Genome‐Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS

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 genome-wide association study (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 < 2 × 10<sup>-6</sup>). 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 < 2 × 10<sup>-6</sup>) 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.

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Journal
Genetic Epidemiology
Published
2025-05-23
DOI
https://doi.org/10.1002/gepi.70010
Citations
1
Primary Topic
Congenital heart defects research
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article
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0.81
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article

Genome‐Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS

David J. Cutler, Karen R. Rabin, Tracie C. Rosser, Yunqi Li et al.
1 citations
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Congenital heart defects research
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article

Genome‐Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS

David J. Cutler, Karen R. Rabin, Tracie C. Rosser, Yunqi Li, Natalina Elliott, Michael Wagner, Stephanie L. Sherman, E. Feldman, Adam J. de Smith, Irene Roberts, Stephanie Burns Wechsler, Joaquı́n M. Espinosa, Lauren Sanclemente, Philip J. Lupo, Angela L. Rachubinski, Paresh Vyas, Elizabeth J. Leslie, Bruce D. Gelb
article en
1 citations

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 genome-wide association study (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 < 2 × 10<sup>-6</sup>). 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 < 2 × 10<sup>-6</sup>) 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.

Genetic EpidemiologyVol. 49(4)
University of Southern California (US), Cincinnati Children's Hospital Medical Center (US), Emory University (US), Baylor College of Medicine (US), University of Oxford (GB), Oxford BioMedica (United Kingdom) (GB), University of Colorado Anschutz Medical Campus (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 28%
Congenital heart defects research
0.81
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