Feldman Elizabeth R, Li Yunqi, Cutler David J, Rosser Tracie C, Wechsler Stephanie B, Sanclemente Lauren, Rachubinski Angela L, Elliott Natalina, Vyas Paresh, Roberts Irene, Rabin Karen R, Wagner Michael, Gelb Bruce D, Espinosa Joaquin M, Lupo Philip J, de Smith Adam J, Sherman Stephanie L, Leslie Elizabeth J
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322.
Center for Genetic Epidemiology, Keck School of Medicine of University of Southern California, Los Angeles, CA.
medRxiv. 2024 Sep 6:2024.09.06.24313183. doi: 10.1101/2024.09.06.24313183.
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). Of these, the 1p35.1 locus (near ) was specifically associated with ASD risk and the 5q35.2 locus (near ) 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) 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.
先天性心脏病（CHD）是最常见的结构性出生缺陷，在唐氏综合征（DS）患儿中，40%-50%存在该疾病。为了描述与DS相关的CHD的遗传结构，我们对一组多民族的患有DS和CHD的儿童（n=886：房室间隔缺损（AVSD），n=438；房间隔缺损（ASD），n=122；室间隔缺损（VSD），n=170；其他类型的CHD，n=156）以及心脏结构正常的DS患儿（DS+NH，n=572）的基因组进行了测序。我们针对常见变异（MAF>0.05）进行了四项全基因组关联研究（GWAS），将患有CHD的DS患儿按CHD亚型分层后与DS+NH对照组进行比较。尽管没有单核苷酸多态性（SNP）达到全基因组显著性水平，但每项分析中的多个位点达到了提示性显著性水平（p<2×10）。其中，1p35.1位点（靠近 ）与ASD风险特异性相关，5q35.2位点（靠近 ）与任何类型的CHD相关。每个提示性位点都包含一个或多个在发育中的心脏中表达的合理候选基因。虽然没有SNP在一个独立的DS+CHD队列（DS+CHD：n=229；DS+NH：n=197）中得到重复验证（p<2×10），但在我们的GWAS中具有提示性的大多数SNP在与复制队列的GWAS进行荟萃分析时仍具有提示性。这些结果建立在先前工作的基础上，以确定与DS相关的CHD的遗传修饰因子。
