Genome-wide association study of down syndrome-associated atrioventricular septal defects

• Authors: Dhanya Ramachandran, Emory University; Zhen Zeng, University of Pittsburgh; Adam E. Locke, Emory University; Jennifer Mulle, Emory University; Lora Bean, Emory University; Tracie Rosser, Emory University; Kenneth Dooley, Emory University; Clifford L. Cua, Nationwide Children’s Hospital; George T. Capone, Kennedy Krieger Institute; Roger H. Reeves, Johns Hopkins University; Cheryl L. Maslen, Children’s Healthcare of Atlanta; David Cutler, Emory University; Eleanor Feingold, University of Pittsburgh; Stephanie Sherman, Emory University; Michael Zwick, Emory University
• Journal Title: G3
• Volume: Volume 5, Number 10
• Publisher: Genetics Society of America: G3 | 2015-01-01, Pages 1961-1971
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1534/g3.115.019943
• Keywords: aneuploidy; birth defect; complex trait; congenital heart defect; trisomy

Abstract

The goal of this study was to identify the contribution of common genetic variants to Down syndrome2associated 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 syndrome2associated 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.