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[Preprint]. 2024 Sep 6:2024.09.06.24313183.
doi: 10.1101/2024.09.06.24313183.

Genome-wide association studies of Down syndrome associated congenital heart defects

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  1
Affiliations

Genome-wide association studies of Down syndrome associated congenital heart defects

Elizabeth R Feldman et al. medRxiv. .

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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<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.
The top panels show locus zoom plots for the lead SNP in each region 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 bottom panels show the odds ratio with a 95% confidence interval for the lead SNP in each region from four of the GWAS’: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black).
Figure 2:
Figure 2:. Four regions achieved suggestive significance in the AVSD+DS GWAS.
The top panels show locus zoom plots for the lead SNP in each region 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 bottom panels show the odds ratio with a 95% confidence interval for the lead SNP in each region from four of the GWAS’: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black).
Figure 3:
Figure 3:. Six regions achieved suggestive significance in the ASD+DS GWAS.
The top panels show locus zoom plots for the lead SNP in each region 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 bottom panels show the odds ratio with a 95% confidence interval for the lead SNP in each region from four of the GWAS’: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black).
Figure 4:
Figure 4:. Four regions achieved suggestive significance in the VSD+DS GWAS.
The top panels show locus zoom plots for the lead SNP in each region 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 bottom panels show the odds ratio with a 95% confidence interval for the lead SNP in each region from four of the GWAS’: AVSD+DS (blue), ASD+DS (pink), VSD+DS (purple), anyCHD+DS (black).
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