Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Rare, Evolutionarily Unlikely Missense Substitutions in <italic>ATM</italic> Confer Increased Risk of Breast Cancer</title><author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Oefner, Peter J" sort="Oefner, Peter J" uniqKey="Oefner P" first="Peter J." last="Oefner">Peter J. Oefner</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Babikyan, Davit" sort="Babikyan, Davit" uniqKey="Babikyan D" first="Davit" last="Babikyan">Davit Babikyan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hartmann, Anne" sort="Hartmann, Anne" uniqKey="Hartmann A" first="Anne" last="Hartmann">Anne Hartmann</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Le Calvez Kelm, Florence" sort="Le Calvez Kelm, Florence" uniqKey="Le Calvez Kelm F" first="Florence" last="Le Calvez-Kelm">Florence Le Calvez-Kelm</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Lesueur, Fabienne" sort="Lesueur, Fabienne" uniqKey="Lesueur F" first="Fabienne" last="Lesueur">Fabienne Lesueur</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Byrnes, Graham B" sort="Byrnes, Graham B" uniqKey="Byrnes G" first="Graham B." last="Byrnes">Graham B. Byrnes</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Chuang, Shu Chun" sort="Chuang, Shu Chun" uniqKey="Chuang S" first="Shu-Chun" last="Chuang">Shu-Chun Chuang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Forey, Nathalie" sort="Forey, Nathalie" uniqKey="Forey N" first="Nathalie" last="Forey">Nathalie Forey</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Feuchtinger, Corinna" sort="Feuchtinger, Corinna" uniqKey="Feuchtinger C" first="Corinna" last="Feuchtinger">Corinna Feuchtinger</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Gioia, Lydie" sort="Gioia, Lydie" uniqKey="Gioia L" first="Lydie" last="Gioia">Lydie Gioia</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hall, Janet" sort="Hall, Janet" uniqKey="Hall J" first="Janet" last="Hall">Janet Hall</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Hashibe, Mia" sort="Hashibe, Mia" uniqKey="Hashibe M" first="Mia" last="Hashibe">Mia Hashibe</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Herte, Barbara" sort="Herte, Barbara" uniqKey="Herte B" first="Barbara" last="Herte">Barbara Herte</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Mckay Chopin, Sandrine" sort="Mckay Chopin, Sandrine" uniqKey="Mckay Chopin S" first="Sandrine" last="Mckay-Chopin">Sandrine Mckay-Chopin</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thomas, Alun" sort="Thomas, Alun" uniqKey="Thomas A" first="Alun" last="Thomas">Alun Thomas</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Vallee, Maxime P" sort="Vallee, Maxime P" uniqKey="Vallee M" first="Maxime P." last="Vallée">Maxime P. Vallée</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Voegele, Catherine" sort="Voegele, Catherine" uniqKey="Voegele C" first="Catherine" last="Voegele">Catherine Voegele</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Webb, Penelope M" sort="Webb, Penelope M" uniqKey="Webb P" first="Penelope M." last="Webb">Penelope M. Webb</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Whiteman, David C" sort="Whiteman, David C" uniqKey="Whiteman D" first="David C." last="Whiteman">David C. Whiteman</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Sangrajrang, Suleeporn" sort="Sangrajrang, Suleeporn" uniqKey="Sangrajrang S" first="Suleeporn" last="Sangrajrang">Suleeporn Sangrajrang</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19781682</idno><idno type="pmc">2756555</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756555</idno><idno type="RBID">PMC:2756555</idno><idno type="doi">10.1016/j.ajhg.2009.08.018</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">001705</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001705</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Rare, Evolutionarily Unlikely Missense Substitutions in <italic>ATM</italic> Confer Increased Risk of Breast Cancer</title><author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Oefner, Peter J" sort="Oefner, Peter J" uniqKey="Oefner P" first="Peter J." last="Oefner">Peter J. Oefner</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Babikyan, Davit" sort="Babikyan, Davit" uniqKey="Babikyan D" first="Davit" last="Babikyan">Davit Babikyan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hartmann, Anne" sort="Hartmann, Anne" uniqKey="Hartmann A" first="Anne" last="Hartmann">Anne Hartmann</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Le Calvez Kelm, Florence" sort="Le Calvez Kelm, Florence" uniqKey="Le Calvez Kelm F" first="Florence" last="Le Calvez-Kelm">Florence Le Calvez-Kelm</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Lesueur, Fabienne" sort="Lesueur, Fabienne" uniqKey="Lesueur F" first="Fabienne" last="Lesueur">Fabienne Lesueur</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Byrnes, Graham B" sort="Byrnes, Graham B" uniqKey="Byrnes G" first="Graham B." last="Byrnes">Graham B. Byrnes</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Chuang, Shu Chun" sort="Chuang, Shu Chun" uniqKey="Chuang S" first="Shu-Chun" last="Chuang">Shu-Chun Chuang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Forey, Nathalie" sort="Forey, Nathalie" uniqKey="Forey N" first="Nathalie" last="Forey">Nathalie Forey</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Feuchtinger, Corinna" sort="Feuchtinger, Corinna" uniqKey="Feuchtinger C" first="Corinna" last="Feuchtinger">Corinna Feuchtinger</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Gioia, Lydie" sort="Gioia, Lydie" uniqKey="Gioia L" first="Lydie" last="Gioia">Lydie Gioia</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hall, Janet" sort="Hall, Janet" uniqKey="Hall J" first="Janet" last="Hall">Janet Hall</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Hashibe, Mia" sort="Hashibe, Mia" uniqKey="Hashibe M" first="Mia" last="Hashibe">Mia Hashibe</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Herte, Barbara" sort="Herte, Barbara" uniqKey="Herte B" first="Barbara" last="Herte">Barbara Herte</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Mckay Chopin, Sandrine" sort="Mckay Chopin, Sandrine" uniqKey="Mckay Chopin S" first="Sandrine" last="Mckay-Chopin">Sandrine Mckay-Chopin</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thomas, Alun" sort="Thomas, Alun" uniqKey="Thomas A" first="Alun" last="Thomas">Alun Thomas</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Vallee, Maxime P" sort="Vallee, Maxime P" uniqKey="Vallee M" first="Maxime P." last="Vallée">Maxime P. Vallée</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Voegele, Catherine" sort="Voegele, Catherine" uniqKey="Voegele C" first="Catherine" last="Voegele">Catherine Voegele</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Webb, Penelope M" sort="Webb, Penelope M" uniqKey="Webb P" first="Penelope M." last="Webb">Penelope M. Webb</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Whiteman, David C" sort="Whiteman, David C" uniqKey="Whiteman D" first="David C." last="Whiteman">David C. Whiteman</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Sangrajrang, Suleeporn" sort="Sangrajrang, Suleeporn" uniqKey="Sangrajrang S" first="Suleeporn" last="Sangrajrang">Suleeporn Sangrajrang</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The susceptibility gene for ataxia telangiectasia, <italic>ATM</italic>, is also an intermediate-risk breast-cancer-susceptibility gene. However, the spectrum and frequency distribution of <italic>ATM</italic> mutations that confer increased risk of breast cancer have been controversial. To assess the contribution of rare variants in this gene to risk of breast cancer, we pooled data from seven published <italic>ATM</italic> case-control mutation-screening studies, including a total of 1544 breast cancer cases and 1224 controls, with data from our own mutation screening of an additional 987 breast cancer cases and 1021 controls. Using an in silico missense-substitution analysis that provides a ranking of missense substitutions from evolutionarily most likely to least likely, we carried out analyses of protein-truncating variants, splice-junction variants, and rare missense variants. We found marginal evidence that the combination of <italic>ATM</italic> protein-truncating and splice-junction variants contribute to breast cancer risk. There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk. On the basis of subset analyses, we hypothesize that rare missense substitutions falling in and around the FAT, kinase, and FATC domains of the protein may be disproportionately responsible for that risk and that a subset of these may confer higher risk than do protein-truncating variants. We conclude that a comparison between the graded distributions of missense substitutions in cases versus controls can complement analyses of truncating variants and help identify susceptibility genes and that this approach will aid interpretation of the data emerging from new sequencing technologies.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-title>American Journal of Human Genetics</journal-title><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">19781682</article-id><article-id pub-id-type="pmc">2756555</article-id><article-id pub-id-type="publisher-id">AJHG464</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2009.08.018</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Rare, Evolutionarily Unlikely Missense Substitutions in <italic>ATM</italic> Confer Increased Risk of Breast Cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tavtigian</surname><given-names>Sean V.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">12</xref></contrib><contrib contrib-type="author"><name><surname>Oefner</surname><given-names>Peter J.</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">12</xref></contrib><contrib contrib-type="author"><name><surname>Babikyan</surname><given-names>Davit</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hartmann</surname><given-names>Anne</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Healey</surname><given-names>Sue</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Le Calvez-Kelm</surname><given-names>Florence</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Lesueur</surname><given-names>Fabienne</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Byrnes</surname><given-names>Graham B.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Chuang</surname><given-names>Shu-Chun</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Forey</surname><given-names>Nathalie</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Feuchtinger</surname><given-names>Corinna</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Gioia</surname><given-names>Lydie</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hall</surname><given-names>Janet</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Hashibe</surname><given-names>Mia</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Herte</surname><given-names>Barbara</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>McKay-Chopin</surname><given-names>Sandrine</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Alun</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Vallée</surname><given-names>Maxime P.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Voegele</surname><given-names>Catherine</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Webb</surname><given-names>Penelope M.</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Whiteman</surname><given-names>David C.</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><collab>Australian Cancer Study</collab><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><collab>Breast Cancer Family Registries (BCFR)</collab><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff9" ref-type="aff">9</xref><xref rid="aff10" ref-type="aff">10</xref><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><collab>Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab)</collab><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Sangrajrang</surname><given-names>Suleeporn</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Hopper</surname><given-names>John L.</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Southey</surname><given-names>Melissa C.</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Andrulis</surname><given-names>Irene L.</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>John</surname><given-names>Esther M.</given-names></name><xref rid="aff10" ref-type="aff">10</xref><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Chenevix-Trench</surname><given-names>Georgia</given-names></name><email>georgia.trench@qimr.edu.au</email><xref rid="aff3" ref-type="aff">3</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><addr-line><sup>1</sup>International Agency for Research on Cancer, 69372 Lyon, France</addr-line></aff><aff id="aff2"><addr-line><sup>2</sup>Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany</addr-line></aff><aff id="aff3"><addr-line><sup>3</sup>Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia</addr-line></aff><aff id="aff4"><addr-line><sup>4</sup>Institut Curie - Recherche; INSERM U612; 91405 Orsay, France</addr-line></aff><aff id="aff5"><addr-line><sup>5</sup>Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA</addr-line></aff><aff id="aff6"><addr-line><sup>6</sup>Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia</addr-line></aff><aff id="aff7"><addr-line><sup>7</sup>Research Division, National Cancer Institute, Bangkok 10400, Thailand</addr-line></aff><aff id="aff8"><addr-line><sup>8</sup>Centre for MEGA Epidemiology, University of Melbourne, Carlton, VIC 3010, Australia</addr-line></aff><aff id="aff9"><addr-line><sup>9</sup>Cancer Care Ontario, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5 Canada</addr-line></aff><aff id="aff10"><addr-line><sup>10</sup>Northern California Cancer Center, Fremont, CA 94538, USA</addr-line></aff><aff id="aff11"><addr-line><sup>11</sup>Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305-5405, USA</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>georgia.trench@qimr.edu.au</email></corresp><fn id="fn1"><label>12</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>09</day><month>10</month><year>2009</year></pub-date><volume>85</volume><issue>4</issue><fpage>427</fpage><lpage>446</lpage><history><date date-type="received"><day>9</day><month>5</month><year>2009</year></date><date date-type="rev-recd"><day>2</day><month>7</month><year>2009</year></date><date date-type="accepted"><day>28</day><month>8</month><year>2009</year></date></history><permissions><copyright-statement>© 2009 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved..</copyright-statement><copyright-year>2009</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder><license><p>This document may be redistributed and reused, subject to <ext-link ext-link-type="uri" xlink:href="http://www.elsevier.com/wps/find/authorsview.authors/supplementalterms1.0">certain conditions</ext-link>.</p></license></permissions><abstract><p>The susceptibility gene for ataxia telangiectasia, <italic>ATM</italic>, is also an intermediate-risk breast-cancer-susceptibility gene. However, the spectrum and frequency distribution of <italic>ATM</italic> mutations that confer increased risk of breast cancer have been controversial. To assess the contribution of rare variants in this gene to risk of breast cancer, we pooled data from seven published <italic>ATM</italic> case-control mutation-screening studies, including a total of 1544 breast cancer cases and 1224 controls, with data from our own mutation screening of an additional 987 breast cancer cases and 1021 controls. Using an in silico missense-substitution analysis that provides a ranking of missense substitutions from evolutionarily most likely to least likely, we carried out analyses of protein-truncating variants, splice-junction variants, and rare missense variants. We found marginal evidence that the combination of <italic>ATM</italic> protein-truncating and splice-junction variants contribute to breast cancer risk. There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk. On the basis of subset analyses, we hypothesize that rare missense substitutions falling in and around the FAT, kinase, and FATC domains of the protein may be disproportionately responsible for that risk and that a subset of these may confer higher risk than do protein-truncating variants. We conclude that a comparison between the graded distributions of missense substitutions in cases versus controls can complement analyses of truncating variants and help identify susceptibility genes and that this approach will aid interpretation of the data emerging from new sequencing technologies.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Domain Organization of <italic>ATM</italic> and Case-Control Distribution of Missense Substitutions by Align-GVGD Grade</p><p>(A) Distribution of rare C0, C15, and C25 missense substitutions superimposed on the domain organization of <italic>ATM</italic>. Note that if two distinct substitutions are located very close to each other, we shifted one by a few amino acids so that the presence of both is visible.</p><p>(B) Distribution of rare C35, C45, C55, and C65 missense substitutions. We labeled the C65 missense substitutions falling from Ile1960 until the end of the protein.</p><p>(C) Sequence-conservation profile across <italic>ATM</italic>. The fraction of invariant positions (GV = 0) across the ATM protein multiple sequence alignment was measured in a 20-residue sliding window. Results were smoothed by inclusion of (1/e × sequence invariance) in the ten residues preceding and trailing each window, then normalized. The analysis was repeated with the use of a conservation criterion of only conservative substitution or invariance (GV < 65) across species.</p><p>Citations correspond to Fernandes et al.,<xref rid="bib91" ref-type="bibr"><sup>91</sup></xref> Lim et al.,<xref rid="bib92" ref-type="bibr"><sup>92</sup></xref> Shafman et al.,<xref rid="bib93" ref-type="bibr"><sup>93</sup></xref> and Khanna et al.<xref rid="bib94" ref-type="bibr"><sup>94</sup></xref></p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p><italic>ATM</italic> Missense Substitutions Graded C65 by Align-GVGD and/or Scored 0.00 by SIFT</p><p>Substitution designations are given over their respective positions in the <italic>ATM</italic> alignment. Amino acid symbols are colored to represent standard Dayhoff groupings.</p><p>(A) Substitutions graded as C65; although most of these were scored 0.00 by SIFT, note that the last two fall at slightly variable positions and were scored as 0.01 by SIFT. “†” indicates that p.S2855R is the first substitution of the two-amino-acid substitution p.SV2855_2856RI.</p><p>(B) Substitutions scored as 0.00 by SIFT but as C55 or lower by Align-GVGD.</p></caption><graphic xlink:href="gr2"></graphic></fig><table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>ATM and Ortholog Sequence Accession Numbers and Cross-Species Sequence Comparisons</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2"><bold>Organism</bold></th><th rowspan="2"><bold>Accession Number</bold></th><th rowspan="2"><bold>GenBank cDNA (%)</bold><xref rid="tblfn1" ref-type="table-fn">a</xref></th><th rowspan="2"><bold>Gene Model (%)</bold><xref rid="tblfn2" ref-type="table-fn">b</xref></th><th rowspan="2"><bold>Confirmation by Sequencing (%)</bold><xref rid="tblfn3" ref-type="table-fn">c</xref></th><th colspan="8"><bold>Pairwise Amino Acid Sequence Identity (%)</bold><xref rid="tblfn4" ref-type="table-fn">d</xref><hr></hr></th></tr><tr><th><bold>Hs</bold></th><th><bold>Mm</bold></th><th><bold>Ss</bold></th><th><bold>Md</bold></th><th><bold>Gg</bold></th><th><bold>Xl</bold></th><th><bold>Dr</bold></th><th><bold>Bf</bold></th></tr></thead><tbody><tr><td><italic>Homo sapiens</italic></td><td>AAB65827.1</td><td align="char">100.0</td><td align="char">0.0</td><td align="char">0.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><italic>Mus musculus</italic></td><td>NP_031525.2</td><td align="char">100.0</td><td align="char">0.0</td><td align="char">0.0</td><td align="char">84.1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><italic>Sus scrofa</italic></td><td>AAT01608.1</td><td align="char">100.0</td><td align="char">0.0</td><td align="char">0.0</td><td align="char">88.4</td><td align="char">82.6</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><italic>Monodelphis domestica</italic></td><td>ACG68567.1, ACG68568.1</td><td align="char">0.0</td><td align="char">88.7<xref rid="tblfn5" ref-type="table-fn">e</xref></td><td align="char">11.3</td><td align="char">80.7</td><td align="char">76.2</td><td align="char">78.9</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><italic>Gallus gallus</italic></td><td>XP_417160.2</td><td align="char">0.0</td><td align="char">99.7 + 0.3<xref rid="tblfn6" ref-type="table-fn">f</xref></td><td align="char">0.0</td><td align="char">69.5</td><td align="char">66.7</td><td align="char">68.5</td><td align="char">70.5</td><td></td><td></td><td></td><td></td></tr><tr><td><italic>Xenopus laevis</italic></td><td>AAT72929.1</td><td align="char">100.0</td><td></td><td align="char">0.0</td><td align="char">64.5</td><td align="char">62.7</td><td align="char">63.6</td><td align="char">65.9</td><td align="char">64.6</td><td></td><td></td><td></td></tr><tr><td><italic>Danio rerio</italic></td><td>BAD91491.1 ACJ03990.1</td><td align="char">89.4</td><td align="char">0.3<xref rid="tblfn6" ref-type="table-fn">f</xref></td><td align="char">10.6</td><td align="char">54.2</td><td align="char">53.2</td><td align="char">53.4</td><td align="char">53.9</td><td align="char">53.4</td><td align="char">54.3</td><td></td><td></td></tr><tr><td><italic>Branchiostoma floridae</italic></td><td>ACG68443.1</td><td align="char">0.0</td><td align="char">0.0</td><td align="char">100.0</td><td align="char">36.9</td><td align="char">36.3</td><td align="char">36.6</td><td align="char">36.5</td><td align="char">37.2</td><td align="char">37.7</td><td align="char">36.6</td><td></td></tr><tr><td><italic>Strongylocentrotus purpuratus</italic></td><td>ABY60856.1</td><td align="char">0.0</td><td align="char">0.0</td><td align="char">100.0</td><td align="char">34.8</td><td align="char">34.6</td><td align="char">34.7</td><td align="char">35.0</td><td align="char">35.9</td><td align="char">35.3</td><td align="char">35.2</td><td align="char">38.1</td></tr></tbody></table><table-wrap-foot><fn id="tblfn1"><label>a</label><p>This is the percentage of the ATM amino acid sequence used in our alignment that was obtained directly from a GenBank cDNA entry.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn2"><label>b</label><p>This is the percentage of the ATM amino acid sequence used in our alignment that was obtained by gene prediction.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn3"><label>c</label><p>This is the percentage of the ATM amino acid sequence used in our alignment that we confirmed by RT-PCR and sequencing from model-organism cDNA.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn4"><label>d</label><p>The two-letter species-name abbreviations are as follows: Hs, <italic>Homo sapiens</italic>; Mm, <italic>Mus musculus</italic>; Ss, <italic>Sus scrofa</italic>; Md, <italic>Monodelphis domestica</italic>; Gg, <italic>Gallus gallus</italic>; Xl, <italic>Xenopus laevis</italic>; Dr, <italic>Danio rerio</italic>; Bf, <italic>Branchiostoma floridae</italic>. Note that the cross-comparison does not require a column for <italic>Strongylocentrotus purpuratus</italic>.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn5"><label>e</label><p>Gene model built at IARC, but similar to Ensemble prediction ENSMODP00000018290.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn6"><label>f</label><p>Corrections to apparent anomalies in a gene-model prediction obtained from GenBank, made by reference to the genomic sequence.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="tbl2"><label>Table 2</label><caption><p>Distribution of Subjects from Studies 8 and 9 by Center and Age</p></caption><table frame="hsides" rules="groups"><thead><tr><th><bold>Study Designation (Subject Source)</bold></th><th><bold>Mutation-Screening Site</bold></th><th><bold>Cases</bold></th><th><bold>Average</bold></th><th><bold>(Range)</bold></th><th><bold>Controls</bold></th><th><bold>Average</bold></th><th><bold>(Range)</bold></th></tr></thead><tbody><tr><td>8 (kConFab)</td><td>Regensburg</td><td align="char">364</td><td align="char">44.3</td><td>(21–71)</td><td>–</td><td></td><td></td></tr><tr><td>8 (ACS)</td><td>Regensburg</td><td>–</td><td></td><td></td><td align="char">362</td><td align="char">58.0</td><td>(19–80)</td></tr><tr><td>9a (kConFab)<xref rid="tblfn7" ref-type="table-fn">a</xref></td><td>IARC</td><td align="char">21</td><td align="char">40.0</td><td>(28–48)</td><td>–</td><td></td><td></td></tr><tr><td>9a (Melbourne CFR)<xref rid="tblfn7 tblfn8" ref-type="table-fn">a,b</xref></td><td>IARC</td><td align="char">260</td><td align="char">34.7</td><td>(23–49)</td><td align="char">262</td><td align="char">36.9</td><td>(22–45)</td></tr><tr><td>9a (Ontario CFR)<xref rid="tblfn7" ref-type="table-fn">a</xref></td><td>IARC</td><td align="char">112</td><td align="char">37.4</td><td>(25–48)</td><td align="char">153</td><td align="char">40.0</td><td>(25–50)</td></tr><tr><td>9b (No. Cal CFR)<xref rid="tblfn9" ref-type="table-fn">c</xref></td><td>IARC</td><td align="char">90</td><td align="char">35.6</td><td>(23–49)</td><td align="char">42</td><td align="char">43.9</td><td>(31–52)</td></tr><tr><td>9b (Thai NCI)<xref rid="tblfn9" ref-type="table-fn">c</xref></td><td>IARC</td><td align="char">140</td><td align="char">35.3</td><td>(17–47)</td><td align="char">202</td><td align="char">35.0</td><td>(18–46)</td></tr></tbody></table><table-wrap-foot><fn id="tblfn7"><label>a</label><p>Except for three subjects noted immediately below (footnote b), all of the subjects in these studies were of recent European ancestry.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn8"><label>b</label><p>The Melbourne CFR sample series included one case and two controls of recent East Asian ancestry. In logistic regressions of the bona fide case-control studies, these were considered as part of study 9b.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn9"><label>c</label><p>All of the subjects in these studies were of recent East Asian ancestry.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="tbl3"><label>Table 3</label><caption><p>Number of Cases and/or Controls by Study</p></caption><table frame="hsides" rules="groups"><thead><tr><th><bold>Study Designation</bold></th><th><bold>Study</bold></th><th><bold>Cases</bold></th><th><bold>Controls</bold></th><th><bold>Total</bold></th></tr></thead><tbody><tr><td>1</td><td>Fitzgerald et al. 1997<xref rid="bib48" ref-type="bibr"><sup>48</sup></xref></td><td align="char">401</td><td align="char">202</td><td align="char">603</td></tr><tr><td>2</td><td>Teraoka et al. 2001<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref></td><td align="char">142</td><td align="char">81</td><td align="char">223</td></tr><tr><td>3</td><td>Sommer et al. 2003<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref></td><td align="char">90</td><td align="char">90</td><td align="char">180</td></tr><tr><td>4</td><td>Thorstenson et al. 2003<xref rid="bib12" ref-type="bibr"><sup>12</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">270</td><td align="char">52</td><td align="char">322</td></tr><tr><td>5</td><td>Renwick et al. 2006<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">443</td><td align="char">521</td><td align="char">964</td></tr><tr><td>6</td><td>Hirsch et al. 2008<xref rid="bib49" ref-type="bibr"><sup>49</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">37</td><td align="char">95</td><td align="char">132</td></tr><tr><td>7</td><td>Soukupova et al. 2008<xref rid="bib50" ref-type="bibr"><sup>50</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">161</td><td align="char">183</td><td align="char">344</td></tr><tr><td>8</td><td>This study, kConFab/Regensburg<xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">364</td><td align="char">362</td><td align="char">726</td></tr><tr><td>9a</td><td>This study, IARC- European</td><td align="char">392</td><td align="char">414</td><td align="char">806</td></tr><tr><td>9b</td><td>This study, IARC- East Asian</td><td align="char">231</td><td align="char">245</td><td align="char">476</td></tr><tr><td colspan="5"><hr></hr></td></tr><tr><td colspan="2"><bold>Bona Fide Case-Control Subtotal</bold></td><td><bold>2531</bold></td><td><bold>2245</bold></td><td><bold>4776</bold></td></tr><tr><td colspan="5"><hr></hr></td></tr><tr><td>10</td><td>Vorechovsky et al. 1996<xref rid="bib51" ref-type="bibr"><sup>51</sup></xref></td><td align="char">38</td><td align="char">0</td><td align="char">38</td></tr><tr><td>11</td><td>Chen et al. 1998<xref rid="bib52" ref-type="bibr"><sup>52</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">100</td><td align="char">0</td><td align="char">100</td></tr><tr><td>12</td><td>Bebb et al. 1999<xref rid="bib53" ref-type="bibr"><sup>53</sup></xref></td><td align="char">47</td><td align="char">0</td><td align="char">47</td></tr><tr><td>13</td><td>Izatt et al. 1999<xref rid="bib5" ref-type="bibr"><sup>5</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">100</td><td align="char">0</td><td align="char">100</td></tr><tr><td>14</td><td>Dörk et al. 2001<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref></td><td align="char">192</td><td align="char">0</td><td align="char">192</td></tr><tr><td>15</td><td>Drumea et al. 2000<xref rid="bib54" ref-type="bibr"><sup>54</sup></xref></td><td align="char">37</td><td align="char">0</td><td align="char">37</td></tr><tr><td>16</td><td>Atencio et al. 2001<xref rid="bib8" ref-type="bibr"><sup>8</sup></xref></td><td align="char">52</td><td align="char">0</td><td align="char">52</td></tr><tr><td>17</td><td>Maillet et al. 2002<xref rid="bib9" ref-type="bibr"><sup>9</sup></xref></td><td align="char">94</td><td align="char">0</td><td align="char">94</td></tr><tr><td>18</td><td>Angele et al. 2003<xref rid="bib11" ref-type="bibr"><sup>11</sup></xref></td><td align="char">51</td><td align="char">0</td><td align="char">51</td></tr><tr><td>19</td><td>Buchholz et al. 2004<xref rid="bib13" ref-type="bibr"><sup>13</sup></xref></td><td align="char">91</td><td align="char">0</td><td align="char">91</td></tr><tr><td>20</td><td>Ho et al. 2007<xref rid="bib57" ref-type="bibr"><sup>57</sup></xref></td><td align="char">131</td><td align="char">0</td><td align="char">131</td></tr><tr><td>21</td><td>Broeks et al. 2008<xref rid="bib58" ref-type="bibr"><sup>58</sup></xref></td><td align="char">437</td><td align="char">0</td><td align="char">437</td></tr><tr><td>22</td><td>Brunet et al. 2008<xref rid="bib59" ref-type="bibr"><sup>59</sup></xref></td><td align="char">43</td><td align="char">0</td><td align="char">43</td></tr><tr><td>23</td><td>Tapia et al. 2008<xref rid="bib60" ref-type="bibr"><sup>60</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">42</td><td align="char">0</td><td align="char">42</td></tr><tr><td>24</td><td>Gonzalez-Hormazabal et al. 2008<xref rid="bib61" ref-type="bibr"><sup>61</sup></xref><xref rid="tblfn10" ref-type="table-fn">a</xref></td><td align="char">126</td><td align="char">0</td><td align="char">126</td></tr><tr><td>25</td><td>Thorstenson et al. 2001<xref rid="bib55" ref-type="bibr"><sup>55</sup></xref><xref rid="tblfn11" ref-type="table-fn">b</xref></td><td align="char">0</td><td align="char">64</td><td align="char">64</td></tr><tr><td>26</td><td>NIEHS<xref rid="bib56" ref-type="bibr"><sup>56</sup></xref></td><td align="char">0</td><td align="char">90</td><td align="char">90</td></tr><tr><td colspan="5"><hr></hr></td></tr><tr><td colspan="2"><bold>All Studies Total</bold></td><td><bold>4112</bold></td><td><bold>2399</bold></td><td><bold>6511</bold></td></tr></tbody></table><table-wrap-foot><fn id="tblfn10"><label>a</label><p>Studies in which more than 50% of the cases had a family history of breast cancer.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn11"><label>b</label><p>We have used only 64 of the 93 controls described in Thorstenson et al (2001).<xref rid="bib55" ref-type="bibr"><sup>55</sup></xref> The remaining 29 controls were of Middle Eastern, South Asian, or Oceanian descent, and there were essentially no breast cancer cases from these groups in the published studies.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="tbl4"><label>Table 4</label><caption><p>Analysis of Truncating and Spliceogenic Splice-Junction Variants</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th><bold>Cases</bold></th><th><bold>Controls</bold></th><th><bold>Crude OR [95% CI]</bold></th><th><bold>Adjusted OR [95% CI]</bold><xref rid="tblfn13" ref-type="table-fn">a</xref></th></tr></thead><tbody><tr><td colspan="5"><bold>Bona Fide Case-Control Studies</bold><xref rid="tblfn14" ref-type="table-fn">b</xref></td></tr><tr><td colspan="5"><hr></hr></td></tr><tr><td>Noncarrier</td><td>2505</td><td>2235</td><td>ref</td><td>ref</td></tr><tr><td>T+SJ</td><td>26</td><td>10</td><td>2.33 [1.12–4.84]</td><td>2.32 [1.12–4.83]</td></tr><tr><td colspan="5"><hr></hr></td></tr><tr><td colspan="5"><bold>All Studies</bold></td></tr><tr><td colspan="5"><hr></hr></td></tr><tr><td>Noncarrier</td><td>4076</td><td>2389</td><td>ref</td><td>ref</td></tr><tr><td>T+SJ</td><td>36</td><td>10</td><td>2.10 [1.04–4.24]</td><td>2.08 [1.03–4.21]</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations are as follows: OR, odds ratio; CI, confidence interval;ref, reference category (OR = 1.0).</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn13"><label>a</label><p>The OR from the analysis of the bona fide case-control studies was adjusted for study. The OR from the analysis of all studies was adjusted for ethnicity and sensitivity of the mutation-screening method employed.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn14"><label>b</label><p>The bona fide case-control studies included both mutation-screened cases and mutation-screened controls that met our ascertainment criteria.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="tbl5"><label>Table 5</label><caption><p>Whole-Gene Analysis of Rare Missense Substitutions, Unstratified or Stratified by Frequency</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="5"><bold>Bona Fide Case-Control Studies</bold><hr></hr></th><th colspan="4"><bold>All Studies</bold><hr></hr></th></tr><tr><th></th><th></th><th></th><th colspan="2"><bold>Test of Significance: OR [95% CI], p Value, or Regression Coefficient [95% CI]</bold><hr></hr></th><th></th><th></th><th colspan="2"><bold>Test of Significance: OR [95% CI], p Value, or regression coefficient [95% CI]</bold><hr></hr></th></tr><tr><th></th><th><bold>Cases</bold></th><th><bold>Controls</bold></th><th><bold>Crude</bold></th><th><bold>Adjusted</bold><xref rid="tblfn16" ref-type="table-fn">a</xref></th><th><bold>Cases</bold></th><th><bold>Controls</bold></th><th><bold>Crude</bold></th><th><bold>Adjusted</bold><xref rid="tblfn17" ref-type="table-fn">b</xref></th></tr></thead><tbody><tr><td>Noncarrier<xref rid="tblfn18" ref-type="table-fn">c</xref></td><td>1788</td><td>1717</td><td>ref</td><td>ref</td><td>3125</td><td>1850</td><td>ref</td><td>ref</td></tr><tr><td>Any rMS<xref rid="tblfn32" ref-type="table-fn">d</xref></td><td>160</td><td>135</td><td>1.14 [0.90–1.44]</td><td>1.14 [0.90–1.44]</td><td>248</td><td>156</td><td>0.94 [0.76–1.16]</td><td>1.06 [0.86–1.31]</td></tr><tr><td colspan="9"><hr></hr></td></tr><tr><td colspan="9"><bold>Stratification by Frequency</bold></td></tr><tr><td colspan="9"><hr></hr></td></tr><tr><td>rMSs observed 1×–3×</td><td>69</td><td>63</td><td>1.05 [0.74–1.49]</td><td>1.05 [0.74–1.49]</td><td>113</td><td>79</td><td>0.86 [0.64–1.15]</td><td>0.89 [0.66–1.20]</td></tr><tr><td>rMSs observed 4×–10×</td><td>55</td><td>43</td><td>1.23 [0.82–1.84]</td><td>1.23 [0.82–1.84]</td><td>74</td><td>46</td><td>0.95 [0.66–1.38]</td><td>1.01 [0.69–1.47]</td></tr><tr><td>rMSs observed 11×–30×</td><td>20</td><td>21</td><td>0.91 [0.49–1.69]</td><td>0.91 [0.49–1.69]</td><td>37</td><td>23</td><td>0.95 [0.56–1.61]</td><td>0.96 [0.57–1.62]</td></tr><tr><td>rMSs observed > 30×</td><td>23</td><td>12</td><td>1.84 [0.91–3.71]</td><td>1.84 [0.91–3.71]</td><td>33</td><td>12</td><td>1.63 [0.84–3.16]</td><td>1.59 [0.82–3.10]</td></tr><tr><td>Test of heterogeneity</td><td></td><td></td><td>p = 0.39</td><td>p = 0.39</td><td></td><td></td><td>p = 0.49</td><td>p = 0.62</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations are as follows: OR, odds ratio; CI, confidence interval; ref, reference category (OR = 1.0).</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn16"><label>a</label><p>Use of unconditional logistic regression with an adjustment for study.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn17"><label>b</label><p>Use of unconditional logistic regression with adjustments for ethnicity and sensitivity of mutation-screening method employed.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn18"><label>c</label><p>Carriers of T+SJ variants are excluded.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn32"><label>d</label><p>Individuals in studies 8 or 9 who carried two (10) or three (1) rare variants are coded according to the highest grade of rare variant that they carried. The co-occurrences are detailed in the footnotes to <xref rid="app2" ref-type="sec">Table S2</xref>.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="tbl6"><label>Table 6</label><caption><p>Analyses of Rare Missense Substitutions, Stratified by Align-GVGD Grade</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="5"><bold>Bona Fide Case-Control Studies</bold><hr></hr></th><th colspan="4"><bold>All Studies</bold><hr></hr></th></tr><tr><th></th><th></th><th></th><th colspan="2"><bold>Test of Significance: ln(OR) [95%CI] or Regression Coefficient [95%CI]</bold><hr></hr></th><th></th><th></th><th colspan="2"><bold>Test of Significance: ln(OR) [95%CI] or Regression Coefficient [95%CI]</bold><hr></hr></th></tr><tr><th></th><th><bold>Cases</bold></th><th><bold>Controls</bold></th><th><bold>Crude</bold></th><th><bold>Adjusted</bold><xref rid="tblfn20" ref-type="table-fn">a</xref></th><th><bold>Cases</bold></th><th><bold>Controls</bold></th><th><bold>Crude</bold></th><th><bold>Adjusted</bold><xref rid="tblfn21" ref-type="table-fn">b</xref></th></tr></thead><tbody><tr><td colspan="9"><bold>Whole-Gene Analysis; Stratification by Align-GVGD Grade</bold></td></tr><tr><td colspan="9"><hr></hr></td></tr><tr><td>Noncarrier<xref rid="tblfn22" ref-type="table-fn">c</xref></td><td>1788</td><td>1717</td><td>ref</td><td>ref</td><td>3125</td><td>1850</td><td>ref</td><td>ref</td></tr><tr><td>C0<xref rid="tblfn23" ref-type="table-fn">d</xref></td><td>86</td><td>89</td><td>−0.07 [−0.38–0.23]</td><td>−0.08 [−0.38–0.23]</td><td>140</td><td>107</td><td>−0.26 [−0.51–0.00]</td><td>−0.09 [−0.36–0.18]</td></tr><tr><td>C15<xref rid="tblfn23" ref-type="table-fn">d</xref></td><td>34</td><td>29</td><td>0.12 [−0.38–0.62]</td><td>0.12 [−0.38–0.62]</td><td>46</td><td>30</td><td>−0.10 [−0.56–0.37]</td><td>−0.07 [−0.54–0.39]</td></tr><tr><td>C25<xref rid="tblfn23" ref-type="table-fn">d</xref></td><td>9</td><td>7</td><td>0.21 [−0.78–1.20]</td><td>0.21 [−0.78–1.20]</td><td>14</td><td>8</td><td>0.04 [−0.84–0.91]</td><td>0.011 [−0.76–0.98]</td></tr><tr><td>C35</td><td>0</td><td>1</td><td>-</td><td>-</td><td>0</td><td>1</td><td>-</td><td>-</td></tr><tr><td>C45</td><td>1</td><td>0</td><td>-</td><td>-</td><td>1</td><td>0</td><td>-</td><td>-</td></tr><tr><td>C55</td><td>5</td><td>4</td><td>0.18 [−1.13–1.50]</td><td>0.18 [-1.13–1.50]</td><td>10</td><td>5</td><td>0.17 [−0.91–1.24]</td><td>0.19 [−0.89–1.27]</td></tr><tr><td>C65</td><td>25</td><td>5</td><td><bold>1.57 [0.61</bold>–<bold>2.53]</bold></td><td><bold>1.57 [0.61</bold>–<bold>2.53]</bold></td><td>37</td><td>5</td><td><bold>1.48 [0.54</bold>–<bold>2.41]</bold></td><td><bold>1.51 [0.58</bold>–<bold>2.45]</bold></td></tr><tr><td>ln(OR) regression coefficients [95% CI]<xref rid="tblfn24" ref-type="table-fn">e</xref></td><td></td><td></td><td><bold>0.13 [0.044</bold>–<bold>0.22]</bold></td><td><bold>0.13 [0.044</bold>–<bold>0.22]</bold></td><td></td><td></td><td><bold>0.085 [0.0077</bold>–<bold>0.16]</bold></td><td><bold>0.11 [0.026</bold>–<bold>0.18]</bold></td></tr><tr><td colspan="9"><hr></hr></td></tr><tr><td colspan="9"><bold>Analysis from Position Ile1960 to the End of the Protein; Stratification by Align-GVGD Grade</bold></td></tr><tr><td colspan="9"><hr></hr></td></tr><tr><td>Noncarrier<xref rid="tblfn22" ref-type="table-fn">c</xref></td><td>1788</td><td>1717</td><td>ref</td><td>ref</td><td>3125</td><td>1850</td><td>ref</td><td>ref</td></tr><tr><td>C0</td><td>22</td><td>21</td><td>0.01 [−0.60–0.61]</td><td>0.01 [−0.59–0.61]</td><td>35</td><td>25</td><td>−0.19 [−0.70–0.33]</td><td>−0.08 [−0.60–0.44]</td></tr><tr><td>C15</td><td>3</td><td>1</td><td>1.06 [−1.21–3.32]</td><td>1.06 [−1.21–3.32]</td><td>4</td><td>1</td><td>0.86 [−1.33–3.05]</td><td>0.91 [−1.28–3.10]</td></tr><tr><td>C25</td><td>2</td><td>2</td><td>−0.04 [−2.00–1.92]</td><td>−0.04 [−2.00–1.92]</td><td>3</td><td>2</td><td>−0.12 [−1.91–1.67]</td><td>−0.07 [−1.86–1.72]</td></tr><tr><td>C35</td><td>0</td><td>0</td><td>-</td><td>-</td><td>0</td><td>0</td><td>-</td><td>-</td></tr><tr><td>C45</td><td>1</td><td>0</td><td>-</td><td>-</td><td>1</td><td>0</td><td>-</td><td>-</td></tr><tr><td>C55</td><td>4</td><td>1</td><td>1.35 [−0.85–3.54]</td><td>1.34 [−0.85–3.54]</td><td>7</td><td>2</td><td>0.73 [−0.84–2.30]</td><td>0.76 [−0.82–2.33]</td></tr><tr><td>C65</td><td>18</td><td>1</td><td><bold>2.85 [0.84</bold>–<bold>4.86]</bold></td><td><bold>2.85 [0.83</bold>–<bold>4.86]</bold></td><td>24</td><td>1</td><td><bold>2.65 [0.65</bold>–<bold>4.66]</bold></td><td><bold>2.65 [0.65</bold>–<bold>4.65]</bold></td></tr><tr><td>ln(OR) regression coefficients [95% CI]<xref rid="tblfn24" ref-type="table-fn">e</xref></td><td></td><td></td><td><bold>0.31 [0.14</bold>–<bold>0.48]</bold></td><td><bold>0.31 [0.14</bold>–<bold>0.48]</bold></td><td></td><td></td><td><bold>0.23 [0.083</bold>–<bold>0.37]</bold></td><td><bold>0.24 [0.091-0.39]</bold></td></tr><tr><td colspan="9"><hr></hr></td></tr><tr><td colspan="9"><bold>Analysis Limited to the Restrictively Defined FAT, Kinase, and FATC Domains; Stratification by Align-GVGD Grade</bold></td></tr><tr><td colspan="9"><hr></hr></td></tr><tr><td>Noncarrier<xref rid="tblfn22" ref-type="table-fn">c</xref></td><td>1788</td><td>1717</td><td>ref</td><td>ref</td><td>3125</td><td>1850</td><td>ref</td><td>ref</td></tr><tr><td>C0</td><td>11</td><td>10</td><td>0.05 [−0.80–0.91]</td><td>0.06 [−0.80–0.91]</td><td>20</td><td>12</td><td>−0.01 [−0.73–0.70]</td><td>0.09 [−0.64–0.81]</td></tr><tr><td>C15</td><td>0</td><td>0</td><td>-</td><td>-</td><td>0</td><td>0</td><td>-</td><td>-</td></tr><tr><td>C25</td><td>0</td><td>0</td><td>-</td><td>-</td><td>0</td><td>0</td><td>-</td><td>-</td></tr><tr><td>C35</td><td>0</td><td>0</td><td>-</td><td>-</td><td>0</td><td>0</td><td>-</td><td>-</td></tr><tr><td>C45</td><td>0</td><td>0</td><td>-</td><td>-</td><td>0</td><td>0</td><td>-</td><td>-</td></tr><tr><td>C55</td><td>3</td><td>1</td><td>1.06 [−1.21–3.32]</td><td>1.05 [−1.21–3.32]</td><td>6</td><td>1</td><td>1.27 [−0.85–3.39]</td><td>1.28 [−0.84–3.40]</td></tr><tr><td>C65</td><td>17</td><td>0</td><td><bold>Infinite [1.45</bold><xref rid="tblfn25" ref-type="table-fn">f</xref>–<bold>∞]</bold></td><td><xref rid="tblfn26" ref-type="table-fn">g</xref></td><td>22</td><td>0</td><td><bold>Infinite [3.39</bold><xref rid="tblfn24" ref-type="table-fn">e</xref> –<bold>∞]</bold></td><td><xref rid="tblfn26" ref-type="table-fn">g</xref></td></tr><tr><td>ln(OR) regression coefficients [95% CI]<xref rid="tblfn24" ref-type="table-fn">e</xref></td><td></td><td></td><td><bold>0.41 [0.15</bold>–<bold>0.68]</bold></td><td><bold>0.41 [0.15</bold>–<bold>0.68]</bold></td><td></td><td></td><td><bold>0.38 [0.13</bold>–<bold>0.63]</bold></td><td><bold>0.40 [0.13</bold>–<bold>0.64]</bold></td></tr></tbody></table><table-wrap-foot><fn><p>Bold font is used to indicate point estimates or trend coefficients with p < 0.05. Abbreviations are as follows: OR, odds ratio; CI, confidence interval; ref, reference category (OR = 1.0).</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn20"><label>a</label><p>Using unconditional logistic regression with an adjustment for study.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn21"><label>b</label><p>Using unconditional logistic regression with adjustments for ethnicity and sensitivity of mutation-screening method employed.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn22"><label>c</label><p>Carriers of T+SJ variants are excluded. Carriers of rMSs that fall outside of the specified region (and no rMS occurring in the region) are excluded.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn23"><label>d</label><p>Individuals in studies 8 or 9 who carried two (8) or three (1) rare variants are coded according to the highest grade of rare variant that they carried. Categories that lose a subject(s) are marked “<sup>d</sup>.” The co-occurrences are detailed in the footnotes to <xref rid="app2" ref-type="sec">Table S2</xref>.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn24"><label>e</label><p>From a standard logistic regression of form ln(OR) = a + b(x) in which a = 0, b is the logistic regression OR trend coefficient, and x is, in this case, missense-substitution grade. Note that the regression coefficient is significant if its 95% CI excludes 0.00.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn25"><label>f</label><p>Lower boundary of this 95% CI was obtained from Fisher's exact test.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn26"><label>g</label><p>Could not be calculated with the use of the adjusted model.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="tbl7"><label>Table 7</label><caption><p>Tests of Sensitivity</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="3"><bold>Test Scenario A</bold><hr></hr></th></tr><tr><th></th><th><bold>OR [CI]</bold></th><th><bold>p-Logistic</bold></th></tr></thead><tbody><tr><td>All case-control studies</td><td>2.32 [1.12–4.83]</td><td>0.024</td></tr><tr><td>Excluding study 1 (Fitzgerald et al.<xref rid="bib48" ref-type="bibr"><sup>48</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>2.93 [1.31–6.55]</td><td>0.009</td></tr><tr><td>Excluding study 2 (Teraoka et al.<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref>)</td><td>2.41 [1.16–5.02]</td><td>0.019</td></tr><tr><td>Excluding study 3 (Sommer et al.<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref>)</td><td>2.31 [1.11–4.80]</td><td>0.025</td></tr><tr><td>Excluding study 4 (Thorstenson et al.)</td><td>2.14 [1.01–4.53]</td><td>0.047</td></tr><tr><td>Excluding study 5 (Renwick et al.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref>)</td><td><bold>1.78 [0.77–4.15]</bold></td><td><bold>0.178</bold></td></tr><tr><td>Excluding study 6 (Hirsch et al.<xref rid="bib49" ref-type="bibr"><sup>49</sup></xref>)</td><td>2.53 [1.18–5.40]</td><td>0.017</td></tr><tr><td>Excluding study 7 (Soukupova et al.<xref rid="bib50" ref-type="bibr"><sup>50</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td><bold>2.01 [0.95–4.24]</bold></td><td><bold>0.066</bold></td></tr><tr><td>Excluding study 8 (kConFab/Regensburg)</td><td><bold>2.04 [0.93–4.46]</bold></td><td><bold>0.076</bold></td></tr><tr><td>Excluding study 9a (IARC, European)</td><td>2.61 [1.17–5.82]</td><td>0.019</td></tr><tr><td>Excluding study 9b (IARC, East Asian)</td><td>2.74 [1.23–6.10]</td><td>0.041</td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td colspan="3"><bold>Test Scenario B</bold></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td></td><td><bold>Coefficient</bold><xref rid="tblfn28" ref-type="table-fn">b</xref></td><td><bold>p-Trend</bold></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td>All case-control studies</td><td>0.1318</td><td>0.00350</td></tr><tr><td>Excluding study 1 (Fitzgerald et al.<xref rid="bib48" ref-type="bibr"><sup>48</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>NA</td><td>NA</td></tr><tr><td>Excluding study 2 (Teraoka et al.<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref>)</td><td>0.1237</td><td>0.00720</td></tr><tr><td>Excluding study 3 (Sommer et al.<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref>)</td><td>0.1288</td><td>0.00490</td></tr><tr><td>Excluding study 4 (Thorstenson et al.)</td><td>0.1129</td><td>0.01630</td></tr><tr><td>Excluding study 5 (Renwick et al.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref>)</td><td><bold>0.0896</bold></td><td><bold>0.05950</bold></td></tr><tr><td>Excluding study 6 (Hirsch et al.<xref rid="bib49" ref-type="bibr"><sup>49</sup></xref>)</td><td>0.1416</td><td>0.00220</td></tr><tr><td>Excluding study 7 (Soukupova et al.<xref rid="bib50" ref-type="bibr"><sup>50</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>NA</td><td>NA</td></tr><tr><td>Excluding study 8 (kConFab/Regensburg)</td><td>0.1151</td><td>0.03120</td></tr><tr><td>Excluding study 9a (IARC, European)</td><td>0.1966</td><td>0.00051</td></tr><tr><td>Excluding study 9b (IARC, East Asian)</td><td>0.1478</td><td>0.00180</td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td colspan="3"><bold>Test Scenario C</bold></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td></td><td><bold>Coefficient</bold><xref rid="tblfn28" ref-type="table-fn">b</xref></td><td><bold>p-Trend</bold></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td>All case-control studies</td><td>0.3082</td><td>0.00048</td></tr><tr><td>Excluding study 1 (Fitzgerald et al.<xref rid="bib48" ref-type="bibr"><sup>48</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>NA</td><td>NA</td></tr><tr><td>Excluding study 2 (Teraoka et al.<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref>)</td><td>0.2913</td><td>0.00082</td></tr><tr><td>Excluding study 3 (Sommer et al.<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref>)</td><td>0.2953</td><td>0.00064</td></tr><tr><td>Excluding study 4 (Thorstenson et al.)</td><td>0.2694</td><td>0.00190</td></tr><tr><td>Excluding study 5 (Renwick et al.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref>)</td><td>0.2664</td><td>0.00370</td></tr><tr><td>Excluding study 6 (Hirsch et al.<xref rid="bib49" ref-type="bibr"><sup>49</sup></xref>)</td><td>0.3206</td><td>0.00050</td></tr><tr><td>Excluding study 7 (Soukupova et al.<xref rid="bib50" ref-type="bibr"><sup>50</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>NA</td><td>NA</td></tr><tr><td>Excluding study 8 (kConFab/Regensburg)</td><td>0.2745</td><td>0.00410</td></tr><tr><td>Excluding study 9a (IARC, European)</td><td>0.5168</td><td>0.00170</td></tr><tr><td>Excluding study 9b (IARC, East Asian)</td><td>0.3202</td><td>0.00057</td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td colspan="3"><bold>Test Scenario D</bold></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td></td><td><bold>Coefficient</bold><xref rid="tblfn28" ref-type="table-fn">b</xref></td><td><bold>p-Trend</bold></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td>All case-control studies</td><td>0.4129</td><td>0.00220</td></tr><tr><td>Excluding study 1 (Fitzgerald et al.<xref rid="bib48" ref-type="bibr"><sup>48</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>NA</td><td>NA</td></tr><tr><td>Excluding study 2 (Teraoka et al.<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref>)</td><td>0.3978</td><td>0.00250</td></tr><tr><td>Excluding study 3 (Sommer et al.<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref>)</td><td>0.3977</td><td>0.00230</td></tr><tr><td>Excluding study 4 (Thorstenson et al.)</td><td>0.3605</td><td>0.00480</td></tr><tr><td>Excluding study 5 (Renwick et al.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref>)</td><td>0.3673</td><td>0.00850</td></tr><tr><td>Excluding study 6 (Hirsch et al.<xref rid="bib49" ref-type="bibr"><sup>49</sup></xref>)</td><td>0.4305</td><td>0.00280</td></tr><tr><td>Excluding study 7 (Soukupova et al.<xref rid="bib50" ref-type="bibr"><sup>50</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>NA</td><td>NA</td></tr><tr><td>Excluding study 8 (kConFab/Regensburg)</td><td>0.3758</td><td>0.00710</td></tr><tr><td>Excluding study 9a (IARC, European)</td><td>0.7865</td><td>0.04762</td></tr><tr><td>Excluding study 9b (IARC, East Asian)</td><td>0.4207</td><td>0.00250</td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td colspan="3"><bold>Test Scenario E</bold></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td></td><td><bold>p-FET</bold><xref rid="tblfn29 tblfn30" ref-type="table-fn">c,d</xref></td><td><bold>p-FET</bold><xref rid="tblfn29 tblfn31" ref-type="table-fn">c,e</xref></td></tr><tr><td colspan="3"><hr></hr></td></tr><tr><td>All case-control studies</td><td>0.0210</td><td>0.0187</td></tr><tr><td>Excluding study 1 (Fitzgerald et al.<xref rid="bib48" ref-type="bibr"><sup>48</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>0.0384</td><td><italic>NA</italic></td></tr><tr><td>Excluding study 2 (Teraoka et al.<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref>)</td><td>0.0218</td><td>0.0366</td></tr><tr><td>Excluding study 3 (Sommer et al.<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref>)</td><td>0.0210</td><td>0.0187</td></tr><tr><td>Excluding study 4 (Thorstenson et al.)</td><td>0.0204</td><td>0.0337</td></tr><tr><td>Excluding study 5 (Renwick et al.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref>)</td><td>0.0357</td><td><bold>0.0568</bold></td></tr><tr><td>Excluding study 6 (Hirsch et al.<xref rid="bib49" ref-type="bibr"><sup>49</sup></xref>)</td><td>0.0226</td><td>0.0342</td></tr><tr><td>Excluding study 7 (Soukupova et al.<xref rid="bib50" ref-type="bibr"><sup>50</sup></xref>)<xref rid="tblfn27" ref-type="table-fn">a</xref></td><td>0.0103</td><td>NA</td></tr><tr><td>Excluding study 8 (kConFab/Regensburg)</td><td>0.0413</td><td><bold>0.0695</bold></td></tr><tr><td>Excluding study 9a (IARC, European)</td><td><bold>0.0845</bold></td><td><bold>0.0705</bold></td></tr><tr><td>Excluding study 9b (IARC, East Asian)</td><td>0.0393</td><td><bold>0.0662</bold></td></tr></tbody></table><table-wrap-foot><fn><p>Bold font is used to indicate leave-one-out analyses resulting in point estimates or trend coefficients with p > 0.05. Abbreviations are as follows: OR, odds ratio; CI, confidence interval; NA, not applicable.</p><p>Test scenario A: logistic regression ORs and p value for T+SJ.</p><p>Test scenario B: trend test on missense substitutions across the whole gene (excluding carriers of T+SJ variants and adjusting for study).</p><p>Test scenario C: trend test on missense substitutions after residue Ile1960 (excluding carriers of T+SJ variants and adjusting for study).</p><p>Test scenario D: trend test on missense substitutions in the FAT+Kinase+FATC domains (excluding carriers of T+SJ variants and adjusting for study).</p><p>Test scenario E: comparison between C65 rMSs in the FAT+Kinase+FATC domains versus T+SJ variants.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn27"><label>a</label><p>Study included in tests of T+SJ variants only.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn28"><label>b</label><p>ln(OR) regression coefficient.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn29"><label>c</label><p>Fisher's exact test.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn30"><label>d</label><p>All of the case-control studies were used.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn31"><label>e</label><p>After exclusion of studies 1 and 7, which used the PTT test and consequently had zero sensitivity for detection.</p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 0017059 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 0017059 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé=
|texte=
}}
| This area was generated with Dilib version V0.6.33. |  |