref-type="table" rid="t1">Table 1</xref>
), based on availability of high quality genomic DNA for WGS and phenotypic information consistent with the extreme phenotype design: six (SCZ1-SCZ6) met DSM-IV criteria for schizophrenia or schizoaffective disorder (<xref rid="bib6" ref-type="bibr">Bassett <italic>et al.</italic>
2003</xref>
) and three (NP1-NP3) had no psychotic disorder at age >50 years (<xref ref-type="table" rid="t1">Table 1</xref>
). Deep phenotyping included direct clinical assessments at multiple time points and review of lifetime medical records, with the use of our established methods (<xref rid="bib27" ref-type="bibr">Fung <italic>et al.</italic>
2010</xref>
; <xref rid="bib68" ref-type="bibr">Vorstman <italic>et al.</italic>
2013</xref>
; <xref rid="bib66" ref-type="bibr">Swaby <italic>et al.</italic>
2011</xref>
; <xref rid="bib12" ref-type="bibr">Butcher <italic>et al.</italic>
2012</xref>
, <xref rid="bib13" ref-type="bibr">2013</xref>
; <xref rid="bib18" ref-type="bibr">Cheung <italic>et al.</italic>
2014</xref>
; <xref rid="bib6" ref-type="bibr">Bassett <italic>et al.</italic>
2003</xref>
). The six subjects with schizophrenia had no other single major feature of 22q11.2DS in common (<xref ref-type="table" rid="t1">Table 1</xref>
). All participants provided written informed consent, and the study was approved by local research ethics boards.</p>
<table-wrap id="t1" position="float"><label>Table 1</label>
<caption><title>Characteristics of nine adults of European ancestry with 22q11.2 deletions and whole-genome sequencing data</title>
</caption>
<table frame="above" rules="groups"><col width="30.55%" span="1"></col>
<col width="8.52%" span="1"></col>
<col width="7.36%" span="1"></col>
<col width="6.77%" span="1"></col>
<col width="8.03%" span="1"></col>
<col width="8.03%" span="1"></col>
<col width="7.31%" span="1"></col>
<col width="7.37%" span="1"></col>
<col width="8.03%" span="1"></col>
<col width="8.03%" span="1"></col>
<thead><tr><th rowspan="2" valign="top" align="left" scope="col" colspan="1">Case Identifier</th>
<th colspan="6" valign="top" align="center" scope="colgroup" rowspan="1">Schizophrenia</th>
<th colspan="3" valign="top" align="center" scope="colgroup" rowspan="1">Nonpsychotic</th>
</tr>
<tr><th valign="top" colspan="1" align="center" scope="colgroup" rowspan="1">SCZ1</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">SCZ2</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">SCZ3</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">SCZ4</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">SCZ5</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">SCZ6</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">NP1</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">NP2</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">NP3</th>
</tr>
</thead>
<tbody><tr><td valign="top" align="left" scope="col" rowspan="1" colspan="1">Schizophrenia phenotype and risk factors</td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Age at last follow-up or at death (yr)</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">56</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">58</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">38</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">48</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">44</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">21</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">61</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">53</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">52</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Age at onset of psychosis (yr)</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">17</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">22</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">15</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">18</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">21</td>
<td valign="top" align="char" char="." rowspan="1" colspan="1">12</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Treatment-resistance<xref ref-type="table-fn" rid="t1n1"><italic><sup>a</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Substance abuse<xref ref-type="table-fn" rid="t1n2"><italic><sup>b</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Developmental brain anomaly<xref ref-type="table-fn" rid="t1n3"><italic><sup>c</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Family history of schizophrenia<xref ref-type="table-fn" rid="t1n4"><italic><sup>d</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No<xref ref-type="table-fn" rid="t1n5"><italic><sup>e</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No<xref ref-type="table-fn" rid="t1n5"><italic><sup>e</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
</tr>
<tr><td valign="top" align="left" scope="col" rowspan="1" colspan="1">Additional demographic, genotypic, and phenotypic features</td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Sex</td>
<td valign="top" align="left" rowspan="1" colspan="1">Female</td>
<td valign="top" align="left" rowspan="1" colspan="1">Male</td>
<td valign="top" align="left" rowspan="1" colspan="1">Male</td>
<td valign="top" align="left" rowspan="1" colspan="1">Female</td>
<td valign="top" align="left" rowspan="1" colspan="1">Male</td>
<td valign="top" align="left" rowspan="1" colspan="1">Female</td>
<td valign="top" align="left" rowspan="1" colspan="1">Male</td>
<td valign="top" align="left" rowspan="1" colspan="1">Male</td>
<td valign="top" align="left" rowspan="1" colspan="1">Female</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> 22q11.2 deletion type<xref ref-type="table-fn" rid="t1n6"><italic><sup>f</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Nested</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
<td valign="top" align="left" rowspan="1" colspan="1">Typical</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"><italic> De novo</italic>
22q11.2 deletion<xref ref-type="table-fn" rid="t1n6"><italic><sup>f</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Probable</td>
<td valign="top" align="left" rowspan="1" colspan="1">Probable</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Probable</td>
<td valign="top" align="left" rowspan="1" colspan="1">Probable</td>
<td valign="top" align="left" rowspan="1" colspan="1">Probable</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Probable</td>
</tr>
<tr><td valign="top" align="left" scope="col" rowspan="1" colspan="1"> Major feature of 22q11.2DS<xref ref-type="table-fn" rid="t1n7"><italic><sup>g</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Congenital heart disease<xref ref-type="table-fn" rid="t1n8"><italic><sup>h</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Cleft palate and/or velopharyngeal insufficiency</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Intellectual disability<xref ref-type="table-fn" rid="t1n9"><italic><sup>i</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Borderline</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Mild</td>
<td valign="top" align="left" rowspan="1" colspan="1">Borderline</td>
<td valign="top" align="left" rowspan="1" colspan="1">Borderline</td>
<td valign="top" align="left" rowspan="1" colspan="1">Mild</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Borderline</td>
<td valign="top" align="left" rowspan="1" colspan="1">Borderline</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Seizures</td>
<td valign="top" align="left" rowspan="1" colspan="1">Single</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Multiple</td>
<td valign="top" align="left" rowspan="1" colspan="1">Multiple</td>
<td valign="top" align="left" rowspan="1" colspan="1">Single</td>
<td valign="top" align="left" rowspan="1" colspan="1">Multiple</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Major mood or anxiety disorder<xref ref-type="table-fn" rid="t1n10"><italic><sup>j</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Parkinson’s disease<xref ref-type="table-fn" rid="t1n11"><italic><sup>k</sup>
</italic>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yes</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
<td valign="top" align="left" rowspan="1" colspan="1">No</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t1n1"><label>a</label>
<p>Requiring trial of clozapine (<xref rid="bib15" ref-type="bibr">Butcher <italic>et al.</italic>
2015</xref>
).</p>
</fn>
<fn id="t1n2"><label>b</label>
<p>Nicotine excepted.</p>
</fn>
<fn id="t1n3"><label>c</label>
<p>On neuroimaging studies (<xref rid="bib1" ref-type="bibr">Andrade <italic>et al.</italic>
2013</xref>
) and/or postmortem examination (<xref rid="bib41" ref-type="bibr">Kiehl <italic>et al.</italic>
2009</xref>
; <xref rid="bib14" ref-type="bibr">Butcher <italic>et al.</italic>
2014</xref>
).</p>
</fn>
<fn id="t1n4"><label>d</label>
<p>Schizophrenia or schizoaffective disorder in a first-degree relative without a 22q11.2 deletion. </p>
</fn>
<fn id="t1n5"><label>e</label>
<p>Both have adult offspring who inherited the 22q11.2 deletion and also do not have a psychotic disorder.</p>
</fn>
<fn id="t1n6"><label>f</label>
<p>Although not part of the study design, <italic>de novo</italic>
22q11.2 deletions are typical in 22q11.2DS; breakpoints for typical (∼2.6−3.0 Mb; ∼90% of 22q11.2DS) and proximal nested (∼1.3−1.5 Mb; ∼5% of 22q11.2DS) 22q11.2 deletions, and <italic>de novo</italic>
status, are defined in <xref rid="bib7" ref-type="bibr">Bassett <italic>et al.</italic>
(2008)</xref>
.</p>
</fn>
<fn id="t1n7"><label>g</label>
<p>As described in <xref rid="bib28" ref-type="bibr">Fung <italic>et al.</italic>
(2015)</xref>
.</p>
</fn>
<fn id="t1n8"><label>h</label>
<p>Tetralogy of Fallot (SCZ2), atrial septal defect and ventricular septal defect (SCZ5, NP3), ventricular septal defect (SCZ6).</p>
</fn>
<fn id="t1n9"><label>i</label>
<p>As assessed in <xref rid="bib12" ref-type="bibr">Butcher <italic>et al.</italic>
(2012)</xref>
.</p>
</fn>
<fn id="t1n10"><label>j</label>
<p>Obsessive compulsive disorder (SCZ6), generalized anxiety disorder (NP2, NP3).</p>
</fn>
<fn id="t1n11"><label>k</label>
<p>Diagnostic details and additional phenotype data for the three subjects with Parkinson's disease are reported elsewhere (<xref rid="bib13" ref-type="bibr">Butcher <italic>et al.</italic>
2013</xref>
).</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3"><title>WGS approach and methods</title>
<p>We submitted a high-quality genomic DNA sample from each subject to Complete Genomics for WGS (<xref rid="bib23" ref-type="bibr">Drmanac <italic>et al.</italic>
2010</xref>
; <xref rid="bib17" ref-type="bibr">Carnevali <italic>et al.</italic>
2012</xref>
). Mean genome coverage per sample was 98.95% (98.81–99.10%) at depth ≥5X and 97.65% (97.30–98.15%) at depth ≥10X, relative to the hg19 human genome reference sequence. In particular, 94.4% and 72.3% of the exome was covered with at least 20X and 40X sequence depth, respectively. Complete Genomics data for each nucleotide position, supplemented by in-house protocols, provided stringent quality filters. For this study, we used only high-quality variants (those with high confidence scores). Variants were then annotated with a custom pipeline based on the ANNOVAR (November 2014) software tool (<xref rid="bib69" ref-type="bibr">Wang <italic>et al.</italic>
2010</xref>
). We defined rare variants as those at <1% of the alternate allele frequency (minor allele frequency = 0.01) threshold in each of three standard [1000 Genomes (<xref rid="bib30" ref-type="bibr">1000 Genomes Project Consortium <italic>et al.</italic>
2012</xref>
), National Heart, Lung, and Blood Institute Exome Sequencing Project (<xref rid="bib26" ref-type="bibr">Fu <italic>et al.</italic>
2013</xref>
), Exome Aggregation Consortium (<ext-link ext-link-type="uri" xlink:href="http://exac.broadinstitute.org/">http://exac.broadinstitute.org/</ext-link>
)], and two in-house, platform-matched databases. Details of all WGS-related laboratory and data interpretation/bioinformatics methods used are provided in the <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/021345SI.pdf">Supporting Information</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/FigureS1.pdf">Figure S1</ext-link>
and <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/FileS1.pdf">File S1</ext-link>
.</p>
</sec>
<sec id="s4"><title>Rare variant burden analyses for coding genes</title>
<p>We considered the possible impact of accumulated deleterious variants affecting protein-coding genes under a haploinsufficiency model, excluding variants in the intact chromosome 22q11.2 region and on the X chromosome, which were examined separately. These variants comprised three categories: loss of function (LoF) variants (stop-gain/nonsense, frameshift, and core splice site), damaging missense variants (predicted to be deleterious per five of seven standard tools), and splicing regulatory variants that (negatively) affect exon inclusion; the latter include intronic variants that are further away from core splice site (LoF) variants (<xref rid="bib72" ref-type="bibr">Xiong <italic>et al.</italic>
2015</xref>
). First, we tested “neurofunctional” gene-sets (<italic>i.e.</italic>
, affecting brain-related functions most likely to be important to schizophrenia expression), separating each variant category (LoF, missense, splicing regulatory). Gene-sets with nominally significant burden for at least one variant category (<italic>P</italic>
< 0.10 for LoF and splicing regulatory, and <italic>P</italic>
< 0.05 for missense variants) were then tested for the joint burden of the three variant categories with a multivariate, two-sample Hotelling’s T-Square test (<xref rid="bib37" ref-type="bibr">Hotelling 1931</xref>
). To investigate a <italic>DGCR8</italic>
/miRNA mechanism, we used the same gene-sets but restricted to those genes predicted to be affected by <italic>DGCR8</italic>
haploinsufficiency (<xref rid="bib64" ref-type="bibr">Stark <italic>et al.</italic>
2008</xref>
). To estimate the burden effect size, we calculated the between-group ratio of the mean absolute variant count (<xref rid="bib38" ref-type="bibr">Hu <italic>et al.</italic>
2009</xref>
). For gene-set burden power calculations, we selected four representative gene-sets showing enrichment for one or more of the variant categories, and used Cohen’s d to express the effect size estimates.</p>
</sec>
<sec id="s5"><title>Copy number variation</title>
<p>We evaluated CNVs and other structural variants (SVs) by using a previously established annotation and prioritization process (<xref rid="bib75" ref-type="bibr">Yuen <italic>et al.</italic>
2015</xref>
). All subjects were confirmed to have 22q11.2 deletions (<xref ref-type="table" rid="t1">Table 1</xref>
). Of the remaining variants, only rare CNVs and SVs that overlapped at least one coding gene exon of a RefSeq gene with known neuronal function were considered in this study.</p>
</sec>
<sec id="s6"><title>Rare variant burden analyses for noncoding RNA genes</title>
<p>We considered two main types of noncoding RNA variants: miRNA derived from mirBase v20 (<xref rid="bib33" ref-type="bibr">Griffiths-Jones 2004</xref>
) and long intergenic noncoding RNA (lincRNA) derived from the Broad catalog (<xref rid="bib16" ref-type="bibr">Cabili <italic>et al.</italic>
2011</xref>
). We tested the burden of high-quality, rare variants prioritized based on regional and nucleotide-level genomic conservation.</p>
</sec>
<sec id="s7"><title>Common variant polygenic risk score</title>
<p>We obtained the list of 102,636 SNPs used by the Psychiatric Genomics Consortium to define a risk score for schizophrenia, together with the original nominal association p-values and odds ratios (<xref rid="bib39" ref-type="bibr">International Schizophrenia Consortium <italic>et al.</italic>
2009</xref>
; <xref rid="bib59" ref-type="bibr">Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014</xref>
). These SNPs were mapped to hg19 coordinates and intersected with the WGS data for our cohort; in particular, WGS variants were matched to risk score SNPs by coordinates and alleles, whereas WGS reference intervals (<italic>i.e.</italic>
, identical to the human reference sequence) were matched by coordinate overlap. A total of 88,301 SNPs was successfully mapped to variants passing quality filters, or reference intervals, in all nine genomes in this study. Allele counts were computed as the number of alleles matching to the allele used for association analysis (possible values: 0, 1, 2). The SNP-wise risk score was then calculated as the product of this allele count and the log(odds-ratio) (<xref rid="bib59" ref-type="bibr">Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014</xref>
). Using nominal p-value thresholds ≤0.001 and ≤0.0001, as well as one more stringent (≤0.00001), and p-values >0.9 and >0.5 as negative controls (<xref rid="bib59" ref-type="bibr">Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014</xref>
), the polygenic risk scores for each 22q11.2DS subject were then calculated as the sum of all respective SNP-wise risk scores (<xref rid="bib39" ref-type="bibr">International Schizophrenia Consortium <italic>et al.</italic>
2009</xref>
). Differences between schizophrenia and no-psychosis groups were tested using a one-sided <italic>t</italic>
-test and a Wilcoxon test. We also calculated the percentage of correctly predicted schizophrenia and no-psychosis subjects at different risk score values, and reported the maximum value as a point-estimate of separation between the two groups.</p>
</sec>
<sec id="s8"><title>Data availability</title>
<p>Supporting Information contains detailed descriptions of all supplemental files. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/FigureS1.pdf">Figure S1</ext-link>
contains selected gene-sets with a higher burden in subjects with schizophrenia. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/FigureS2.pdf">Figure S2</ext-link>
contains distribution boxplots of subjects' polygenic risk scores for the schizophrenia and nonpsychotic groups. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS1.xlsx">Table S1</ext-link>
contains high quality, rare coding variants. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS2.xls">Table S2</ext-link>
contains source and size of gene-sets used in the burden analyses. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS3.xlsx">Table S3</ext-link>
contains details of burden analyses for each type of variants. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS4.xls">Table S4</ext-link>
contains most recurrent splicing regulatory predictive features detected in this study. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS5.xls">Table S5</ext-link>
contains details of power calculations. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS6.xlsx">Table S6</ext-link>
contains details of burden analyses for lincRNA. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS7.xlsx">Table S7</ext-link>
contains details of lincRNA with high quality, rare variants and miRNA with high quality rare variants.</p>
</sec>
</sec>
<sec sec-type="results" id="s9"><title>Results</title>
<p>Details of subjects with 22q11.2DS are in <xref ref-type="table" rid="t1">Table 1</xref>
. Subjects had an average of 13.8 and 94.3 high-quality, rare variants disrupting coding genes (LoF and missense categories, respectively), with similar findings for both the schizophrenia and non-psychotic groups (<ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS3.xlsx">Table S3</ext-link>
). There were few additional variants in the intact chromosome 22q11.2 region (<xref ref-type="table" rid="t2">Table 2</xref>
).</p>
<table-wrap id="t2" position="float"><label>Table 2</label>
<caption><title>Selected brain function related gene-set results for rare single nucleotide variants</title>
</caption>
<table frame="above" rules="groups"><col width="50.52%" span="1"></col>
<col width="8.8%" span="1"></col>
<col width="6.63%" span="1"></col>
<col width="6.62%" span="1"></col>
<col width="5.31%" span="1"></col>
<col width="4.94%" span="1"></col>
<col width="6.82%" span="1"></col>
<col width="10.36%" span="1"></col>
<thead><tr><th rowspan="3" valign="top" align="left" scope="col" colspan="1">Brain Function Related Gene-Set</th>
<th colspan="3" valign="top" align="center" scope="colgroup" rowspan="1">Genes Disrupted in SCZ Cases</th>
<th rowspan="2" colspan="2" valign="top" align="center" scope="colgroup">Mean Number of Variants per Subject<xref ref-type="table-fn" rid="t2n1"><italic><sup>a</sup>
</italic>
</xref>
</th>
<th rowspan="3" valign="top" align="center" scope="col" colspan="1"><italic>P</italic>
<xref ref-type="table-fn" rid="t2n2"><italic><sup>b</sup>
</italic>
</xref>
</th>
<th rowspan="3" valign="top" align="center" scope="col" colspan="1">Estimated Effect Size (Ratio of Means)</th>
</tr>
<tr><th valign="top" colspan="1" align="center" scope="colgroup" rowspan="1">Per Gene-Set</th>
<th colspan="2" valign="top" align="center" scope="colgroup" rowspan="1">In Neuron Projection Gene-Set</th>
</tr>
<tr><th valign="top" colspan="1" align="center" scope="colgroup" rowspan="1">Total n</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">n</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">(%)</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">SCZ</th>
<th valign="top" align="center" scope="col" rowspan="1" colspan="1">NP</th>
</tr>
</thead>
<tbody><tr><td valign="top" align="left" scope="col" rowspan="1" colspan="1">Damaging missense variants</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Neuron projection (GO)</td>
<td valign="top" align="center" rowspan="1" colspan="1">53</td>
<td valign="top" align="center" rowspan="1" colspan="1">53</td>
<td valign="top" align="center" rowspan="1" colspan="1">(100)</td>
<td valign="top" align="center" rowspan="1" colspan="1">9.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">5.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.009</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.80</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes<xref ref-type="table-fn" rid="t2n5"><italic><sup>c</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">16</td>
<td valign="top" align="center" rowspan="1" colspan="1">16</td>
<td valign="top" align="center" rowspan="1" colspan="1">(100)</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.67</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.67</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.025</td>
<td valign="top" align="center" rowspan="1" colspan="1">4.00</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Synaptic pathways (KEGG)</td>
<td valign="top" align="center" rowspan="1" colspan="1">15</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">(20)</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.50</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.053</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.50</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes<xref ref-type="table-fn" rid="t2n6"><italic><sup>d</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">7</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">(0)</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.17</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.005</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> GABAergic synapse (KEGG)<xref ref-type="table-fn" rid="t2n3"><italic><sup>e</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">7</td>
<td valign="top" align="center" rowspan="1" colspan="1">1</td>
<td valign="top" align="center" rowspan="1" colspan="1">(14)</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.17</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.015</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">(0)</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.50</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.039</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Cholinergic synapse (KEGG)<xref ref-type="table-fn" rid="t2n3"><italic><sup>e</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">6</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
<td valign="top" align="center" rowspan="1" colspan="1">(33)</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.33</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.152</td>
<td valign="top" align="center" rowspan="1" colspan="1">3.00</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">(0)</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.50</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.038</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Abnormal sensory system (MGI)</td>
<td valign="top" align="center" rowspan="1" colspan="1">58</td>
<td valign="top" align="center" rowspan="1" colspan="1">13</td>
<td valign="top" align="center" rowspan="1" colspan="1">(22)</td>
<td valign="top" align="center" rowspan="1" colspan="1">10.17</td>
<td valign="top" align="center" rowspan="1" colspan="1">8.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.029</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.27</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes</td>
<td valign="top" align="center" rowspan="1" colspan="1">19</td>
<td valign="top" align="center" rowspan="1" colspan="1">7</td>
<td valign="top" align="center" rowspan="1" colspan="1">(37)</td>
<td valign="top" align="center" rowspan="1" colspan="1">3.33</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.024</td>
<td valign="top" align="center" rowspan="1" colspan="1">3.33</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Neural function or pathway, union, stringent (GO, KEGG, NCI, Reactome)</td>
<td valign="top" align="center" rowspan="1" colspan="1">65</td>
<td valign="top" align="center" rowspan="1" colspan="1">49</td>
<td valign="top" align="center" rowspan="1" colspan="1">(75)</td>
<td valign="top" align="center" rowspan="1" colspan="1">11.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">6.33</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.026</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.74</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes</td>
<td valign="top" align="center" rowspan="1" colspan="1">21</td>
<td valign="top" align="center" rowspan="1" colspan="1">13</td>
<td valign="top" align="center" rowspan="1" colspan="1">(62)</td>
<td valign="top" align="center" rowspan="1" colspan="1">3.50</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.67</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.023</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.10</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Nervous system abnormality, autosomal dominant or X-linked (HPO)</td>
<td valign="top" align="center" rowspan="1" colspan="1">31</td>
<td valign="top" align="center" rowspan="1" colspan="1">9</td>
<td valign="top" align="center" rowspan="1" colspan="1">(29)</td>
<td valign="top" align="center" rowspan="1" colspan="1">5.50</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.67</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.018</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.06</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Higher mental function abnormality, autosomal dominant or X-linked (HPO)</td>
<td valign="top" align="center" rowspan="1" colspan="1">5</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
<td valign="top" align="center" rowspan="1" colspan="1">(40)</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.83</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.019</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Nervous signal transmission (GO)</td>
<td valign="top" align="center" rowspan="1" colspan="1">26</td>
<td valign="top" align="center" rowspan="1" colspan="1">12</td>
<td valign="top" align="center" rowspan="1" colspan="1">(46)</td>
<td valign="top" align="center" rowspan="1" colspan="1">4.33</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.049</td>
<td valign="top" align="center" rowspan="1" colspan="1">2.17</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Schizophrenia risk candidate genes (six WES studies)<xref ref-type="table-fn" rid="t2n4"><italic><sup>f</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">45</td>
<td valign="top" align="center" rowspan="1" colspan="1">14</td>
<td valign="top" align="center" rowspan="1" colspan="1">(31)</td>
<td valign="top" align="center" rowspan="1" colspan="1">7.50</td>
<td valign="top" align="center" rowspan="1" colspan="1">7.67</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.573</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.98</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes<xref ref-type="table-fn" rid="t2n7"><italic><sup>g</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">11</td>
<td valign="top" align="center" rowspan="1" colspan="1">7</td>
<td valign="top" align="center" rowspan="1" colspan="1">(64)</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.83</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.020</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.83</td>
</tr>
<tr><td valign="top" align="left" scope="col" rowspan="1" colspan="1">Loss of function variants</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Post-synaptic density (<xref rid="bib9" ref-type="bibr">Bayes <italic>et al.</italic>
2011</xref>
)<xref ref-type="table-fn" rid="t2n8"><italic><sup>h</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">8</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
<td valign="top" align="center" rowspan="1" colspan="1">(25)</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.33</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.33</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.128</td>
<td valign="top" align="center" rowspan="1" colspan="1">4.00</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Restricted to <italic>DGCR8</italic>
-related genes</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
<td valign="top" align="center" rowspan="1" colspan="1">(50)</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.67</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.047</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> Abnormal sensory system (MGI)</td>
<td valign="top" align="center" rowspan="1" colspan="1">6</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
<td valign="top" align="center" rowspan="1" colspan="1">(33)</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.00</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.013</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
<tr><td valign="top" align="left" scope="col" rowspan="1" colspan="1">Splicing regulatory variants</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"><italic> FMR1</italic>
targets (<xref rid="bib3" ref-type="bibr">Ascano <italic>et al.</italic>
2012</xref>
)<xref ref-type="table-fn" rid="t2n9"><italic><sup>i</sup>
</italic>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">7</td>
<td valign="top" align="center" rowspan="1" colspan="1">1</td>
<td valign="top" align="center" rowspan="1" colspan="1">(14)</td>
<td valign="top" align="center" rowspan="1" colspan="1">1.17</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">0.018</td>
<td valign="top" align="center" rowspan="1" colspan="1">nc</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>SCZ, schizophrenia subgroup of 22q11.2DS subjects; NP, nonpsychotic subgroup of 22q11.2DS subjects; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; nc, not calculable (based on no variants present in the non-psychotic group); MGI, Mouse Genome Informatics; NCI, National Cancer Institute; HPO, Human Phenotype Ontology.</p>
</fn>
<fn><p>Gene-sets portrayed are all those with nominal p value <0.05 before and/or after restriction to <italic>DGCR8</italic>
related genes, with <2000 genes in gene-set. All high-quality, rare variants contributing to the results are reported in <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS1.xlsx">Table S1</ext-link>
. For source and total size of each gene-set, see <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS2.xls">Table S2</ext-link>
; for total gene overlap between gene-sets, see <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS2.xls">Table S2</ext-link>
; for burden analysis results for all gene-sets, see <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS3.xlsx">Table S3</ext-link>
.</p>
</fn>
<fn><p>Genes implicated by variants in the schizophrenia group (genes in the Neuron projection (GO) gene-set, thus contributing to the Hotelling analysis results, are in bold font): </p>
</fn>
<fn id="t2n1"><label>a</label>
<p>Variants in the intact chromosome 22q11.2 region and on the X chromosome were <italic>a priori</italic>
excluded from the burden analyses. In total, there were three rare damaging missense variants in the 22q11.2 region [involving the genes <italic>DGCR2</italic>
(NP1), <italic>GNB1L</italic>
(NP3), and <italic>TRMT2A</italic>
(SCZ1)], and eight rare, damaging SNVs (seven missense, one LoF) on the X chromosome [involving the genes <italic>COL4A6</italic>
(NP3), <italic>JADE3</italic>
(SCZ3), <italic>KLHL15</italic>
(SCZ6), <italic>LRCH2</italic>
(SCZ6), <italic>PFKFB1</italic>
(NP3), <italic>SLC25A43</italic>
(NP3; LoF variant), <italic>SLITRK2</italic>
(SCZ2), and <italic>TBC1D8B</italic>
(NP1)]. Only two would have contributed to the results in this table. <italic>DGCR2</italic>
is in the Schizophrenia risk candidate genes (6 WES studies) gene-set and <italic>SLITRK2</italic>
(<xref rid="bib54" ref-type="bibr">Piton <italic>et al.</italic>
2011</xref>
) is in the Neuron projection (GO) gene-set. Neither gene is in the <italic>DGCR8</italic>
-related gene-set.</p>
</fn>
<fn id="t2n2"><label>b</label>
<p>Nominal (one-sided t-test) p value using percent values (means corrected for total number of all variants of that type per subject, <italic>e.g.</italic>
, all missense variants)</p>
</fn>
<fn id="t2n5"><label>c</label>
<p><italic><bold>ACTN4</bold>
, <bold>ANK1</bold>
, <bold>ARHGEF7</bold>
, <bold>BSN</bold>
, <bold>COL3A1</bold>
, <bold>COL9A1</bold>
, <bold>ITM2C</bold>
, <bold>MAP1B</bold>
, <bold>MAP2</bold>
, <bold>MYH10</bold>
, <bold>MYH9</bold>
, <bold>PTPRG</bold>
, <bold>SLITRK6</bold>
, <bold>STIM1</bold>
, <bold>TGFB2</bold>
, <bold>ZDHHC5</bold>
</italic>
.</p>
</fn>
<fn id="t2n6"><label>d</label>
<p><italic>ADCY3, KCNQ5, PLCL1, PLD1, PPP2R3A, PRKACB, SLC1A7</italic>
.</p>
</fn>
<fn id="t2n3"><label>e</label>
<p>Gene-set having 100% overlap with Synaptic pathways (KEGG) gene-set.</p>
</fn>
<fn id="t2n4"><label>f</label>
<p>WES, whole-exome sequencing studies: (<xref rid="bib31" ref-type="bibr">Girard <italic>et al.</italic>
2011</xref>
; <xref rid="bib74" ref-type="bibr">Xu <italic>et al.</italic>
2012</xref>
; <xref rid="bib35" ref-type="bibr">Gulsuner <italic>et al.</italic>
2013</xref>
; <xref rid="bib25" ref-type="bibr">Fromer <italic>et al.</italic>
2014</xref>
; <xref rid="bib44" ref-type="bibr">McCarthy <italic>et al.</italic>
2014</xref>
; <xref rid="bib34" ref-type="bibr">Guipponi <italic>et al.</italic>
2014</xref>
).</p>
</fn>
<fn id="t2n7"><label>g</label>
<p><italic><bold>ANK1</bold>
, <bold>COL3A1</bold>
, EPHA2, <bold>ITM2C</bold>
, KCNQ5, <bold>MYH10</bold>
, <bold>MYH9</bold>
, NUP210, <bold>PTPRG</bold>
, UTRN, <bold>ZDHHC5</bold>
</italic>
.</p>
</fn>
<fn id="t2n8"><label>h</label>
<p><italic><bold>ABLIM1</bold>
, DDX6, <bold>EXOC4</bold>
, FARSB, ITSN2, PDE1A, TAGLN2, UBR4</italic>
(<italic><bold>ABLIM1</bold>
</italic>
, <italic><bold>EXOC4</bold>
</italic>
, <italic>ITSN2</italic>
, <italic>TAGLN2</italic>
= with <italic>DGCR8</italic>
restriction)</p>
</fn>
<fn id="t2n9"><label>i</label>
<p><italic>AP1B1, <bold>AP3D1</bold>
, DNM2, RYR2, SETDB2, VPRBP, ZNF107</italic>
.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<sec id="s10"><title>Burden of rare variants impacting neurofunctional protein-coding genes</title>
<p><xref ref-type="table" rid="t2">Table 2</xref>
shows all gene-sets with <2000 protein-coding genes and nominally significant (<italic>P</italic>
< 0.05, schizophrenia > nonpsychotic group) burden for rare deleterious variants. Only neurofunctional gene-sets met these criteria. On testing burden jointly for all three variant categories, only the Neuron projection [Gene Ontology (GO)] gene-set was significant (Hotelling’s T-Square <italic>P</italic>
= 0.02). <xref ref-type="table" rid="t2">Table 2</xref>
shows the overlap between this and the other neurofunctional gene-sets for genes implicated in the schizophrenia group.</p>
<p>As predicted by a multiple within-person rare variant hypothesis for schizophrenia (<xref rid="bib20" ref-type="bibr">Costain <italic>et al.</italic>
2013</xref>
; <xref rid="bib46" ref-type="bibr">Merico <italic>et al.</italic>
2014</xref>
), there were several variants per subject involving these neurofunctional gene-sets. There were no significant between-group differences for larger gene-sets, or even all brain-expressed variants (<ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS3.xlsx">Table S3</ext-link>
). The findings support an approach focused on high-quality variants and gene-sets of neurofunctional relevance, even in this small sample. <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS1.xlsx">Table S1</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS2.xls">Table S2</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS3.xlsx">Table S3</ext-link>
, and <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS4.xls">Table S4</ext-link>
show details for all high-quality, rare variants, gene-sets used, and burden analysis results.</p>
<p>We used the data available for the three variant types to perform power calculations for the Neuron projection (GO) gene-set burden test and three other gene-sets (Table S5). For N = 100 subjects per group, power for the GO gene-set was >0.99 for damaging missense variants and for LoF variants, and >0.94 for splicing regulatory variants (Cohen’s d effect sizes: 1.90, 0.88, 0.55, respectively; the effect size estimates are based on the nine genomes presented in this study). For the Post-synaptic density (<xref rid="bib9" ref-type="bibr">Bayes <italic>et al.</italic>
2011</xref>
) gene-set, power was >0.99 for LoF variants and for splicing regulatory variants. Other results showing power >0.99 are in <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS5.xls">Table S5</ext-link>
.</p>
</sec>
<sec id="s11"><title>Support for the <italic>DGCR8</italic>
/miRNA hypothesis</title>
<p>Consistent with a miRNA hypothesis for schizophrenia, restricting to genes predicted to be affected by <italic>DGCR8</italic>
haploinsufficiency (<xref rid="bib64" ref-type="bibr">Stark <italic>et al.</italic>
2008</xref>
; <xref rid="bib46" ref-type="bibr">Merico <italic>et al.</italic>
2014</xref>
) tended to increase estimated effect sizes (<xref ref-type="table" rid="t2">Table 2</xref>
and <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/FigureS1.pdf">Figure S1</ext-link>
), despite the decrease in number of variants per subject. For missense variants, these gene-sets included Neuron projection (GO) and Synaptic pathways (Kyoto Encyclopedia of Genes and Genomes KEGG), with no overlap of the genes involved between these gene-sets. For LoF variants, the Post-synaptic density (<xref rid="bib9" ref-type="bibr">Bayes <italic>et al.</italic>
2011</xref>
) gene-set was implicated (<xref ref-type="table" rid="t2">Table 2</xref>
). Restricting to <italic>DGCR8</italic>
-related genes did not tend to increase effect size for splicing regulatory variants (<ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/FigureS1.pdf">Figure S1</ext-link>
). Notably, applying the <italic>DGCR8</italic>
-related gene filter revealed nominally significant burden in 22q11.2DS-schizophrenia for rare damaging missense variants using a gene-set from idiopathic schizophrenia WES studies (<italic>de novo</italic>
nonsynonymous variants) (<xref rid="bib31" ref-type="bibr">Girard <italic>et al.</italic>
2011</xref>
; <xref rid="bib74" ref-type="bibr">Xu <italic>et al.</italic>
2012</xref>
; <xref rid="bib35" ref-type="bibr">Gulsuner <italic>et al.</italic>
2013</xref>
; <xref rid="bib25" ref-type="bibr">Fromer <italic>et al.</italic>
2014</xref>
; <xref rid="bib44" ref-type="bibr">McCarthy <italic>et al.</italic>
2014</xref>
; <xref rid="bib34" ref-type="bibr">Guipponi <italic>et al.</italic>
2014</xref>
). Several of the genes involved overlapped those in the Neuron projection (GO) gene-set (<xref ref-type="table" rid="t2">Table 2</xref>
).</p>
</sec>
<sec id="s12"><title>Rare CNV disrupting candidate genes for schizophrenia</title>
<p>Similar to our previous study focusing on CNV >10 kb in size (<xref rid="bib7" ref-type="bibr">Bassett <italic>et al.</italic>
2008</xref>
), we interrogated the genome outside of the 22q11.2 region for additional rare CNVs and SVs. In one individual with schizophrenia (SCZ4), we identified and confirmed via quantitative polymerase chain reaction a rare maternally inherited 84-kb deletion at 21q22.3. This CNV disrupts exons of the genes <italic>PCNT</italic>
and <italic>DIP2A</italic>
, the latter gene implicating <italic>DGCR8</italic>
and <italic>FMR1</italic>
interactome mechanisms (<xref rid="bib64" ref-type="bibr">Stark <italic>et al.</italic>
2008</xref>
; <xref rid="bib21" ref-type="bibr">Darnell <italic>et al.</italic>
2011</xref>
).</p>
</sec>
<sec id="s13"><title>Rare variants disrupting noncoding RNA genes</title>
<p>There were multiple rare variants outside of protein-coding genes, on average involving 2.0 and 1.3 lincRNA genes per subject in the schizophrenia and nonpsychotic groups, respectively (<ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS6.xlsx">Table S6</ext-link>
). Restricting to highly conserved (top 10%) lincRNAs, the burden was greater in the schizophrenia group (mean 1.3 <italic>vs.</italic>
0; nominal <italic>P</italic>
= 0.039) (<ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS6.xlsx">Table S6</ext-link>
). However, perhaps related to their small size, miRNA genes contained few rare variants, even after broadening the rarity definition to <5%, preventing statistical testing of burden (<ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/TableS7.xlsx">Table S7</ext-link>
).</p>
</sec>
<sec id="s14"><title>Schizophrenia polygenic risk score</title>
<p>Use of the selected schizophrenia-associated SNPs [at nominal p-value thresholds ≤0.001 and ≤0.0001 from the Psychiatric Consortium Study (<xref rid="bib39" ref-type="bibr">International Schizophrenia Consortium <italic>et al.</italic>
2009</xref>
; <xref rid="bib59" ref-type="bibr">Schizophrenia Working Group Of The Psychiatric Genomics Consortium 2014</xref>
)] resulted in greater polygenic risk scores in the 22q11.2DS schizophrenia than in the nonpsychotic group (for the two thresholds, respectively, based on 2866 and 1059 SNPs: means: 0.00798 <italic>vs.</italic>
−2.482, 0.601 <italic>vs.</italic>
−1.238; <italic>t</italic>
-test p-values: <italic>P</italic>
= 0.094, <italic>P</italic>
= 0.064; Wilcoxon test p-values: <italic>P</italic>
= 0.083, <italic>P</italic>
= 0.190; maximum correctly predicted percentages: 83%, 75%) (<ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/content/suppl/2015/09/16/g3.115.021345.DC1/FigureS2.pdf">Figure S2</ext-link>
). These trends did not reach our definition of statistical significance, however. The Wilcoxon and <italic>t</italic>
-test p-values were greater (0.136 and 0.274, respectively) using association threshold <italic>P</italic>
≤ 0.00001 (451 SNPs). As expected, almost no difference (Wilcoxon and <italic>t</italic>
-test <italic>P</italic>
= 0.32−0.80) was observed for negative control SNPs (18,675 and 1976 SNPs at association p-value thresholds <italic>P</italic>
> 0.5 and <italic>P</italic>
> 0.9, respectively).</p>
</sec>
</sec>
<sec sec-type="discussion" id="s15"><title>Discussion</title>
<p>Historically, the psychiatric genetics field has not used a genetic model or a functionally and mechanistically driven approach as a means to evaluate germline genetic variation in schizophrenia. We demonstrate the potential success of exploiting the enhanced homogeneity and thus power of a genomic disorder (rare and highly penetrant CNV) to investigate expression of a major associated disease phenotype. This study of schizophrenia in 22q11.2DS had two primary goals: (i) to demonstrate an effective approach to analyzing and interpreting WGS data, based on previous success in autism (<xref rid="bib75" ref-type="bibr">Yuen <italic>et al.</italic>
2015</xref>
), and (ii) to identify and prioritize testable, biologically plausible hypotheses for further investigation in a larger sample. That there were findings reaching our definition of nominal statistical significance was unexpected in this small sample. The results demonstrate the power and generalizability of 22q11.2DS as a model for understanding the genetic architecture of idiopathic schizophrenia, and provide support for multiple rare variants within individuals and a miRNA-related mechanism. These are concepts with previous evidence (<xref rid="bib32" ref-type="bibr">Girirajan <italic>et al.</italic>
2012</xref>
; <xref rid="bib70" ref-type="bibr">Warnica <italic>et al.</italic>
2015</xref>
).</p>
<p>By definition, individuals with 22q11.2DS have a 22q11.2 deletion, thus identifying additional rare variants would support a multiple rare variant hypothesis for schizophrenia at the individual level. The findings of this study indicate that this is likely to involve not only exonic variants, as expected, but also variants in regulatory regions and noncoding RNA genes typically not detectable by WES technologies. In the subgroup of individuals with schizophrenia, there was evidence for enrichment of damaging variants in highly conserved lincRNA (nonprotein-coding) genes, and of certain splicing regulatory variants that affect protein-coding genes. Although functional characterization of lincRNAs is limited as yet, the strategy used here may help to identify lincRNAs that contribute to schizophrenia. lincRNAs are involved in epigenetic mechanisms including chromatin binding, and in splicing processes (<xref rid="bib5" ref-type="bibr">Barry <italic>et al.</italic>
2014</xref>
; <xref rid="bib57" ref-type="bibr">Quek <italic>et al.</italic>
2015</xref>
; <xref rid="bib22" ref-type="bibr">Derrien <italic>et al.</italic>
2012</xref>
; <xref rid="bib47" ref-type="bibr">Moran <italic>et al.</italic>
2012</xref>
). Interestingly, the gene-set most affected by splicing regulatory variants in this study implicates mRNA targets of <italic>FMR1</italic>
, and thus post-transcriptional regulation of gene expression, including that involved in neuronal development and synaptic plasticity (<xref rid="bib53" ref-type="bibr">Pinto <italic>et al.</italic>
2014</xref>
; <xref rid="bib65" ref-type="bibr">Suhl <italic>et al.</italic>
2014</xref>
).</p>
<p>The burden analyses of the coding sequence variants further demonstrated the effectiveness of the approach used to analyze and interpret WGS data. In the subgroup of individuals with schizophrenia, using biologically informed filters revealed a greater burden of damaging variants affecting protein-coding genes involved in neuron projection (axonal and dendritic development), a gene-set previously implicated in schizophrenia using other approaches (<xref rid="bib20" ref-type="bibr">Costain <italic>et al.</italic>
2013</xref>
; <xref rid="bib46" ref-type="bibr">Merico <italic>et al.</italic>
2014</xref>
).</p>
<p>Restricting to genes affected by <italic>DGCR8</italic>
haploinsufficiency tended to increase effect sizes for neurofunctionally relevant gene-sets. The findings thus provide further support for a miRNA hypothesis for schizophrenia and the utility of 22q11.2DS as a model for this mechanism (<xref rid="bib70" ref-type="bibr">Warnica <italic>et al.</italic>
2015</xref>
; <xref rid="bib46" ref-type="bibr">Merico <italic>et al.</italic>
2014</xref>
; <xref rid="bib49" ref-type="bibr">Morrow 2015</xref>
; <xref rid="bib29" ref-type="bibr">Geaghan and Cairns 2014</xref>
; <xref rid="bib48" ref-type="bibr">Moreau <italic>et al.</italic>
2011</xref>
). The 22q11.2 deletion appears to act as a threshold-lowering first hit, likely in part related to haploinsufficiency of gene <italic>DGCR8</italic>
and its effects on miRNA buffering, to reveal effects of rare variants elsewhere in the genome (<xref rid="bib64" ref-type="bibr">Stark <italic>et al.</italic>
2008</xref>
; <xref rid="bib24" ref-type="bibr">Forstner <italic>et al.</italic>
2013</xref>
; <xref rid="bib61" ref-type="bibr">Schofield <italic>et al.</italic>
2011</xref>
; <xref rid="bib11" ref-type="bibr">Brzustowicz and Bassett 2012</xref>
; <xref rid="bib46" ref-type="bibr">Merico <italic>et al.</italic>
2014</xref>
). This included variants, present in each of the 22q11.2DS subjects with schizophrenia, in genes previously reported for idiopathic schizophrenia in WES studies (<xref rid="bib31" ref-type="bibr">Girard <italic>et al.</italic>
2011</xref>
; <xref rid="bib74" ref-type="bibr">Xu <italic>et al.</italic>
2012</xref>
; <xref rid="bib35" ref-type="bibr">Gulsuner <italic>et al.</italic>
2013</xref>
; <xref rid="bib25" ref-type="bibr">Fromer <italic>et al.</italic>
2014</xref>
; <xref rid="bib44" ref-type="bibr">McCarthy <italic>et al.</italic>
2014</xref>
; <xref rid="bib34" ref-type="bibr">Guipponi <italic>et al.</italic>
2014</xref>
).</p>
<p>Lastly, the polygenic risk score appears informative for the nine 22q11.2DS genomes, although probably because of the small sample size, the results do not achieve significance. Future studies with sufficient power to jointly model rare variant burden and common variant polygenic risk score would be useful, and could determine whether restricting the polygenic risk score SNPs to those implicating genes from neurofunctional gene-sets would amplify between-group differences.</p>
<sec id="s16"><title>Advantages and limitations</title>
<p>Although this initial study produced several nominally significant results, there was no correction for multiple comparisons. Part of our <italic>a priori</italic>
design was that any findings would require replication with the use of larger samples. The estimates of effect size and power indicate that feasible sample sizes of individuals with 22q11.2DS will allow such replication, using a comparable design and approach. Our analytic strategy was designed to minimize both false-positive and false-negative results. In the absence of between-group differences in total burden of rare variants, individual false-positive results would be expected to affect both groups equally. All individuals would be expected to harbor multiple rare variants involved in neurofunctional gene-sets. Among genes in neurofunctional gene-sets, a specific subset may eventually be identified to make a greater contribution to the expression of schizophrenia in all, or in certain subforms, of the disorder. These could include genes where there are individual, rare damaging variants with large effect. Nonetheless, we expect a substantial level of polygenicity, as suggested by rare variant studies of schizophrenia and other neuropsychiatric disorders such as autism, as well as by the paucity of linkage findings for schizophrenia (<xref rid="bib42" ref-type="bibr">Kirov <italic>et al.</italic>
2012</xref>
; <xref rid="bib20" ref-type="bibr">Costain <italic>et al.</italic>
2013</xref>
; <xref rid="bib31" ref-type="bibr">Girard <italic>et al.</italic>
2011</xref>
; <xref rid="bib74" ref-type="bibr">Xu <italic>et al.</italic>
2012</xref>
; <xref rid="bib50" ref-type="bibr">Need <italic>et al.</italic>
2012</xref>
; <xref rid="bib35" ref-type="bibr">Gulsuner <italic>et al.</italic>
2013</xref>
; <xref rid="bib67" ref-type="bibr">Timms <italic>et al.</italic>
2013</xref>
; <xref rid="bib25" ref-type="bibr">Fromer <italic>et al.</italic>
2014</xref>
; <xref rid="bib56" ref-type="bibr">Purcell <italic>et al.</italic>
2014</xref>
; <xref rid="bib44" ref-type="bibr">McCarthy <italic>et al.</italic>
2014</xref>
; <xref rid="bib34" ref-type="bibr">Guipponi <italic>et al.</italic>
2014</xref>
; <xref rid="bib53" ref-type="bibr">Pinto <italic>et al.</italic>
2014</xref>
; <xref rid="bib75" ref-type="bibr">Yuen <italic>et al.</italic>
2015</xref>
).</p>
<p>As for the largest WES study in schizophrenia to date (<xref rid="bib56" ref-type="bibr">Purcell <italic>et al.</italic>
2014</xref>
), and our previous CNV studies (<xref rid="bib53" ref-type="bibr">Pinto <italic>et al.</italic>
2014</xref>
; <xref rid="bib20" ref-type="bibr">Costain <italic>et al.</italic>
2013</xref>
; <xref rid="bib62" ref-type="bibr">Silversides <italic>et al.</italic>
2012</xref>
), increased stringency of methods and approach, including quality, rarity, and deleteriousness of variants, generally strengthened the findings. Individual sequence variants were not validated by the use of a second method. Using a comparable WGS analytic pipeline, we found that greater than 90% of rare <italic>de novo</italic>
SNVs were validated in a study of autism (<xref rid="bib75" ref-type="bibr">Yuen <italic>et al.</italic>
2015</xref>
); we expect this to be the minimum validation rate in this study. We would not restrict future studies to <italic>de novo</italic>
variants, however, because most rare variants are inherited and may have enhanced impact in the context of a 22q11.2 deletion (<xref rid="bib64" ref-type="bibr">Stark <italic>et al.</italic>
2008</xref>
; <xref rid="bib24" ref-type="bibr">Forstner <italic>et al.</italic>
2013</xref>
; <xref rid="bib61" ref-type="bibr">Schofield <italic>et al.</italic>
2011</xref>
; <xref rid="bib11" ref-type="bibr">Brzustowicz and Bassett 2012</xref>
; <xref rid="bib46" ref-type="bibr">Merico <italic>et al.</italic>
2014</xref>
). For variants in nongenic regulatory regions, WGS is essential for detection with clear advantages over WES studies, including one involving two individuals with 22q11.2DS (<xref rid="bib4" ref-type="bibr">Balan <italic>et al.</italic>
2014</xref>
). Increasingly sophisticated methods offer promise for improved <italic>in silico</italic>
evaluation of all variant types. Proof that a variant is causal, however, requires a laboratory-based functional analysis.</p>
<p>The size of this study limited the ability to explore interacting factors or to study other hypotheses of interest, including the role of individual common variants and nongenetic factors. Previous studies of SNPs on the intact chromosome 22q11.2 have shown conflicting or negative results, however reduced gene dosage of neurofunctional genes within the 22q11.2 region may contribute to schizophrenia risk (<xref rid="bib52" ref-type="bibr">Philip and Bassett 2011</xref>
; <xref rid="bib2" ref-type="bibr">Arinami 2006</xref>
; <xref rid="bib55" ref-type="bibr">Prasad <italic>et al.</italic>
2008</xref>
; <xref rid="bib40" ref-type="bibr">Karayiorgou <italic>et al.</italic>
2010</xref>
). Although we did not identify rare variants disrupting candidate genes in this region in individuals with schizophrenia, rare phenotypes may be attributable to unmasking of such variants (<xref rid="bib45" ref-type="bibr">McDonald-McGinn <italic>et al.</italic>
2013</xref>
). Our WGS approach could be generalizable to other phenotypes associated with 22q11.2DS, and help explain variable expression and incomplete penetrance in other genomic disorders. Also, although additional rare CNVs overlapping exons may play a minor role, consistent with previous results (<xref rid="bib7" ref-type="bibr">Bassett <italic>et al.</italic>
2008</xref>
; <xref rid="bib71" ref-type="bibr">Williams <italic>et al.</italic>
2013</xref>
), methods for studying small CNVs require refining. Nonetheless, the initial evidence of multiple rare variants within an individual, coupled with suggestive findings for polygenic common variant risk, provided by this study is consistent with a longstanding threshold model of schizophrenia.</p>
<p>Early studies of 22q11.2 deletions foreshadowed a more general role for rare CNV in understanding the global genetic architecture of schizophrenia in the population (<xref rid="bib42" ref-type="bibr">Kirov <italic>et al.</italic>
2012</xref>
; <xref rid="bib20" ref-type="bibr">Costain <italic>et al.</italic>
2013</xref>
; <xref rid="bib63" ref-type="bibr">Stankiewicz and Lupski 2010</xref>
; <xref rid="bib43" ref-type="bibr">Lowther <italic>et al.</italic>
2015</xref>
; <xref rid="bib8" ref-type="bibr">Bassett <italic>et al.</italic>
2010</xref>
; <xref rid="bib36" ref-type="bibr">Hochstenbach <italic>et al.</italic>
2011</xref>
; <xref rid="bib19" ref-type="bibr">Costain and Bassett 2012</xref>
; <xref rid="bib76" ref-type="bibr">Zarrei <italic>et al.</italic>
2015</xref>
; <xref rid="bib58" ref-type="bibr">Rees <italic>et al.</italic>
2014</xref>
). Here, results from this study indicate that, for the individual, to uncover the symphony of variants that increase the likelihood of the expression of schizophrenia, researchers can take advantage of the fact that a highly penetrant rare CNV like the 22q11.2 deletion represents an incomplete part of the genetic architecture. This study design may lead to the discovery of novel additional pathways from genotype to phenotype in schizophrenia. Findings from this study provide support for a tractable, mechanistically and functionally based approach for evaluating the myriad rare coding-sequence variants identified by WGS and their potential role along with common variant risk in individual genetic architecture, the importance of evaluating variants in noncoding sequence, and the enhanced power to identify relevant rare variants that may be afforded by a more genetically homogeneous sample. The main genetic sharing between unrelated individuals with schizophrenia appears to be at the pathway/mechanistic level, thus a research design with this focus promises robust findings. Studies that also combine common variant risk with a rare damaging variant gene-set burden model may be of particular interest.</p>
</sec>
</sec>
<sec id="s17"><title></title>
</sec>
<sec sec-type="supplementary-material"><title>Supplementary Material</title>
<supplementary-material id="PMC_1" content-type="local-data"><caption><title>Supporting Information</title>
</caption>
<media mimetype="text" mime-subtype="html" xlink:href="supp_5_11_2453__index.html"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="pdf" xlink:href="supp_g3.115.021345_021345SI.pdf"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="pdf" xlink:href="supp_g3.115.021345_FigureS1.pdf"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="pdf" xlink:href="supp_g3.115.021345_FigureS2.pdf"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="pdf" xlink:href="supp_g3.115.021345_FileS1.pdf"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="vnd.ms-excel" xlink:href="supp_g3.115.021345_TableS1.xlsx"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="vnd.ms-excel" xlink:href="supp_g3.115.021345_TableS2.xls"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="vnd.ms-excel" xlink:href="supp_g3.115.021345_TableS3.xlsx"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="vnd.ms-excel" xlink:href="supp_g3.115.021345_TableS4.xls"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="vnd.ms-excel" xlink:href="supp_g3.115.021345_TableS5.xls"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="vnd.ms-excel" xlink:href="supp_g3.115.021345_TableS6.xlsx"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="vnd.ms-excel" xlink:href="supp_g3.115.021345_TableS7.xlsx"></media>
</supplementary-material>
</sec>
</body>
<back><ack><title>Acknowledgments</title>
<p>We thank the adults with 22q11.2DS and their families for their generous contributions to this and related research studies. The authors express gratitude to the students, research assistants, and staff affiliated with the Clinical Genetics Research Program and The Centre for Applied Genomics. Special thanks go to Thanuja Selvanayagam for assistance with laboratory experiments and to Monica Torsan for help with formatting. We thank Complete Genomics Inc. for providing the two Complete Genomics control data sets. We also thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at <ext-link ext-link-type="uri" xlink:href="http://exac.broadinstitute.org/about">http://exac.broadinstitute.org/about</ext-link>
. Finally, we thank Prof. Sarah Bergen for valuable suggestions for the calculation of the polygenic risk score. This work was supported by grants from Canadian Institutes of Health Research (CIHR) (MOP-97800 and MOP-89066), Genome Canada, and the University of Toronto McLaughlin Centre. S.W.S. holds the GlaxoSmithKline–CIHR Endowed Chair in Genome Sciences at The Hospital for Sick Children and the University of Toronto. A.S.B. holds the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, and the Dalglish Chair in 22q11.2 Deletion Syndrome.</p>
</ack>
<fn-group><fn id="fn1" fn-type="supplementary-material"><p>Supporting information is available online at <ext-link ext-link-type="uri" xlink:href="http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.021345/-/DC1">www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.021345/-/DC1</ext-link>
</p>
</fn>
<fn id="fn2"><p>Communicating editor: J. E. Richards</p>
</fn>
</fn-group>
<ref-list><title>Literature Cited</title>
<ref id="bib1"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Andrade</surname>
<given-names>D. M.</given-names>
</name>
<name><surname>Krings</surname>
<given-names>T.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<name><surname>Kiehl</surname>
<given-names>T. R.</given-names>
</name>
<name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
</person-group>
, <year>2013</year>
<article-title>Hippocampal malrotation is associated with chromosome 22q11.2 microdeletion.</article-title>
<source>Can. J. Neurol. Sci.</source>
<volume>40</volume>
: <fpage>652</fpage>
–<lpage>656</lpage>
.<pub-id pub-id-type="pmid">23968937</pub-id>
</mixed-citation>
</ref>
<ref id="bib2"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arinami</surname>
<given-names>T.</given-names>
</name>
</person-group>
, <year>2006</year>
<article-title>Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia.</article-title>
<source>J. Hum. Genet.</source>
<volume>51</volume>
: <fpage>1037</fpage>
–<lpage>1045</lpage>
.<pub-id pub-id-type="pmid">16969581</pub-id>
</mixed-citation>
</ref>
<ref id="bib3"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ascano</surname>
<given-names>M.</given-names>
<suffix>Jr</suffix>
</name>
<name><surname>Mukherjee</surname>
<given-names>N.</given-names>
</name>
<name><surname>Bandaru</surname>
<given-names>P.</given-names>
</name>
<name><surname>Miller</surname>
<given-names>J. B.</given-names>
</name>
<name><surname>Nusbaum</surname>
<given-names>J. D.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>FMRP targets distinct mRNA sequence elements to regulate protein expression.</article-title>
<source>Nature</source>
<volume>492</volume>
: <fpage>382</fpage>
–<lpage>386</lpage>
.<pub-id pub-id-type="pmid">23235829</pub-id>
</mixed-citation>
</ref>
<ref id="bib4"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Balan</surname>
<given-names>S.</given-names>
</name>
<name><surname>Iwayama</surname>
<given-names>Y.</given-names>
</name>
<name><surname>Toyota</surname>
<given-names>T.</given-names>
</name>
<name><surname>Toyoshima</surname>
<given-names>M.</given-names>
</name>
<name><surname>Maekawa</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>22q11.2 deletion carriers and schizophrenia-associated novel variants.</article-title>
<source>Br. J. Psychiatry</source>
<volume>204</volume>
: <fpage>398</fpage>
–<lpage>399</lpage>
.<pub-id pub-id-type="pmid">24482440</pub-id>
</mixed-citation>
</ref>
<ref id="bib5"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barry</surname>
<given-names>G.</given-names>
</name>
<name><surname>Briggs</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Vanichkina</surname>
<given-names>D. P.</given-names>
</name>
<name><surname>Poth</surname>
<given-names>E. M.</given-names>
</name>
<name><surname>Beveridge</surname>
<given-names>N. J.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing.</article-title>
<source>Mol. Psychiatry</source>
<volume>19</volume>
: <fpage>486</fpage>
–<lpage>494</lpage>
.<pub-id pub-id-type="pmid">23628989</pub-id>
</mixed-citation>
</ref>
<ref id="bib6"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<name><surname>AbdelMalik</surname>
<given-names>P.</given-names>
</name>
<name><surname>Gheorghiu</surname>
<given-names>M.</given-names>
</name>
<name><surname>Husted</surname>
<given-names>J.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2003</year>
<article-title>The schizophrenia phenotype in 22q11 deletion syndrome.</article-title>
<source>Am. J. Psychiatry</source>
<volume>160</volume>
: <fpage>1580</fpage>
–<lpage>1586</lpage>
.<pub-id pub-id-type="pmid">12944331</pub-id>
</mixed-citation>
</ref>
<ref id="bib7"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
<name><surname>Marshall</surname>
<given-names>C. R.</given-names>
</name>
<name><surname>Lionel</surname>
<given-names>A. C.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<name><surname>Scherer</surname>
<given-names>S. W.</given-names>
</name>
</person-group>
, <year>2008</year>
<article-title>Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome.</article-title>
<source>Hum. Mol. Genet.</source>
<volume>17</volume>
: <fpage>4045</fpage>
–<lpage>4053</lpage>
.<pub-id pub-id-type="pmid">18806272</pub-id>
</mixed-citation>
</ref>
<ref id="bib8"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
<name><surname>Scherer</surname>
<given-names>S. W.</given-names>
</name>
<name><surname>Brzustowicz</surname>
<given-names>L. M.</given-names>
</name>
</person-group>
, <year>2010</year>
<article-title>Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease.</article-title>
<source>Am. J. Psychiatry</source>
<volume>167</volume>
: <fpage>899</fpage>
–<lpage>914</lpage>
.<pub-id pub-id-type="pmid">20439386</pub-id>
</mixed-citation>
</ref>
<ref id="bib9"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bayes</surname>
<given-names>A.</given-names>
</name>
<name><surname>van de Lagemaat</surname>
<given-names>L. N.</given-names>
</name>
<name><surname>Collins</surname>
<given-names>M. O.</given-names>
</name>
<name><surname>Croning</surname>
<given-names>M. D.</given-names>
</name>
<name><surname>Whittle</surname>
<given-names>I. R.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2011</year>
<article-title>Characterization of the proteome, diseases and evolution of the human postsynaptic density.</article-title>
<source>Nat. Neurosci.</source>
<volume>14</volume>
: <fpage>19</fpage>
–<lpage>21</lpage>
.<pub-id pub-id-type="pmid">21170055</pub-id>
</mixed-citation>
</ref>
<ref id="bib10"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beveridge</surname>
<given-names>N. J.</given-names>
</name>
<name><surname>Cairns</surname>
<given-names>M. J.</given-names>
</name>
</person-group>
, <year>2012</year>
<article-title>MicroRNA dysregulation in schizophrenia.</article-title>
<source>Neurobiol. Dis.</source>
<volume>46</volume>
: <fpage>263</fpage>
–<lpage>271</lpage>
.<pub-id pub-id-type="pmid">22207190</pub-id>
</mixed-citation>
</ref>
<ref id="bib11"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brzustowicz</surname>
<given-names>L. M.</given-names>
</name>
<name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
</person-group>
, <year>2012</year>
<article-title>miRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome.</article-title>
<source>Front. Genet.</source>
<volume>3</volume>
: <fpage>291</fpage>
.<pub-id pub-id-type="pmid">23248646</pub-id>
</mixed-citation>
</ref>
<ref id="bib12"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Butcher</surname>
<given-names>N. J.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Karas</surname>
<given-names>D.</given-names>
</name>
<name><surname>Ho</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>Functional outcomes of adults with 22q11.2 deletion syndrome.</article-title>
<source>Genet. Med.</source>
<volume>14</volume>
: <fpage>836</fpage>
–<lpage>843</lpage>
.<pub-id pub-id-type="pmid">22744446</pub-id>
</mixed-citation>
</ref>
<ref id="bib13"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Butcher</surname>
<given-names>N.</given-names>
</name>
<name><surname>Kiehl</surname>
<given-names>T.</given-names>
</name>
<name><surname>Hazrati</surname>
<given-names>L.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E.</given-names>
</name>
<name><surname>Rogaeva</surname>
<given-names>E.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2013</year>
<article-title>Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.</article-title>
<source>JAMA Neurol.</source>
<volume>70</volume>
: <fpage>1359</fpage>
–<lpage>1366</lpage>
.<pub-id pub-id-type="pmid">24018986</pub-id>
</mixed-citation>
</ref>
<ref id="bib14"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Butcher</surname>
<given-names>N.</given-names>
</name>
<name><surname>Marras</surname>
<given-names>C.</given-names>
</name>
<name><surname>Pondal</surname>
<given-names>M.</given-names>
</name>
<name><surname>Christopher</surname>
<given-names>L.</given-names>
</name>
<name><surname>Strafella</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>Motor dysfunction in adults with hemizygous 22q11.2 deletions at high risk of early-onset Parkinson’s disease.</article-title>
<source>Mov. Disord.</source>
<volume>29</volume>
(<issue>Suppl 1</issue>
): <fpage>S122</fpage>
.</mixed-citation>
</ref>
<ref id="bib15"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Butcher</surname>
<given-names>N.</given-names>
</name>
<name><surname>Fung</surname>
<given-names>W.</given-names>
</name>
<name><surname>Fitzpatrick</surname>
<given-names>L.</given-names>
</name>
<name><surname>Guna</surname>
<given-names>A.</given-names>
</name>
<name><surname>Andrade</surname>
<given-names>D.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2015</year>
<article-title>Response to clozapine in a clinically identifiable subtype of schizophrenia.</article-title>
<source>Br. J. Psychiatry</source>
<volume>206</volume>
: <fpage>484</fpage>
–<lpage>491</lpage>
.<pub-id pub-id-type="pmid">25745132</pub-id>
</mixed-citation>
</ref>
<ref id="bib16"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cabili</surname>
<given-names>M. N.</given-names>
</name>
<name><surname>Trapnell</surname>
<given-names>C.</given-names>
</name>
<name><surname>Goff</surname>
<given-names>L.</given-names>
</name>
<name><surname>Koziol</surname>
<given-names>M.</given-names>
</name>
<name><surname>Tazon-Vega</surname>
<given-names>B.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2011</year>
<article-title>Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses.</article-title>
<source>Genes Dev.</source>
<volume>25</volume>
: <fpage>1915</fpage>
–<lpage>1927</lpage>
.<pub-id pub-id-type="pmid">21890647</pub-id>
</mixed-citation>
</ref>
<ref id="bib17"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carnevali</surname>
<given-names>P.</given-names>
</name>
<name><surname>Baccash</surname>
<given-names>J.</given-names>
</name>
<name><surname>Halpern</surname>
<given-names>A. L.</given-names>
</name>
<name><surname>Nazarenko</surname>
<given-names>I.</given-names>
</name>
<name><surname>Nilsen</surname>
<given-names>G. B.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>Computational techniques for human genome resequencing using mated gapped reads.</article-title>
<source>J. Comput. Biol.</source>
<volume>19</volume>
: <fpage>279</fpage>
–<lpage>292</lpage>
.<pub-id pub-id-type="pmid">22175250</pub-id>
</mixed-citation>
</ref>
<ref id="bib18"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheung</surname>
<given-names>E. N.</given-names>
</name>
<name><surname>George</surname>
<given-names>S. R.</given-names>
</name>
<name><surname>Costain</surname>
<given-names>G. A.</given-names>
</name>
<name><surname>Andrade</surname>
<given-names>D. M.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>Prevalence of hypocalcemia and its associated features in 22q11.2 deletion syndrome.</article-title>
<source>Clin. Endocrinol. (Oxf.)</source>
<volume>81</volume>
: <fpage>190</fpage>
–<lpage>196</lpage>
.<pub-id pub-id-type="pmid">24735350</pub-id>
</mixed-citation>
</ref>
<ref id="bib19"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
</person-group>
, <year>2012</year>
<article-title>Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era.</article-title>
<source>Appl. Clin. Genet.</source>
<volume>5</volume>
: <fpage>1</fpage>
–<lpage>18</lpage>
.<pub-id pub-id-type="pmid">23144566</pub-id>
</mixed-citation>
</ref>
<ref id="bib20"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Lionel</surname>
<given-names>A. C.</given-names>
</name>
<name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<name><surname>Forsythe</surname>
<given-names>P.</given-names>
</name>
<name><surname>Russell</surname>
<given-names>K.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2013</year>
<article-title>Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.</article-title>
<source>Hum. Mol. Genet.</source>
<volume>22</volume>
: <fpage>4485</fpage>
–<lpage>4501</lpage>
.<pub-id pub-id-type="pmid">23813976</pub-id>
</mixed-citation>
</ref>
<ref id="bib21"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Darnell</surname>
<given-names>J. C.</given-names>
</name>
<name><surname>Van Driesche</surname>
<given-names>S. J.</given-names>
</name>
<name><surname>Zhang</surname>
<given-names>C.</given-names>
</name>
<name><surname>Hung</surname>
<given-names>K. Y.</given-names>
</name>
<name><surname>Mele</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2011</year>
<article-title>FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.</article-title>
<source>Cell</source>
<volume>146</volume>
: <fpage>247</fpage>
–<lpage>261</lpage>
.<pub-id pub-id-type="pmid">21784246</pub-id>
</mixed-citation>
</ref>
<ref id="bib22"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Derrien</surname>
<given-names>T.</given-names>
</name>
<name><surname>Johnson</surname>
<given-names>R.</given-names>
</name>
<name><surname>Bussotti</surname>
<given-names>G.</given-names>
</name>
<name><surname>Tanzer</surname>
<given-names>A.</given-names>
</name>
<name><surname>Djebali</surname>
<given-names>S.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression.</article-title>
<source>Genome Res.</source>
<volume>22</volume>
: <fpage>1775</fpage>
–<lpage>1789</lpage>
.<pub-id pub-id-type="pmid">22955988</pub-id>
</mixed-citation>
</ref>
<ref id="bib23"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Drmanac</surname>
<given-names>R.</given-names>
</name>
<name><surname>Sparks</surname>
<given-names>A. B.</given-names>
</name>
<name><surname>Callow</surname>
<given-names>M. J.</given-names>
</name>
<name><surname>Halpern</surname>
<given-names>A. L.</given-names>
</name>
<name><surname>Burns</surname>
<given-names>N. L.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2010</year>
<article-title>Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays.</article-title>
<source>Science</source>
<volume>327</volume>
: <fpage>78</fpage>
–<lpage>81</lpage>
.<pub-id pub-id-type="pmid">19892942</pub-id>
</mixed-citation>
</ref>
<ref id="bib24"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Forstner</surname>
<given-names>A. J.</given-names>
</name>
<name><surname>Degenhardt</surname>
<given-names>F.</given-names>
</name>
<name><surname>Schratt</surname>
<given-names>G.</given-names>
</name>
<name><surname>Nothen</surname>
<given-names>M. M.</given-names>
</name>
</person-group>
, <year>2013</year>
<article-title>MicroRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review.</article-title>
<source>Front. Mol. Neurosci.</source>
<volume>6</volume>
: <fpage>47</fpage>
.<pub-id pub-id-type="pmid">24367288</pub-id>
</mixed-citation>
</ref>
<ref id="bib25"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fromer</surname>
<given-names>M.</given-names>
</name>
<name><surname>Pocklington</surname>
<given-names>A. J.</given-names>
</name>
<name><surname>Kavanagh</surname>
<given-names>D. H.</given-names>
</name>
<name><surname>Williams</surname>
<given-names>H. J.</given-names>
</name>
<name><surname>Dwyer</surname>
<given-names>S.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>De novo mutations in schizophrenia implicate synaptic networks.</article-title>
<source>Nature</source>
<volume>506</volume>
: <fpage>179</fpage>
–<lpage>184</lpage>
.<pub-id pub-id-type="pmid">24463507</pub-id>
</mixed-citation>
</ref>
<ref id="bib26"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fu</surname>
<given-names>W.</given-names>
</name>
<name><surname>O’Connor</surname>
<given-names>T. D.</given-names>
</name>
<name><surname>Jun</surname>
<given-names>G.</given-names>
</name>
<name><surname>Kang</surname>
<given-names>H. M.</given-names>
</name>
<name><surname>Abecasis</surname>
<given-names>G.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2013</year>
<article-title>Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.</article-title>
<source>Nature</source>
<volume>493</volume>
: <fpage>216</fpage>
–<lpage>220</lpage>
.<pub-id pub-id-type="pmid">23201682</pub-id>
</mixed-citation>
</ref>
<ref id="bib27"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fung</surname>
<given-names>W. L.</given-names>
</name>
<name><surname>McEvilly</surname>
<given-names>R.</given-names>
</name>
<name><surname>Fong</surname>
<given-names>J.</given-names>
</name>
<name><surname>Silversides</surname>
<given-names>C.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2010</year>
<article-title>Elevated prevalence of generalized anxiety disorder in adults with 22q11.2 deletion syndrome.</article-title>
<source>Am. J. Psychiatry</source>
<volume>167</volume>
: <fpage>998</fpage>
.<pub-id pub-id-type="pmid">20693476</pub-id>
</mixed-citation>
</ref>
<ref id="bib28"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fung</surname>
<given-names>W. L.</given-names>
</name>
<name><surname>Butcher</surname>
<given-names>N. J.</given-names>
</name>
<name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Andrade</surname>
<given-names>D. M.</given-names>
</name>
<name><surname>Boot</surname>
<given-names>E.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2015</year>
<article-title>Practical guidelines for managing adults with 22q11.2 deletion syndrome.</article-title>
<source>Genet. Med.</source>
<volume>17</volume>
: <fpage>599</fpage>
–<lpage>609</lpage>
.<pub-id pub-id-type="pmid">25569435</pub-id>
</mixed-citation>
</ref>
<ref id="bib29"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Geaghan</surname>
<given-names>M.</given-names>
</name>
<name><surname>Cairns</surname>
<given-names>M. J.</given-names>
</name>
</person-group>
, <year>2014</year>
<article-title>MicroRNA and posttranscriptional dysregulation in psychiatry.</article-title>
<source>Biol. Psychiatry</source>
<volume>78</volume>
: <fpage>231</fpage>
–<lpage>239</lpage>
.<pub-id pub-id-type="pmid">25636176</pub-id>
</mixed-citation>
</ref>
<ref id="bib30"><mixed-citation publication-type="journal"><person-group person-group-type="author"><collab>1000 Genomes Project Consortium</collab>
<name><surname>Abecasis</surname>
<given-names>G. R.</given-names>
</name>
<name><surname>Auton</surname>
<given-names>A.</given-names>
</name>
<name><surname>Brooks</surname>
<given-names>L. D.</given-names>
</name>
<name><surname>DePristo</surname>
<given-names>M. A.</given-names>
</name>
<name><surname>Durbin</surname>
<given-names>R. M.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>An integrated map of genetic variation from 1,092 human genomes.</article-title>
<source>Nature</source>
<volume>491</volume>
: <fpage>56</fpage>
–<lpage>65</lpage>
.<pub-id pub-id-type="pmid">23128226</pub-id>
</mixed-citation>
</ref>
<ref id="bib31"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Girard</surname>
<given-names>S. L.</given-names>
</name>
<name><surname>Gauthier</surname>
<given-names>J.</given-names>
</name>
<name><surname>Noreau</surname>
<given-names>A.</given-names>
</name>
<name><surname>Xiong</surname>
<given-names>L.</given-names>
</name>
<name><surname>Zhou</surname>
<given-names>S.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2011</year>
<article-title>Increased exonic de novo mutation rate in individuals with schizophrenia.</article-title>
<source>Nat. Genet.</source>
<volume>43</volume>
: <fpage>860</fpage>
–<lpage>863</lpage>
.<pub-id pub-id-type="pmid">21743468</pub-id>
</mixed-citation>
</ref>
<ref id="bib32"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Girirajan</surname>
<given-names>S.</given-names>
</name>
<name><surname>Rosenfeld</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Coe</surname>
<given-names>B. P.</given-names>
</name>
<name><surname>Parikh</surname>
<given-names>S.</given-names>
</name>
<name><surname>Friedman</surname>
<given-names>N.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>Phenotypic heterogeneity of genomic disorders and rare copy-number variants.</article-title>
<source>N. Engl. J. Med.</source>
<volume>367</volume>
: <fpage>1321</fpage>
–<lpage>1331</lpage>
.<pub-id pub-id-type="pmid">22970919</pub-id>
</mixed-citation>
</ref>
<ref id="bib33"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Griffiths-Jones</surname>
<given-names>S.</given-names>
</name>
</person-group>
, <year>2004</year>
<article-title>The microRNA registry.</article-title>
<source>Nucleic Acids Res.</source>
<volume>32</volume>
: <fpage>D109</fpage>
–<lpage>D111</lpage>
.<pub-id pub-id-type="pmid">14681370</pub-id>
</mixed-citation>
</ref>
<ref id="bib34"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guipponi</surname>
<given-names>M.</given-names>
</name>
<name><surname>Santoni</surname>
<given-names>F. A.</given-names>
</name>
<name><surname>Setola</surname>
<given-names>V.</given-names>
</name>
<name><surname>Gehrig</surname>
<given-names>C.</given-names>
</name>
<name><surname>Rotharmel</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes.</article-title>
<source>PLoS One</source>
<volume>9</volume>
: <fpage>e112745</fpage>
.<pub-id pub-id-type="pmid">25420024</pub-id>
</mixed-citation>
</ref>
<ref id="bib35"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gulsuner</surname>
<given-names>S.</given-names>
</name>
<name><surname>Walsh</surname>
<given-names>T.</given-names>
</name>
<name><surname>Watts</surname>
<given-names>A. C.</given-names>
</name>
<name><surname>Lee</surname>
<given-names>M. K.</given-names>
</name>
<name><surname>Thornton</surname>
<given-names>A. M.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2013</year>
<article-title>Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.</article-title>
<source>Cell</source>
<volume>154</volume>
: <fpage>518</fpage>
–<lpage>529</lpage>
.<pub-id pub-id-type="pmid">23911319</pub-id>
</mixed-citation>
</ref>
<ref id="bib36"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hochstenbach</surname>
<given-names>R.</given-names>
</name>
<name><surname>Buizer-Voskamp</surname>
<given-names>J. E.</given-names>
</name>
<name><surname>Vorstman</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Ophoff</surname>
<given-names>R. A.</given-names>
</name>
</person-group>
, <year>2011</year>
<article-title>Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research.</article-title>
<source>Cytogenet. Genome Res.</source>
<volume>135</volume>
: <fpage>174</fpage>
–<lpage>202</lpage>
.<pub-id pub-id-type="pmid">22056632</pub-id>
</mixed-citation>
</ref>
<ref id="bib37"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hotelling</surname>
<given-names>H.</given-names>
</name>
</person-group>
, <year>1931</year>
<article-title>The generalization of Student’s ratio.</article-title>
<source>Ann. Math. Stat.</source>
<volume>2</volume>
: <fpage>360</fpage>
–<lpage>378</lpage>
.</mixed-citation>
</ref>
<ref id="bib38"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hu</surname>
<given-names>P.</given-names>
</name>
<name><surname>Greenwood</surname>
<given-names>C. M.</given-names>
</name>
<name><surname>Beyene</surname>
<given-names>J.</given-names>
</name>
</person-group>
, <year>2009</year>
<article-title>Using the ratio of means as the effect size measure in combining results of microarray experiments.</article-title>
<source>BMC Syst. Biol.</source>
<volume>3</volume>
: <fpage>106</fpage>
.<pub-id pub-id-type="pmid">19891778</pub-id>
</mixed-citation>
</ref>
<ref id="bib39"><mixed-citation publication-type="journal"><person-group person-group-type="author"><collab>International Schizophrenia Consortium</collab>
<name><surname>Purcell</surname>
<given-names>S. M.</given-names>
</name>
<name><surname>Wray</surname>
<given-names>N. R.</given-names>
</name>
<name><surname>Stone</surname>
<given-names>J. L.</given-names>
</name>
<name><surname>Visscher</surname>
<given-names>P. M.</given-names>
</name>
<name><surname>O’Donovan</surname>
<given-names>M. C.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2009</year>
<article-title>Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.</article-title>
<source>Nature</source>
<volume>460</volume>
: <fpage>748</fpage>
–<lpage>752</lpage>
.<pub-id pub-id-type="pmid">19571811</pub-id>
</mixed-citation>
</ref>
<ref id="bib40"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karayiorgou</surname>
<given-names>M.</given-names>
</name>
<name><surname>Simon</surname>
<given-names>T. J.</given-names>
</name>
<name><surname>Gogos</surname>
<given-names>J. A.</given-names>
</name>
</person-group>
, <year>2010</year>
<article-title>22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia.</article-title>
<source>Nat. Rev. Neurosci.</source>
<volume>11</volume>
: <fpage>402</fpage>
–<lpage>416</lpage>
.<pub-id pub-id-type="pmid">20485365</pub-id>
</mixed-citation>
</ref>
<ref id="bib41"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kiehl</surname>
<given-names>T. R.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<name><surname>Mikulis</surname>
<given-names>D. J.</given-names>
</name>
<name><surname>George</surname>
<given-names>S. R.</given-names>
</name>
<name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
</person-group>
, <year>2009</year>
<article-title>Neuropathologic features in adults with 22q11.2 deletion syndrome.</article-title>
<source>Cereb. Cortex</source>
<volume>19</volume>
: <fpage>153</fpage>
–<lpage>164</lpage>
.<pub-id pub-id-type="pmid">18483005</pub-id>
</mixed-citation>
</ref>
<ref id="bib42"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kirov</surname>
<given-names>G.</given-names>
</name>
<name><surname>Pocklington</surname>
<given-names>A. J.</given-names>
</name>
<name><surname>Holmans</surname>
<given-names>P.</given-names>
</name>
<name><surname>Ivanov</surname>
<given-names>D.</given-names>
</name>
<name><surname>Ikeda</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.</article-title>
<source>Mol. Psychiatry</source>
<volume>17</volume>
: <fpage>142</fpage>
–<lpage>153</lpage>
.<pub-id pub-id-type="pmid">22083728</pub-id>
</mixed-citation>
</ref>
<ref id="bib43"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lowther</surname>
<given-names>C.</given-names>
</name>
<name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Stavropoulos</surname>
<given-names>D. J.</given-names>
</name>
<name><surname>Melvin</surname>
<given-names>R.</given-names>
</name>
<name><surname>Silversides</surname>
<given-names>C. K.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2015</year>
<article-title>Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature.</article-title>
<source>Genet. Med.</source>
<volume>17</volume>
: <fpage>149</fpage>
–<lpage>157</lpage>
.<pub-id pub-id-type="pmid">25077648</pub-id>
</mixed-citation>
</ref>
<ref id="bib44"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McCarthy</surname>
<given-names>S. E.</given-names>
</name>
<name><surname>Gillis</surname>
<given-names>J.</given-names>
</name>
<name><surname>Kramer</surname>
<given-names>M.</given-names>
</name>
<name><surname>Lihm</surname>
<given-names>J.</given-names>
</name>
<name><surname>Yoon</surname>
<given-names>S.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.</article-title>
<source>Mol. Psychiatry</source>
<volume>19</volume>
: <fpage>652</fpage>
–<lpage>658</lpage>
.<pub-id pub-id-type="pmid">24776741</pub-id>
</mixed-citation>
</ref>
<ref id="bib45"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McDonald-McGinn</surname>
<given-names>D. M.</given-names>
</name>
<name><surname>Fahiminiya</surname>
<given-names>S.</given-names>
</name>
<name><surname>Revil</surname>
<given-names>T.</given-names>
</name>
<name><surname>Nowakowska</surname>
<given-names>B. A.</given-names>
</name>
<name><surname>Suhl</surname>
<given-names>J.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2013</year>
<article-title>Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.</article-title>
<source>J. Med. Genet.</source>
<volume>50</volume>
: <fpage>80</fpage>
–<lpage>90</lpage>
.<pub-id pub-id-type="pmid">23231787</pub-id>
</mixed-citation>
</ref>
<ref id="bib46"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Butcher</surname>
<given-names>N. J.</given-names>
</name>
<name><surname>Warnica</surname>
<given-names>W.</given-names>
</name>
<name><surname>Ogura</surname>
<given-names>L.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>MicroRNA dysregulation, gene networks and risk for schizophrenia in 22q11.2 deletion syndrome.</article-title>
<source>Front. Neurol.</source>
<volume>5</volume>
: <fpage>238</fpage>
.<pub-id pub-id-type="pmid">25484875</pub-id>
</mixed-citation>
</ref>
<ref id="bib47"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Moran</surname>
<given-names>V. A.</given-names>
</name>
<name><surname>Perera</surname>
<given-names>R. J.</given-names>
</name>
<name><surname>Khalil</surname>
<given-names>A. M.</given-names>
</name>
</person-group>
, <year>2012</year>
<article-title>Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs.</article-title>
<source>Nucleic Acids Res.</source>
<volume>40</volume>
: <fpage>6391</fpage>
–<lpage>6400</lpage>
.<pub-id pub-id-type="pmid">22492512</pub-id>
</mixed-citation>
</ref>
<ref id="bib48"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Moreau</surname>
<given-names>M. P.</given-names>
</name>
<name><surname>Bruse</surname>
<given-names>S. E.</given-names>
</name>
<name><surname>David-Rus</surname>
<given-names>R.</given-names>
</name>
<name><surname>Buyske</surname>
<given-names>S.</given-names>
</name>
<name><surname>Brzustowicz</surname>
<given-names>L. M.</given-names>
</name>
</person-group>
, <year>2011</year>
<article-title>Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.</article-title>
<source>Biol. Psychiatry</source>
<volume>69</volume>
: <fpage>188</fpage>
–<lpage>193</lpage>
.<pub-id pub-id-type="pmid">21183010</pub-id>
</mixed-citation>
</ref>
<ref id="bib49"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morrow</surname>
<given-names>E. M.</given-names>
</name>
</person-group>
, <year>2015</year>
<article-title>MicroRNAs in copy number variants in schizophrenia: misregulation of genome-wide gene expression programs.</article-title>
<source>Biol. Psychiatry</source>
<volume>77</volume>
: <fpage>93</fpage>
–<lpage>94</lpage>
.<pub-id pub-id-type="pmid">25524307</pub-id>
</mixed-citation>
</ref>
<ref id="bib50"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Need</surname>
<given-names>A. C.</given-names>
</name>
<name><surname>McEvoy</surname>
<given-names>J. P.</given-names>
</name>
<name><surname>Gennarelli</surname>
<given-names>M.</given-names>
</name>
<name><surname>Heinzen</surname>
<given-names>E. L.</given-names>
</name>
<name><surname>Ge</surname>
<given-names>D.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.</article-title>
<source>Am. J. Hum. Genet.</source>
<volume>91</volume>
: <fpage>303</fpage>
–<lpage>312</lpage>
.<pub-id pub-id-type="pmid">22863191</pub-id>
</mixed-citation>
</ref>
<ref id="bib51"><mixed-citation publication-type="journal"><person-group person-group-type="author"><collab>Pathway Analysis Subgroup of Psychiatric Genomics Consortium Network</collab>
</person-group>
, <year>2015</year>
<article-title>Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways.</article-title>
<source>Nat. Neurosci.</source>
<volume>18</volume>
: <fpage>199</fpage>
–<lpage>209</lpage>
.<pub-id pub-id-type="pmid">25599223</pub-id>
</mixed-citation>
</ref>
<ref id="bib52"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Philip</surname>
<given-names>N.</given-names>
</name>
<name><surname>Bassett</surname>
<given-names>A.</given-names>
</name>
</person-group>
, <year>2011</year>
<article-title>Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome.</article-title>
<source>Behav. Genet.</source>
<volume>41</volume>
: <fpage>403</fpage>
–<lpage>412</lpage>
.<pub-id pub-id-type="pmid">21573985</pub-id>
</mixed-citation>
</ref>
<ref id="bib53"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pinto</surname>
<given-names>D.</given-names>
</name>
<name><surname>Delaby</surname>
<given-names>E.</given-names>
</name>
<name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<name><surname>Barbosa</surname>
<given-names>M.</given-names>
</name>
<name><surname>Merikangas</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.</article-title>
<source>Am. J. Hum. Genet.</source>
<volume>94</volume>
: <fpage>677</fpage>
–<lpage>694</lpage>
.<pub-id pub-id-type="pmid">24768552</pub-id>
</mixed-citation>
</ref>
<ref id="bib54"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Piton</surname>
<given-names>A.</given-names>
</name>
<name><surname>Gauthier</surname>
<given-names>J.</given-names>
</name>
<name><surname>Hamdan</surname>
<given-names>F. F.</given-names>
</name>
<name><surname>Lafreniere</surname>
<given-names>R. G.</given-names>
</name>
<name><surname>Yang</surname>
<given-names>Y.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2011</year>
<article-title>Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.</article-title>
<source>Mol. Psychiatry</source>
<volume>16</volume>
: <fpage>867</fpage>
–<lpage>880</lpage>
.<pub-id pub-id-type="pmid">20479760</pub-id>
</mixed-citation>
</ref>
<ref id="bib55"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Prasad</surname>
<given-names>S. E.</given-names>
</name>
<name><surname>Howley</surname>
<given-names>S.</given-names>
</name>
<name><surname>Murphy</surname>
<given-names>K. C.</given-names>
</name>
</person-group>
, <year>2008</year>
<article-title>Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome.</article-title>
<source>Dev. Disabil. Res. Rev.</source>
<volume>14</volume>
: <fpage>26</fpage>
–<lpage>34</lpage>
.<pub-id pub-id-type="pmid">18636634</pub-id>
</mixed-citation>
</ref>
<ref id="bib56"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Purcell</surname>
<given-names>S. M.</given-names>
</name>
<name><surname>Moran</surname>
<given-names>J. L.</given-names>
</name>
<name><surname>Fromer</surname>
<given-names>M.</given-names>
</name>
<name><surname>Ruderfer</surname>
<given-names>D.</given-names>
</name>
<name><surname>Solovieff</surname>
<given-names>N.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>A polygenic burden of rare disruptive mutations in schizophrenia.</article-title>
<source>Nature</source>
<volume>506</volume>
: <fpage>185</fpage>
–<lpage>190</lpage>
.<pub-id pub-id-type="pmid">24463508</pub-id>
</mixed-citation>
</ref>
<ref id="bib57"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Quek</surname>
<given-names>X. C.</given-names>
</name>
<name><surname>Thomson</surname>
<given-names>D. W.</given-names>
</name>
<name><surname>Maag</surname>
<given-names>J. L.</given-names>
</name>
<name><surname>Bartonicek</surname>
<given-names>N.</given-names>
</name>
<name><surname>Signal</surname>
<given-names>B.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2015</year>
<article-title>lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs.</article-title>
<source>Nucleic Acids Res.</source>
<volume>43</volume>
: <fpage>D168</fpage>
–<lpage>D173</lpage>
.<pub-id pub-id-type="pmid">25332394</pub-id>
</mixed-citation>
</ref>
<ref id="bib58"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rees</surname>
<given-names>E.</given-names>
</name>
<name><surname>Walters</surname>
<given-names>J. T.</given-names>
</name>
<name><surname>Georgieva</surname>
<given-names>L.</given-names>
</name>
<name><surname>Isles</surname>
<given-names>A. R.</given-names>
</name>
<name><surname>Chambert</surname>
<given-names>K. D.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>Analysis of copy number variations at 15 schizophrenia-associated loci.</article-title>
<source>Br. J. Psychiatry</source>
<volume>204</volume>
: <fpage>108</fpage>
–<lpage>114</lpage>
.<pub-id pub-id-type="pmid">24311552</pub-id>
</mixed-citation>
</ref>
<ref id="bib59"><mixed-citation publication-type="journal"><person-group person-group-type="author"><collab>Schizophrenia Working Group of the Psychiatric Genomics Consortium</collab>
</person-group>
, <year>2014</year>
<article-title>Biological insights from 108 schizophrenia-associated genetic loci.</article-title>
<source>Nature</source>
<volume>511</volume>
: <fpage>421</fpage>
–<lpage>427</lpage>
.<pub-id pub-id-type="pmid">25056061</pub-id>
</mixed-citation>
</ref>
<ref id="bib60"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schneider</surname>
<given-names>M.</given-names>
</name>
<name><surname>Debbane</surname>
<given-names>M.</given-names>
</name>
<name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<name><surname>Fung</surname>
<given-names>W. L.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2014</year>
<article-title>Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.</article-title>
<source>Am. J. Psychiatry</source>
<volume>171</volume>
: <fpage>627</fpage>
–<lpage>639</lpage>
.<pub-id pub-id-type="pmid">24577245</pub-id>
</mixed-citation>
</ref>
<ref id="bib61"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schofield</surname>
<given-names>C. M.</given-names>
</name>
<name><surname>Hsu</surname>
<given-names>R.</given-names>
</name>
<name><surname>Barker</surname>
<given-names>A. J.</given-names>
</name>
<name><surname>Gertz</surname>
<given-names>C. C.</given-names>
</name>
<name><surname>Blelloch</surname>
<given-names>R.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2011</year>
<article-title>Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortex.</article-title>
<source>Neural Dev.</source>
<volume>6</volume>
: <fpage>11</fpage>
.<pub-id pub-id-type="pmid">21466685</pub-id>
</mixed-citation>
</ref>
<ref id="bib62"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Silversides</surname>
<given-names>C. K.</given-names>
</name>
<name><surname>Lionel</surname>
<given-names>A. C.</given-names>
</name>
<name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<name><surname>Migita</surname>
<given-names>O.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways.</article-title>
<source>PLoS Genet.</source>
<volume>8</volume>
: <fpage>e1002843</fpage>
.<pub-id pub-id-type="pmid">22912587</pub-id>
</mixed-citation>
</ref>
<ref id="bib63"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stankiewicz</surname>
<given-names>P.</given-names>
</name>
<name><surname>Lupski</surname>
<given-names>J. R.</given-names>
</name>
</person-group>
, <year>2010</year>
<article-title>Structural variation in the human genome and its role in disease.</article-title>
<source>Annu. Rev. Med.</source>
<volume>61</volume>
: <fpage>437</fpage>
–<lpage>455</lpage>
.<pub-id pub-id-type="pmid">20059347</pub-id>
</mixed-citation>
</ref>
<ref id="bib64"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stark</surname>
<given-names>K. L.</given-names>
</name>
<name><surname>Xu</surname>
<given-names>B.</given-names>
</name>
<name><surname>Bagchi</surname>
<given-names>A.</given-names>
</name>
<name><surname>Lai</surname>
<given-names>W. S.</given-names>
</name>
<name><surname>Liu</surname>
<given-names>H.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2008</year>
<article-title>Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model.</article-title>
<source>Nat. Genet.</source>
<volume>40</volume>
: <fpage>751</fpage>
–<lpage>760</lpage>
.<pub-id pub-id-type="pmid">18469815</pub-id>
</mixed-citation>
</ref>
<ref id="bib65"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Suhl</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Chopra</surname>
<given-names>P.</given-names>
</name>
<name><surname>Anderson</surname>
<given-names>B. R.</given-names>
</name>
<name><surname>Bassell</surname>
<given-names>G. J.</given-names>
</name>
<name><surname>Warren</surname>
<given-names>S. T.</given-names>
</name>
</person-group>
, <year>2014</year>
<article-title>Analysis of FMRP mRNA target datasets reveals highly associated mRNAs mediated by G-quadruplex structures formed via clustered WGGA sequences.</article-title>
<source>Hum. Mol. Genet.</source>
<volume>23</volume>
: <fpage>5479</fpage>
–<lpage>5491</lpage>
.<pub-id pub-id-type="pmid">24876161</pub-id>
</mixed-citation>
</ref>
<ref id="bib66"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Swaby</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Silversides</surname>
<given-names>C. K.</given-names>
</name>
<name><surname>Bekeschus</surname>
<given-names>S. C.</given-names>
</name>
<name><surname>Piran</surname>
<given-names>S.</given-names>
</name>
<name><surname>Oechslin</surname>
<given-names>E. N.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2011</year>
<article-title>Complex congenital heart disease in unaffected relatives of adults with 22q11.2 deletion syndrome.</article-title>
<source>Am. J. Cardiol.</source>
<volume>107</volume>
: <fpage>466</fpage>
–<lpage>471</lpage>
.<pub-id pub-id-type="pmid">21257016</pub-id>
</mixed-citation>
</ref>
<ref id="bib67"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Timms</surname>
<given-names>A. E.</given-names>
</name>
<name><surname>Dorschner</surname>
<given-names>M. O.</given-names>
</name>
<name><surname>Wechsler</surname>
<given-names>J.</given-names>
</name>
<name><surname>Choi</surname>
<given-names>K. Y.</given-names>
</name>
<name><surname>Kirkwood</surname>
<given-names>R.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2013</year>
<article-title>Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families.</article-title>
<source>JAMA Psychiatry</source>
<volume>70</volume>
: <fpage>582</fpage>
–<lpage>590</lpage>
.<pub-id pub-id-type="pmid">23553203</pub-id>
</mixed-citation>
</ref>
<ref id="bib68"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vorstman</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Breetvelt</surname>
<given-names>E. J.</given-names>
</name>
<name><surname>Thode</surname>
<given-names>K. I.</given-names>
</name>
<name><surname>Chow</surname>
<given-names>E. W.</given-names>
</name>
<name><surname>Bassett</surname>
<given-names>A. S.</given-names>
</name>
</person-group>
, <year>2013</year>
<article-title>Expression of autism spectrum and schizophrenia in patients with a 22q11.2 deletion.</article-title>
<source>Schizophr. Res.</source>
<volume>143</volume>
: <fpage>55</fpage>
–<lpage>59</lpage>
.<pub-id pub-id-type="pmid">23153825</pub-id>
</mixed-citation>
</ref>
<ref id="bib69"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname>
<given-names>K.</given-names>
</name>
<name><surname>Li</surname>
<given-names>M.</given-names>
</name>
<name><surname>Hakonarson</surname>
<given-names>H.</given-names>
</name>
</person-group>
, <year>2010</year>
<article-title>ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.</article-title>
<source>Nucleic Acids Res.</source>
<volume>38</volume>
: <fpage>e164</fpage>
.<pub-id pub-id-type="pmid">20601685</pub-id>
</mixed-citation>
</ref>
<ref id="bib70"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Warnica</surname>
<given-names>W.</given-names>
</name>
<name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<name><surname>Costain</surname>
<given-names>G.</given-names>
</name>
<name><surname>Alfred</surname>
<given-names>S. E.</given-names>
</name>
<name><surname>Wei</surname>
<given-names>J.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2015</year>
<article-title>Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets.</article-title>
<source>Biol. Psychiatry</source>
<volume>77</volume>
: <fpage>158</fpage>
–<lpage>166</lpage>
.<pub-id pub-id-type="pmid">25034949</pub-id>
</mixed-citation>
</ref>
<ref id="bib71"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Williams</surname>
<given-names>H. J.</given-names>
</name>
<name><surname>Monks</surname>
<given-names>S.</given-names>
</name>
<name><surname>Murphy</surname>
<given-names>K. C.</given-names>
</name>
<name><surname>Kirov</surname>
<given-names>G.</given-names>
</name>
<name><surname>O’Donovan</surname>
<given-names>M. C.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2013</year>
<article-title>Schizophrenia two-hit hypothesis in velo-cardio facial syndrome.</article-title>
<source>Am. J. Med. Genet. B. Neuropsychiatr. Genet.</source>
<volume>162B</volume>
: <fpage>177</fpage>
–<lpage>182</lpage>
.<pub-id pub-id-type="pmid">23335482</pub-id>
</mixed-citation>
</ref>
<ref id="bib72"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xiong</surname>
<given-names>H. Y.</given-names>
</name>
<name><surname>Alipanahi</surname>
<given-names>B.</given-names>
</name>
<name><surname>Lee</surname>
<given-names>L. J.</given-names>
</name>
<name><surname>Bretschneider</surname>
<given-names>H.</given-names>
</name>
<name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2015</year>
<article-title>RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.</article-title>
<source>Science</source>
<volume>347</volume>
: <fpage>1254806</fpage>
.<pub-id pub-id-type="pmid">25525159</pub-id>
</mixed-citation>
</ref>
<ref id="bib73"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xu</surname>
<given-names>B.</given-names>
</name>
<name><surname>Karayiorgou</surname>
<given-names>M.</given-names>
</name>
<name><surname>Gogos</surname>
<given-names>J. A.</given-names>
</name>
</person-group>
, <year>2010</year>
<article-title>MicroRNAs in psychiatric and neurodevelopmental disorders.</article-title>
<source>Brain Res.</source>
<volume>1338</volume>
: <fpage>78</fpage>
–<lpage>88</lpage>
.<pub-id pub-id-type="pmid">20388499</pub-id>
</mixed-citation>
</ref>
<ref id="bib74"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xu</surname>
<given-names>B.</given-names>
</name>
<name><surname>Ionita-Laza</surname>
<given-names>I.</given-names>
</name>
<name><surname>Roos</surname>
<given-names>J. L.</given-names>
</name>
<name><surname>Boone</surname>
<given-names>B.</given-names>
</name>
<name><surname>Woodrick</surname>
<given-names>S.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2012</year>
<article-title>De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia.</article-title>
<source>Nat. Genet.</source>
<volume>44</volume>
: <fpage>1365</fpage>
–<lpage>1369</lpage>
.<pub-id pub-id-type="pmid">23042115</pub-id>
</mixed-citation>
</ref>
<ref id="bib75"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yuen</surname>
<given-names>R. K.</given-names>
</name>
<name><surname>Thiruvahindrapuram</surname>
<given-names>B.</given-names>
</name>
<name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<name><surname>Walker</surname>
<given-names>S.</given-names>
</name>
<name><surname>Tammimies</surname>
<given-names>K.</given-names>
</name>
<etal></etal>
</person-group>
, <year>2015</year>
<article-title>Whole-genome sequencing of quartet families with autism spectrum disorder.</article-title>
<source>Nat. Med.</source>
<volume>21</volume>
: <fpage>185</fpage>
–<lpage>191</lpage>
.<pub-id pub-id-type="pmid">25621899</pub-id>
</mixed-citation>
</ref>
<ref id="bib76"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zarrei</surname>
<given-names>M.</given-names>
</name>
<name><surname>MacDonald</surname>
<given-names>J. R.</given-names>
</name>
<name><surname>Merico</surname>
<given-names>D.</given-names>
</name>
<name><surname>Scherer</surname>
<given-names>S. W.</given-names>
</name>
</person-group>
, <year>2015</year>
<article-title>A copy number variation map of the human genome.</article-title>
<source>Nat. Rev. Genet.</source>
<volume>16</volume>
: <fpage>172</fpage>
–<lpage>183</lpage>
.<pub-id pub-id-type="pmid">25645873</pub-id>
</mixed-citation>
</ref>
</ref-list>
</back>
</pmc>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000063 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000063 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Canada |area= ParkinsonCanadaV1 |flux= Pmc |étape= Corpus |type= RBID |clé= |texte= }}
![]() | This area was generated with Dilib version V0.6.29. | ![]() |