Language
English
Publication Date
6-1-2025
Journal
Genetic Epidemiology
DOI
10.1002/gepi.70010
PMID
40407036
PMCID
PMC12278782
PubMedCentral® Posted Date
7-21-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF>0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p< 2x10−6). Of these, the 1p35.1 locus (near RBBP4) was specifically associated with ASD risk and the 5q35.2 locus (near MSX2) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (p< 2x10−6) in an independent cohort of DS+CHD (DS+CHD: n=229; DS+NH: n=197), most SNPs that were suggestive in our GWASs remained suggestive when meta-analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS-associated CHD.
Keywords
Humans, Down Syndrome, Genome-Wide Association Study, Heart Defects, Congenital, Polymorphism, Single Nucleotide, Female, Male, Genetic Predisposition to Disease, Child, Case-Control Studies, Child, Preschool, Risk Factors, Down syndrome, congenital heart defect, genome-wide association study, birth defect, trisomy 21
Published Open-Access
yes
Recommended Citation
Feldman, Elizabeth R; Li, Yunqi; Cutler, David J; et al., "Genome-Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS" (2025). Faculty and Staff Publications. 4124.
https://digitalcommons.library.tmc.edu/baylor_docs/4124