Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome

Cristina E Trevino,Kenneth J Dooley,James E O’Brien,Cheryl L Maslen,David J Cutler,H Richard Johnston,Douglas C Bittel,Bernard Keavney ,Heather J Cordell,Tracie C Rosser,Elizabeth Goldmuntz,Stephanie L Sherman,Roger H Reeves,Peter J Gruber,A J Agopian ,Aaron M Holleman,George T Capone,Lalita Wadhwa,Holly Corbitt,L Clifford ,Michael P Epstein,Jennifer G Mullé ,Benjamin L Rambo-Martin,Jai Oberoi,Michael E Zwick

doi:10.1038/s41598-020-74650-4

Abstract

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.

Highlights

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population
We examined the role of rare and common single nucleotide variants (SNVs) in DS-associated AVSD by analyzing data from whole exome sequencing, whole genome sequencing, and genome-wide SNP imputation in cases with DS + AVSD and DS + NH controls
We used SNV-set analyses to examine both rare and common variant associations and polygenic risk score methods to investigate the combined effect of common variants across the genome

Summary

Introduction

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. There have been several studies of the role of common variants in DS-associated AVSD, including the largest genome-wide association study (GWAS) to date with 210 complete AVSD cases with DS (DS + AVSD) and 242 controls with DS and structurally normal hearts (DS + NH) These studies have not identified any common variants (single nucleotide polymorphisms [SNP] or copy number variants [CNV]) exceeding genome-wide significance, despite adequate sample sizes for detecting common variants with large effect sizes[3,4,5]. These findings suggest that rare variants may play an important role in DS-associated AVSD, warranting further study with larger sample sizes

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