{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T15:25:04Z","timestamp":1792250704731,"version":"4.4.0"},"reference-count":45,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40%\u201350% of children born with Down syndrome (DS). To characterize the genetic architecture of DS\u2010associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (<jats:italic>n<\/jats:italic>\u2009=\u2009886: atrioventricular septal defects (AVSD), <jats:italic>n<\/jats:italic>\u2009=\u2009438; atrial septal defects (ASD), <jats:italic>n<\/jats:italic>\u2009=\u2009122; ventricular septal defects (VSD), <jats:italic>n<\/jats:italic>\u2009=\u2009170; other types of CHD, <jats:italic>n<\/jats:italic>\u2009=\u2009156) and DS with a structurally normal heart (DS\u2009+\u2009NH, <jats:italic>n<\/jats:italic>\u2009=\u2009572). We performed four genome\u2010wide association study (GWAS) for common variants (MAF\u2009&gt;\u20090.05) comparing DS with CHD, stratified by CHD\u2010subtype, to DS\u2009+\u2009NH controls. Although no SNP achieved genome\u2010wide significance, multiple loci in each analysis achieved suggestive significance (<jats:italic>p<\/jats:italic>\u2009&lt;\u20092\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>). Of these, the 1p35.1 locus (near <jats:italic>RBBP4<\/jats:italic>) was specifically associated with ASD risk, and the 5q35.2 locus (near <jats:italic>MSX2<\/jats:italic>) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (<jats:italic>p<\/jats:italic>\u2009&lt;\u20092\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>) in an independent cohort of DS\u2009+\u2009CHD (DS\u2009+\u2009CHD: <jats:italic>n<\/jats:italic>\u2009=\u2009229; DS\u2009+\u2009NH: <jats:italic>n<\/jats:italic>\u2009=\u2009197), most SNPs that were suggestive in our GWASs remained suggestive when meta\u2010analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS\u2010associated CHD.<\/jats:p>","DOI":"10.1002\/gepi.70010","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T10:31:27Z","timestamp":1747996287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genome\u2010Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS"],"prefix":"10.1002","volume":"49","author":[{"given":"Elizabeth R.","family":"Feldman","sequence":"first","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunqi","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology Keck School of Medicine of University of Southern California Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Cutler","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracie C.","family":"Rosser","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie B.","family":"Wechsler","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Sanclemente","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela L.","family":"Rachubinski","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalina","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and MRC Molecular Haematology Unit Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paresh","family":"Vyas","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and MRC Molecular Haematology Unit Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and MRC Molecular Haematology Unit Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen R.","family":"Rabin","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wagner","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Gelb","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin M.","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome University of Colorado Anschutz Medical Campus Aurora Colorado 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