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. 2025 Jun;49(4):e70010.
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

Elizabeth R Feldman  1 , Yunqi Li  2 , David J Cutler  1 , Tracie C Rosser  1 , Stephanie B Wechsler  1 , Lauren Sanclemente  3 , Angela L Rachubinski  4 , Natalina Elliott  5 , Paresh Vyas  5 , Irene Roberts  5 , Karen R Rabin  3 , Michael Wagner  6 , Bruce D Gelb  7 , Joaquin M Espinosa  4 , Philip J Lupo  3 , Adam J de Smith  2 , Stephanie L Sherman  1 , Elizabeth J Leslie-Clarkson  1
Affiliations

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

Elizabeth R Feldman et al. Genet Epidemiol. 2025 Jun.

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.

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Figures

Figure 1:
Figure 1:. Two regions achieved suggestive significance in the any CHD+DS GWAS.
(A) The 5q11.2 locus and (B) the 5q35.2 locus. The left panels show regional association plots for each locus with the left y-axis displaying the −log10(p-value) and the right y-axis displaying the recombination rate. Points are colored according to their strength of linkage disequilibrium with the lead SNP (purple diamond). The right panels show the odds ratio with a 95% confidence interval for the lead SNP (large dot) in each region from four of the GWASs: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black), and the odds ratios for SNPs within 250kb downstream or upstream of the lead SNP with p<2x10−4 (small dots).
Figure 2:
Figure 2:. Four regions achieved suggestive significance in the AVSD+DS GWAS.
Regional association plots are shown for (A) the 5q32.2 locus, (B) the 12q13.12 locus, (C) the 13q21.33 locus, (D) the 19q13.3 locus with the left y-axis displaying the −log10(p-value) and the right y-axis displaying the recombination rate. Points are colored according to their strength of linkage disequilibrium with the lead SNP (purple diamond). (E) Plots for each locus showing the odds ratio with a 95% confidence interval for the lead SNP (large dot) from four of the GWASs: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black), and the odds ratios for SNPs within 250kb downstream or upstream of the lead SNP with p<2x10−4 (small dots).
Figure 3:
Figure 3:. Six regions achieved suggestive significance in the ASD+DS GWAS.
Regional association plots are shown for (A) the 1p35.1 locus, (B) the 1q41 locus, (C) the 8p11.21 locus, (D) the 10p11.21 locus, (E) the 10q26.3 locus, and (F) the 12q13.12 locus with the left y-axis displaying the −log10(p-value) and the right y-axis displaying the recombination rate. Points are colored according to their strength of linkage disequilibrium with the lead SNP (purple diamond). (G) Plots for each locus showing the odds ratio with a 95% confidence interval for the lead SNP (large dot) in each locus from four of the GWASs: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black), and the odds ratios for SNPs within 250kb downstream or upstream of the lead SNP with p<2x10−4 (small dots).
Figure 4:
Figure 4:. Four regions achieved suggestive significance in the VSD+DS GWAS.
Regional association plots are shown for (A) 4q34.3, (B) 5q33.1, (C) 14q21.2, and (D) 17q24.1 with with the left y-axis displaying the −log10(p-value) and the right y-axis displaying the recombination rate. Points are colored according to their strength of linkage disequilibrium with the lead SNP (purple diamond). (E) Plots for each locus showing the odds ratio with a 95% confidence interval for the lead SNP (large dot) in each region from four of the GWASs: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black), and the odds ratios for SNPs within 250kb downstream or upstream of the lead SNP with p<2x10−4 (small dots).
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References

    1. Abdulla R (1998). Perspective in pediatric cardiology. Volume 5. Genetic and environmental risk factors of major cardiovascular malformations. Pediatr Cardiol, 19(5), 435. 10.1007/s002469900346 - DOI - PubMed
    1. Agopian AJ, Mitchell LE, Glessner J, Bhalla AD, Sewda A, Hakonarson H, & Goldmuntz E (2014). Genome-wide association study of maternal and inherited loci for conotruncal heart defects. PLoS One, 9(5), e96057. 10.1371/journal.pone.0096057 - DOI - PMC - PubMed
    1. Bakkers* J (2011). Zebrafish as a model to study cardiac development and human cardiac disease. Cardiovasc Res. - PMC - PubMed
    1. Bergmann MW (2010). WNT signaling in adult cardiac hypertrophy and remodeling: lessons learned from cardiac development. Circ Res, 107(10), 1198–1208. 10.1161/CIRCRESAHA.110.223768 - DOI - PubMed
    1. Boneva RS, Botto LD, Moore CA, Yang Q, Correa A, & Erickson JD (2001). Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979-1997. Circulation, 103(19), 2376–2381. 10.1161/01.cir.103.19.2376 - DOI - PubMed

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