Congenital heart defects involving left sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 215kb region on chromosome 20q11 (p= 1.72x10(-8) for rs3746446; imputed SNP rs6088703 p= 3.01 x 10(-9), odds ratio= 1.6 for both). This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest p in region= 4.51x10(-5), OR=1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (p= 0.03 for rs3746446) resulting in p= 9.49x10(-9) for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest p= 9.35x10(-7) for rs12045807). Both regions include genes involved in cardiac development - MYH7B/miR499A on chromosome 20 and CTSK, CTSS, and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high (hg (2) range= 0.22-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.
This research output has an Altmetric Attention Score of 8. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 08 August 2023.
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