title: Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects.
abstract: The goal of this study was to identify the contribution of common genetic variants to Down syndrome-associated 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 >2.0) do not account for the elevated risk of Down syndrome-associated 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.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Ramachandran
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pennsylvania 15261.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Genetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Atlanta, Georgia 30033.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Locke
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia 30033.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Mulle
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033.
authors.forename: Lora J H
authors.initials: LJ
authors.lastname: Bean
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033.
authors.forename: Tracie C
authors.initials: TC
authors.lastname: Rosser
authors.affiliation: Department of Pediatrics, Sibley Heart Center Cardiology, Children's Healthcare of Atlanta, Atlanta, Georgia 30033.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dooley
authors.affiliation: Heart Center, Nationwide Children's Hospital, Columbus, Ohio 43205.
authors.forename: Clifford L
authors.initials: CL
authors.lastname: Cua
authors.affiliation: Kennedy Krieger Institute, Baltimore, Maryland 21205.
authors.forename: George T
authors.initials: GT
authors.lastname: Capone
authors.affiliation: Department of Physiology and McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
authors.affiliation: Department of Pediatrics, Sibley Heart Center Cardiology, Children's Healthcare of Atlanta, Atlanta, Georgia 30033.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Maslen
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania 15261.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Sherman
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033 mzwick@emory.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zwick
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics*; D056726:Genetic Association Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006343:Heart Septal Defects / Q000209:etiology* / Q000473:pathology*; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
keywords: aneuploidy; birth defect; complex trait; congenital heart defect; trisomy