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

Elizabeth R Feldman; Yunqi Li; David J Cutler; Tracie C Rosser; Stephanie B Wechsler; Lauren Sanclemente; Angela L Rachubinski; Natalina Elliott; Paresh Vyas; Irene Roberts; Karen R Rabin; Michael Wagner; Bruce D Gelb; Joaquin M Espinosa; Philip J Lupo; Adam J de Smith; Stephanie L Sherman; Elizabeth J Leslie-Clarkson

doi:10.1002/gepi.70010

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

Genet Epidemiol. 2025 Jun;49(4):e70010. doi: 10.1002/gepi.70010.

Authors

Elizabeth R Feldman¹, Yunqi Li², David J Cutler¹, Tracie C Rosser¹, Stephanie B Wechsler¹, Lauren Sanclemente³, Angela L Rachubinski⁴, Natalina Elliott⁵, Paresh Vyas⁵, Irene Roberts⁵, Karen R Rabin³, Michael Wagner⁶, Bruce D Gelb⁷, Joaquin M Espinosa⁴, Philip J Lupo³, Adam J de Smith², Stephanie L Sherman¹, Elizabeth J Leslie-Clarkson¹

Affiliations

¹ Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
² Center for Genetic Epidemiology, Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
³ Baylor College of Medicine, Houston, Texas, USA.
⁴ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
⁵ Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK.
⁶ Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁷ Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 40407036
DOI: 10.1002/gepi.70010

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^-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 < 2 × 10^-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: Down syndrome; birth defect; congenital heart defect; genome‐wide association study; trisomy 21.

MeSH terms

Case-Control Studies
Child
Child, Preschool
Down Syndrome* / complications
Down Syndrome* / genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Heart Defects, Congenital* / genetics
Humans
Male
Polymorphism, Single Nucleotide
Risk Factors