High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression
Identifieur interne : 000083 ( Pmc/Checkpoint ); précédent : 000082; suivant : 000084High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression
Auteurs : Marian L. Hamshere ; Kate Langley ; Joanna Martin ; Sharifah Shameem Agha ; Evangelia Stergiakouli ; Richard J. L. Anney ; Jan Buitelaar ; Stephen V. Faraone ; Klaus-Peter Lesch ; Benjamin M. Neale ; Barbara Franke ; Edmund Sonuga-Barke ; Philip Asherson ; Andrew Merwood ; Jonna Kuntsi ; Sarah E. Medland ; Stephan Ripke ; Hans-Christoph Steinhausen ; Christine Freitag ; Andreas Reif ; Tobias J. Renner ; Marcel Romanos ; Jasmin Romanos ; Andreas Warnke ; Jobst Meyer ; Haukur Palmason ; Alejandro Arias Vasquez ; Nanda Lambregts-Rommelse ; Herbert Roeyers ; Joseph Biederman ; Alysa E. Doyle ; Hakon Hakonarson ; Aribert Rothenberger ; Tobias Banaschewski ; Robert D. Oades ; James J. Mcgough ; Lindsey Kent ; Nigel Williams ; Michael J. Owen ; Peter Holmans ; Michael C. O Onovan ; Anita ThaparSource :
- The American Journal of Psychiatry [ 0002-953X ] ; 2013.
Abstract
Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder.
Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression.
Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items.
Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.
Url:
DOI: 10.1176/appi.ajp.2013.12081129
PubMed: 23599091
PubMed Central: 3935265
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression</title>
<author><name sortKey="Hamshere, Marian L" sort="Hamshere, Marian L" uniqKey="Hamshere M" first="Marian L." last="Hamshere">Marian L. Hamshere</name>
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<author><name sortKey="Langley, Kate" sort="Langley, Kate" uniqKey="Langley K" first="Kate" last="Langley">Kate Langley</name>
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<author><name sortKey="Martin, Joanna" sort="Martin, Joanna" uniqKey="Martin J" first="Joanna" last="Martin">Joanna Martin</name>
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<author><name sortKey="Agha, Sharifah Shameem" sort="Agha, Sharifah Shameem" uniqKey="Agha S" first="Sharifah Shameem" last="Agha">Sharifah Shameem Agha</name>
</author>
<author><name sortKey="Stergiakouli, Evangelia" sort="Stergiakouli, Evangelia" uniqKey="Stergiakouli E" first="Evangelia" last="Stergiakouli">Evangelia Stergiakouli</name>
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<author><name sortKey="Anney, Richard J L" sort="Anney, Richard J L" uniqKey="Anney R" first="Richard J. L." last="Anney">Richard J. L. Anney</name>
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<author><name sortKey="Buitelaar, Jan" sort="Buitelaar, Jan" uniqKey="Buitelaar J" first="Jan" last="Buitelaar">Jan Buitelaar</name>
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<author><name sortKey="Faraone, Stephen V" sort="Faraone, Stephen V" uniqKey="Faraone S" first="Stephen V." last="Faraone">Stephen V. Faraone</name>
</author>
<author><name sortKey="Lesch, Klaus Peter" sort="Lesch, Klaus Peter" uniqKey="Lesch K" first="Klaus-Peter" last="Lesch">Klaus-Peter Lesch</name>
</author>
<author><name sortKey="Neale, Benjamin M" sort="Neale, Benjamin M" uniqKey="Neale B" first="Benjamin M." last="Neale">Benjamin M. Neale</name>
</author>
<author><name sortKey="Franke, Barbara" sort="Franke, Barbara" uniqKey="Franke B" first="Barbara" last="Franke">Barbara Franke</name>
</author>
<author><name sortKey="Sonuga Barke, Edmund" sort="Sonuga Barke, Edmund" uniqKey="Sonuga Barke E" first="Edmund" last="Sonuga-Barke">Edmund Sonuga-Barke</name>
</author>
<author><name sortKey="Asherson, Philip" sort="Asherson, Philip" uniqKey="Asherson P" first="Philip" last="Asherson">Philip Asherson</name>
</author>
<author><name sortKey="Merwood, Andrew" sort="Merwood, Andrew" uniqKey="Merwood A" first="Andrew" last="Merwood">Andrew Merwood</name>
</author>
<author><name sortKey="Kuntsi, Jonna" sort="Kuntsi, Jonna" uniqKey="Kuntsi J" first="Jonna" last="Kuntsi">Jonna Kuntsi</name>
</author>
<author><name sortKey="Medland, Sarah E" sort="Medland, Sarah E" uniqKey="Medland S" first="Sarah E." last="Medland">Sarah E. Medland</name>
</author>
<author><name sortKey="Ripke, Stephan" sort="Ripke, Stephan" uniqKey="Ripke S" first="Stephan" last="Ripke">Stephan Ripke</name>
</author>
<author><name sortKey="Steinhausen, Hans Christoph" sort="Steinhausen, Hans Christoph" uniqKey="Steinhausen H" first="Hans-Christoph" last="Steinhausen">Hans-Christoph Steinhausen</name>
</author>
<author><name sortKey="Freitag, Christine" sort="Freitag, Christine" uniqKey="Freitag C" first="Christine" last="Freitag">Christine Freitag</name>
</author>
<author><name sortKey="Reif, Andreas" sort="Reif, Andreas" uniqKey="Reif A" first="Andreas" last="Reif">Andreas Reif</name>
</author>
<author><name sortKey="Renner, Tobias J" sort="Renner, Tobias J" uniqKey="Renner T" first="Tobias J." last="Renner">Tobias J. Renner</name>
</author>
<author><name sortKey="Romanos, Marcel" sort="Romanos, Marcel" uniqKey="Romanos M" first="Marcel" last="Romanos">Marcel Romanos</name>
</author>
<author><name sortKey="Romanos, Jasmin" sort="Romanos, Jasmin" uniqKey="Romanos J" first="Jasmin" last="Romanos">Jasmin Romanos</name>
</author>
<author><name sortKey="Warnke, Andreas" sort="Warnke, Andreas" uniqKey="Warnke A" first="Andreas" last="Warnke">Andreas Warnke</name>
</author>
<author><name sortKey="Meyer, Jobst" sort="Meyer, Jobst" uniqKey="Meyer J" first="Jobst" last="Meyer">Jobst Meyer</name>
</author>
<author><name sortKey="Palmason, Haukur" sort="Palmason, Haukur" uniqKey="Palmason H" first="Haukur" last="Palmason">Haukur Palmason</name>
</author>
<author><name sortKey="Vasquez, Alejandro Arias" sort="Vasquez, Alejandro Arias" uniqKey="Vasquez A" first="Alejandro Arias" last="Vasquez">Alejandro Arias Vasquez</name>
</author>
<author><name sortKey="Lambregts Rommelse, Nanda" sort="Lambregts Rommelse, Nanda" uniqKey="Lambregts Rommelse N" first="Nanda" last="Lambregts-Rommelse">Nanda Lambregts-Rommelse</name>
</author>
<author><name sortKey="Roeyers, Herbert" sort="Roeyers, Herbert" uniqKey="Roeyers H" first="Herbert" last="Roeyers">Herbert Roeyers</name>
</author>
<author><name sortKey="Biederman, Joseph" sort="Biederman, Joseph" uniqKey="Biederman J" first="Joseph" last="Biederman">Joseph Biederman</name>
</author>
<author><name sortKey="Doyle, Alysa E" sort="Doyle, Alysa E" uniqKey="Doyle A" first="Alysa E." last="Doyle">Alysa E. Doyle</name>
</author>
<author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name>
</author>
<author><name sortKey="Rothenberger, Aribert" sort="Rothenberger, Aribert" uniqKey="Rothenberger A" first="Aribert" last="Rothenberger">Aribert Rothenberger</name>
</author>
<author><name sortKey="Banaschewski, Tobias" sort="Banaschewski, Tobias" uniqKey="Banaschewski T" first="Tobias" last="Banaschewski">Tobias Banaschewski</name>
</author>
<author><name sortKey="Oades, Robert D" sort="Oades, Robert D" uniqKey="Oades R" first="Robert D." last="Oades">Robert D. Oades</name>
</author>
<author><name sortKey="Mcgough, James J" sort="Mcgough, James J" uniqKey="Mcgough J" first="James J." last="Mcgough">James J. Mcgough</name>
</author>
<author><name sortKey="Kent, Lindsey" sort="Kent, Lindsey" uniqKey="Kent L" first="Lindsey" last="Kent">Lindsey Kent</name>
</author>
<author><name sortKey="Williams, Nigel" sort="Williams, Nigel" uniqKey="Williams N" first="Nigel" last="Williams">Nigel Williams</name>
</author>
<author><name sortKey="Owen, Michael J" sort="Owen, Michael J" uniqKey="Owen M" first="Michael J." last="Owen">Michael J. Owen</name>
</author>
<author><name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name>
</author>
<author><name sortKey="O Onovan, Michael C" sort="O Onovan, Michael C" uniqKey="O Onovan M" first="Michael C." last="O Onovan">Michael C. O Onovan</name>
</author>
<author><name sortKey="Thapar, Anita" sort="Thapar, Anita" uniqKey="Thapar A" first="Anita" last="Thapar">Anita Thapar</name>
</author>
</analytic>
<series><title level="j">The American Journal of Psychiatry</title>
<idno type="ISSN">0002-953X</idno>
<idno type="eISSN">1535-7228</idno>
<imprint><date when="2013">2013</date>
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<front><div type="abstract" xml:lang="en"><sec><title>Objective</title>
<p>Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder.</p>
</sec>
<sec><title>Method</title>
<p>Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression.</p>
</sec>
<sec><title>Results</title>
<p>Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items.</p>
</sec>
<sec><title>Conclusions</title>
<p>Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.</p>
</sec>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Thapar, A" uniqKey="Thapar A">A Thapar</name>
</author>
<author><name sortKey="Holmes, J" uniqKey="Holmes J">J Holmes</name>
</author>
<author><name sortKey="Poulton, K" uniqKey="Poulton K">K Poulton</name>
</author>
<author><name sortKey="Harrington, R" uniqKey="Harrington R">R Harrington</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Faraone, Sv" uniqKey="Faraone S">SV Faraone</name>
</author>
<author><name sortKey="Mick, E" uniqKey="Mick E">E Mick</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Faraone, Sv" uniqKey="Faraone S">SV Faraone</name>
</author>
<author><name sortKey="Biederman, J" uniqKey="Biederman J">J Biederman</name>
</author>
<author><name sortKey="Monuteaux, Mc" uniqKey="Monuteaux M">MC Monuteaux</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Williams, Nm" uniqKey="Williams N">NM Williams</name>
</author>
<author><name sortKey="Franke, B" uniqKey="Franke B">B Franke</name>
</author>
<author><name sortKey="Mick, E" uniqKey="Mick E">E Mick</name>
</author>
<author><name sortKey="Anney, Rjl" uniqKey="Anney R">RJL Anney</name>
</author>
<author><name sortKey="Freitag, Cm" uniqKey="Freitag C">CM Freitag</name>
</author>
<author><name sortKey="Gill, M" uniqKey="Gill M">M Gill</name>
</author>
<author><name sortKey="Thapar, A" uniqKey="Thapar A">A Thapar</name>
</author>
<author><name sortKey="O Onovan, Mc" uniqKey="O Onovan M">MC O’Donovan</name>
</author>
<author><name sortKey="Owen, Mj" uniqKey="Owen M">MJ Owen</name>
</author>
<author><name sortKey="Holmans, P" uniqKey="Holmans P">P Holmans</name>
</author>
<author><name sortKey="Kent, L" uniqKey="Kent L">L Kent</name>
</author>
<author><name sortKey="Middleton, F" uniqKey="Middleton F">F Middleton</name>
</author>
<author><name sortKey="Zhang James, Y" uniqKey="Zhang James Y">Y Zhang-James</name>
</author>
<author><name sortKey="Liu, L" uniqKey="Liu L">L Liu</name>
</author>
<author><name sortKey="Meyer, J" uniqKey="Meyer J">J Meyer</name>
</author>
<author><name sortKey="Nguyen, Tt" uniqKey="Nguyen T">TT Nguyen</name>
</author>
<author><name sortKey="Romanos, J" uniqKey="Romanos J">J Romanos</name>
</author>
<author><name sortKey="Romanos, M" uniqKey="Romanos M">M Romanos</name>
</author>
<author><name sortKey="Seitz, C" uniqKey="Seitz C">C Seitz</name>
</author>
<author><name sortKey="Renner, Tj" uniqKey="Renner T">TJ Renner</name>
</author>
<author><name sortKey="Walitza, S" uniqKey="Walitza S">S Walitza</name>
</author>
<author><name sortKey="Warnke, A" uniqKey="Warnke A">A Warnke</name>
</author>
<author><name sortKey="Palmason, H" uniqKey="Palmason H">H Palmason</name>
</author>
<author><name sortKey="Buitelaar, J" uniqKey="Buitelaar J">J Buitelaar</name>
</author>
<author><name sortKey="Rommelse, N" uniqKey="Rommelse N">N Rommelse</name>
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<author><name sortKey="Vasquez, Aa" uniqKey="Vasquez A">AA Vasquez</name>
</author>
<author><name sortKey="Hawi, Z" uniqKey="Hawi Z">Z Hawi</name>
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<author><name sortKey="Langley, K" uniqKey="Langley K">K Langley</name>
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<author><name sortKey="Sergeant, J" uniqKey="Sergeant J">J Sergeant</name>
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<author><name sortKey="Steinhausen, Hc" uniqKey="Steinhausen H">HC Steinhausen</name>
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<author><name sortKey="Roeyers, H" uniqKey="Roeyers H">H Roeyers</name>
</author>
<author><name sortKey="Biederman, J" uniqKey="Biederman J">J Biederman</name>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Psychiatry</journal-id>
<journal-id journal-id-type="iso-abbrev">Am J Psychiatry</journal-id>
<journal-id journal-id-type="pmc">Am J Psychiatry</journal-id>
<journal-id journal-id-type="publisher-id">American Psychiatric Association</journal-id>
<journal-title-group><journal-title>The American Journal of Psychiatry</journal-title>
</journal-title-group>
<issn pub-type="ppub">0002-953X</issn>
<issn pub-type="epub">1535-7228</issn>
<publisher><publisher-name>American Psychiatric Association</publisher-name>
<publisher-loc>Arlington, VA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23599091</article-id>
<article-id pub-id-type="pmc">3935265</article-id>
<article-id pub-id-type="publisher-id">AJP_12081129</article-id>
<article-id pub-id-type="doi">10.1176/appi.ajp.2013.12081129</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>New Research</subject>
<subj-group><subject>Articles</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Hamshere</surname>
<given-names>Marian L.</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Langley</surname>
<given-names>Kate</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Martin</surname>
<given-names>Joanna</given-names>
</name>
<degrees>B.Sc.(Hons)</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Agha</surname>
<given-names>Sharifah Shameem</given-names>
</name>
<degrees>M.Sc.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Stergiakouli</surname>
<given-names>Evangelia</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Anney</surname>
<given-names>Richard J.L.</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Buitelaar</surname>
<given-names>Jan</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Faraone</surname>
<given-names>Stephen V.</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Lesch</surname>
<given-names>Klaus-Peter</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Neale</surname>
<given-names>Benjamin M.</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Franke</surname>
<given-names>Barbara</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Sonuga-Barke</surname>
<given-names>Edmund</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Asherson</surname>
<given-names>Philip</given-names>
</name>
<degrees>M.R.C.Psych., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Merwood</surname>
<given-names>Andrew</given-names>
</name>
<degrees>M.Sc.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Kuntsi</surname>
<given-names>Jonna</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Medland</surname>
<given-names>Sarah E.</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Ripke</surname>
<given-names>Stephan</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Steinhausen</surname>
<given-names>Hans-Christoph</given-names>
</name>
<degrees>M.D., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Freitag</surname>
<given-names>Christine</given-names>
</name>
<degrees>M.D., M.A</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Reif</surname>
<given-names>Andreas</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Renner</surname>
<given-names>Tobias J.</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Romanos</surname>
<given-names>Marcel</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Romanos</surname>
<given-names>Jasmin</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Warnke</surname>
<given-names>Andreas</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Meyer</surname>
<given-names>Jobst</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Palmason</surname>
<given-names>Haukur</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Vasquez</surname>
<given-names>Alejandro Arias</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Lambregts-Rommelse</surname>
<given-names>Nanda</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Roeyers</surname>
<given-names>Herbert</given-names>
</name>
<degrees>M.D., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Biederman</surname>
<given-names>Joseph</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Doyle</surname>
<given-names>Alysa E.</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Hakonarson</surname>
<given-names>Hakon</given-names>
</name>
<degrees>M.D., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Rothenberger</surname>
<given-names>Aribert</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Banaschewski</surname>
<given-names>Tobias</given-names>
</name>
<degrees>M.D., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Oades</surname>
<given-names>Robert D.</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>McGough</surname>
<given-names>James J.</given-names>
</name>
<degrees>M.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Kent</surname>
<given-names>Lindsey</given-names>
</name>
<degrees>M.D., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Williams</surname>
<given-names>Nigel</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Owen</surname>
<given-names>Michael J.</given-names>
</name>
<degrees>F.R.C.Psych., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Holmans</surname>
<given-names>Peter</given-names>
</name>
<degrees>Ph.D.</degrees>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>O’Donovan</surname>
<given-names>Michael C.</given-names>
</name>
<degrees>F.R.C.Psych., Ph.D.</degrees>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Thapar</surname>
<given-names>Anita</given-names>
</name>
<degrees>F.R.C.Psych., Ph.D.</degrees>
</contrib>
<aff id="aff1">From the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, U.K.; Department of Psychiatry, Trinity Centre for Health Sciences, Dublin, Ireland; Departments of Cognitive Neuroscience, Human Genetics, and Psychiatry, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; Departments of Psychiatry and of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse; ADHD Clinical Research Network, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics, and Psychotherapy, and Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; King’s College London, MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, London; Institute for Disorder of Impulse and Attention, School of Psychology, University of Southampton, Highfield, Southampton, U.K.; Quantitative Genetics, Queensland Institute of Medical Research, Brisbane, Australia; Clinical Psychology and Epidemiology, Institute of Psychology, University of Basel, Basel, Switzerland; Aalborg Psychiatric Hospital, Aarhus University Hospital, Aarhus, Denmark; Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland; Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Goethe University, Frankfurt am Main, Germany; Institute of Psychobiology, Department of Neurobehavioral Genetics, University of Trier, Trier, Germany; Department of Experimental Clinical and Health Psychology, Ghent University, Dunantlaan, Ghent, Belgium; Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Boston; Department of Psychiatry, Harvard Medical School, Boston; Center for Applied Genomics and Department of Pediatrics, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, Philadelphia; Child and Adolescent Psychiatry, University of Goettingen, Goettingen, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; Clinic for Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany; UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; School of Medicine, St. Andrews University, St. Andrews, U.K.</aff>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Dr. Thapar (<email>thapar@cf.ac.uk</email>
) or Dr. O’Donovan (<email>odonovanmc@cf.ac.uk</email>
).</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>8</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>19</day>
<month>4</month>
<year>2013</year>
</pub-date>
<volume>170</volume>
<issue>8</issue>
<fpage>909</fpage>
<lpage>916</lpage>
<history><date date-type="received"><day>29</day>
<month>8</month>
<year>2012</year>
</date>
<date date-type="rev-recd"><day>10</day>
<month>12</month>
<year>2012</year>
</date>
<date date-type="accepted"><day>03</day>
<month>1</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>Copyright © American Psychiatric Association. For permission to use (where not already granted under a license) please go to <ext-link ext-link-type="uri" xlink:href="http://psychiatryonline.org/public/termsofuse.aspx">http://psychiatryonline.org/public/termsofuse.aspx</ext-link>
</copyright-statement>
<copyright-year>2014</copyright-year>
<license license-type="openaccess"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>
and <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/legalcode">http://creativecommons.org/licenses/by-nc/3.0/legalcode</ext-link>
.</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="909.pdf"></self-uri>
<abstract><sec><title>Objective</title>
<p>Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder.</p>
</sec>
<sec><title>Method</title>
<p>Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression.</p>
</sec>
<sec><title>Results</title>
<p>Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items.</p>
</sec>
<sec><title>Conclusions</title>
<p>Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.</p>
</sec>
</abstract>
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<meta-value>v1</meta-value>
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</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Agha, Sharifah Shameem" sort="Agha, Sharifah Shameem" uniqKey="Agha S" first="Sharifah Shameem" last="Agha">Sharifah Shameem Agha</name>
<name sortKey="Anney, Richard J L" sort="Anney, Richard J L" uniqKey="Anney R" first="Richard J. L." last="Anney">Richard J. L. Anney</name>
<name sortKey="Asherson, Philip" sort="Asherson, Philip" uniqKey="Asherson P" first="Philip" last="Asherson">Philip Asherson</name>
<name sortKey="Banaschewski, Tobias" sort="Banaschewski, Tobias" uniqKey="Banaschewski T" first="Tobias" last="Banaschewski">Tobias Banaschewski</name>
<name sortKey="Biederman, Joseph" sort="Biederman, Joseph" uniqKey="Biederman J" first="Joseph" last="Biederman">Joseph Biederman</name>
<name sortKey="Buitelaar, Jan" sort="Buitelaar, Jan" uniqKey="Buitelaar J" first="Jan" last="Buitelaar">Jan Buitelaar</name>
<name sortKey="Doyle, Alysa E" sort="Doyle, Alysa E" uniqKey="Doyle A" first="Alysa E." last="Doyle">Alysa E. Doyle</name>
<name sortKey="Faraone, Stephen V" sort="Faraone, Stephen V" uniqKey="Faraone S" first="Stephen V." last="Faraone">Stephen V. Faraone</name>
<name sortKey="Franke, Barbara" sort="Franke, Barbara" uniqKey="Franke B" first="Barbara" last="Franke">Barbara Franke</name>
<name sortKey="Freitag, Christine" sort="Freitag, Christine" uniqKey="Freitag C" first="Christine" last="Freitag">Christine Freitag</name>
<name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name>
<name sortKey="Hamshere, Marian L" sort="Hamshere, Marian L" uniqKey="Hamshere M" first="Marian L." last="Hamshere">Marian L. Hamshere</name>
<name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name>
<name sortKey="Kent, Lindsey" sort="Kent, Lindsey" uniqKey="Kent L" first="Lindsey" last="Kent">Lindsey Kent</name>
<name sortKey="Kuntsi, Jonna" sort="Kuntsi, Jonna" uniqKey="Kuntsi J" first="Jonna" last="Kuntsi">Jonna Kuntsi</name>
<name sortKey="Lambregts Rommelse, Nanda" sort="Lambregts Rommelse, Nanda" uniqKey="Lambregts Rommelse N" first="Nanda" last="Lambregts-Rommelse">Nanda Lambregts-Rommelse</name>
<name sortKey="Langley, Kate" sort="Langley, Kate" uniqKey="Langley K" first="Kate" last="Langley">Kate Langley</name>
<name sortKey="Lesch, Klaus Peter" sort="Lesch, Klaus Peter" uniqKey="Lesch K" first="Klaus-Peter" last="Lesch">Klaus-Peter Lesch</name>
<name sortKey="Martin, Joanna" sort="Martin, Joanna" uniqKey="Martin J" first="Joanna" last="Martin">Joanna Martin</name>
<name sortKey="Mcgough, James J" sort="Mcgough, James J" uniqKey="Mcgough J" first="James J." last="Mcgough">James J. Mcgough</name>
<name sortKey="Medland, Sarah E" sort="Medland, Sarah E" uniqKey="Medland S" first="Sarah E." last="Medland">Sarah E. Medland</name>
<name sortKey="Merwood, Andrew" sort="Merwood, Andrew" uniqKey="Merwood A" first="Andrew" last="Merwood">Andrew Merwood</name>
<name sortKey="Meyer, Jobst" sort="Meyer, Jobst" uniqKey="Meyer J" first="Jobst" last="Meyer">Jobst Meyer</name>
<name sortKey="Neale, Benjamin M" sort="Neale, Benjamin M" uniqKey="Neale B" first="Benjamin M." last="Neale">Benjamin M. Neale</name>
<name sortKey="O Onovan, Michael C" sort="O Onovan, Michael C" uniqKey="O Onovan M" first="Michael C." last="O Onovan">Michael C. O Onovan</name>
<name sortKey="Oades, Robert D" sort="Oades, Robert D" uniqKey="Oades R" first="Robert D." last="Oades">Robert D. Oades</name>
<name sortKey="Owen, Michael J" sort="Owen, Michael J" uniqKey="Owen M" first="Michael J." last="Owen">Michael J. Owen</name>
<name sortKey="Palmason, Haukur" sort="Palmason, Haukur" uniqKey="Palmason H" first="Haukur" last="Palmason">Haukur Palmason</name>
<name sortKey="Reif, Andreas" sort="Reif, Andreas" uniqKey="Reif A" first="Andreas" last="Reif">Andreas Reif</name>
<name sortKey="Renner, Tobias J" sort="Renner, Tobias J" uniqKey="Renner T" first="Tobias J." last="Renner">Tobias J. Renner</name>
<name sortKey="Ripke, Stephan" sort="Ripke, Stephan" uniqKey="Ripke S" first="Stephan" last="Ripke">Stephan Ripke</name>
<name sortKey="Roeyers, Herbert" sort="Roeyers, Herbert" uniqKey="Roeyers H" first="Herbert" last="Roeyers">Herbert Roeyers</name>
<name sortKey="Romanos, Jasmin" sort="Romanos, Jasmin" uniqKey="Romanos J" first="Jasmin" last="Romanos">Jasmin Romanos</name>
<name sortKey="Romanos, Marcel" sort="Romanos, Marcel" uniqKey="Romanos M" first="Marcel" last="Romanos">Marcel Romanos</name>
<name sortKey="Rothenberger, Aribert" sort="Rothenberger, Aribert" uniqKey="Rothenberger A" first="Aribert" last="Rothenberger">Aribert Rothenberger</name>
<name sortKey="Sonuga Barke, Edmund" sort="Sonuga Barke, Edmund" uniqKey="Sonuga Barke E" first="Edmund" last="Sonuga-Barke">Edmund Sonuga-Barke</name>
<name sortKey="Steinhausen, Hans Christoph" sort="Steinhausen, Hans Christoph" uniqKey="Steinhausen H" first="Hans-Christoph" last="Steinhausen">Hans-Christoph Steinhausen</name>
<name sortKey="Stergiakouli, Evangelia" sort="Stergiakouli, Evangelia" uniqKey="Stergiakouli E" first="Evangelia" last="Stergiakouli">Evangelia Stergiakouli</name>
<name sortKey="Thapar, Anita" sort="Thapar, Anita" uniqKey="Thapar A" first="Anita" last="Thapar">Anita Thapar</name>
<name sortKey="Vasquez, Alejandro Arias" sort="Vasquez, Alejandro Arias" uniqKey="Vasquez A" first="Alejandro Arias" last="Vasquez">Alejandro Arias Vasquez</name>
<name sortKey="Warnke, Andreas" sort="Warnke, Andreas" uniqKey="Warnke A" first="Andreas" last="Warnke">Andreas Warnke</name>
<name sortKey="Williams, Nigel" sort="Williams, Nigel" uniqKey="Williams N" first="Nigel" last="Williams">Nigel Williams</name>
</noCountry>
</tree>
</affiliations>
</record>
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