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Author Notes:

Email Address: mzwick@emory.edu

We gratefully acknowledge the individuals with DS and their families for participating in this research.

We thank Katy Lesowski and Jessica Hunter (Oregon Health & Science University), Kay Taylor and Valerie Deleon (John Hopkins University/Kennedy Krieger Institute), Lindsay Kehoe (Children’s National Medical Center), and Helen Smith and Elizabeth Sablon (Emory University), who engaged and collaborated with the families to collect the needed information.

Our thanks to Shoshona Lee (Emory University), Weiya He (Emory University), and Ashima Amin (Emory University) and the Emory Integrated Genomics Core (EIGC) for technical assistance.

The content is solely the responsibility of the authors and does not represent the official views of the NIH.

Research Funding:

This work is a collaborative effort with the DS Heart Project (R.H.R.) and was supported by R01 HL092981-01A1 (M.E.Z.), R01 HL083300 (R.H.R) from National Institutes of Health (NIH)/National Heart, Lung and Blood Institute

R01 HD38979 (S.L.S and E. Feingold) from NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

Training Program in Human Disease Genetics 1T32MH087977 (D.R.), and the American Heart Association Pre-doctoral Fellowship (A.E.L.)

Supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.

Additional support was provided by OCTRI (UL1 RR024140) from the National Center for Research Resources, a component of the NIH, and the NIH Roadmap for Medical Research.


  • aneuploidy
  • birth defect
  • complex trait
  • congenital heart defect
  • trisomy

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

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Journal Title:



Volume 5, Number 10


, Pages 1961-1971

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2015 Ramachandran et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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