{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:11:16Z","timestamp":1762866676824},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The goal of this study was to identify the contribution of common genetic variants to Down syndrome\u2212associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio &amp;gt;2.0) do not account for the elevated risk of Down syndrome\u2212associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.<\/jats:p>","DOI":"10.1534\/g3.115.019943","type":"journal-article","created":{"date-parts":[[2015,7,24]],"date-time":"2015-07-24T23:53:47Z","timestamp":1437782027000},"page":"1961-1971","source":"Crossref","is-referenced-by-count":31,"title":["Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects"],"prefix":"10.1093","volume":"5","author":[{"given":"Dhanya","family":"Ramachandran","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, Georgia, 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Pittsburgh, Pennsylvania 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam E","family":"Locke","sequence":"additional","affiliation":[{"name":"Genetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Atlanta, Georgia 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer G","family":"Mulle","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lora J H","family":"Bean","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, Georgia, 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracie C","family":"Rosser","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, Georgia, 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth J","family":"Dooley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Sibley Heart Center Cardiology, Children\u2019s Healthcare of Atlanta, Atlanta, Georgia 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clifford L","family":"Cua","sequence":"additional","affiliation":[{"name":"Heart Center, Nationwide Children\u2019s Hospital, Columbus, Ohio 43205"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George T","family":"Capone","sequence":"additional","affiliation":[{"name":"Kennedy Krieger Institute, Baltimore, Maryland 21205"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger H","family":"Reeves","sequence":"additional","affiliation":[{"name":"Department of Physiology and McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheryl L","family":"Maslen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Sibley Heart Center Cardiology, Children\u2019s Healthcare of Atlanta, Atlanta, Georgia 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J","family":"Cutler","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, Georgia, 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanor","family":"Feingold","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie L","family":"Sherman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, Georgia, 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael E","family":"Zwick","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, Georgia, 30033"},{"name":"Department of Human Genetics, Emory University, Atlanta, Georgia, 30033"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,10,1]]},"reference":[{"key":"2021042106480539400_bib1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.ajhg.2012.08.017","article-title":"An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.","volume":"91","author":"Ackerman","year":"2012","journal-title":"Am. 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