
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.09.06.24313183
preprint
1
Article
Genome-wide association studies of Down syndrome associated congenital heart defects
Feldman Elizabeth R. http://orcid.org/0000-0003-2969-415X

Li Yunqi http://orcid.org/0000-0002-8887-9691

Cutler David J. http://orcid.org/0000-0001-6394-6731

Rosser Tracie C.
Wechsler Stephanie B. http://orcid.org/0000-0002-9321-0220

Sanclemente Lauren
Rachubinski Angela L.
Elliott Natalina
Vyas Paresh http://orcid.org/0000-0003-3931-0914

Roberts Irene http://orcid.org/0000-0002-6094-6397

Rabin Karen R. http://orcid.org/0000-0002-4081-8195

Wagner Michael
Gelb Bruce D. http://orcid.org/0000-0001-8527-5027

Espinosa Joaquin M. http://orcid.org/0000-0001-9048-1941

Lupo Philip J. http://orcid.org/0000-0003-0978-5863

de Smith Adam J.
Sherman Stephanie L.
Leslie Elizabeth J. http://orcid.org/0000-0002-5735-1712

06 9 2024
2024.09.06.24313183https://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.09.06.24313183
nihpp-2024.09.06.24313183.pdf
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.
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pmc
