Abstract
There is strong evidence for a genetic contribution to non-syndromic congenital heart defects (CHDs). However, exome- and genome-wide studies conducted at the variant and gene-level have identified few genome-wide significant CHD-related genes. Gene-set analyses are a useful complement to such studies and candidate gene-set analyses of rare variants have provided insight into the genetics of CHDs. However, similar analyses have not been conducted using data on common genetic variants. Consequently, we conducted common variant analyses of 15 CHD candidate gene-sets, using data from two common types of CHDs: conotruncal heart defects (1431 cases) and left ventricular outflow tract defects (509 cases). After Bonferroni correction for evaluation of multiple gene-sets, the cytoskeletal gene-set was significantly associated with conotruncal heart defects (βS = 0.09; 95% confidence interval (CI) 0.03–0.15). This association was stronger when analyses were restricted to the sub-set of cytoskeletal genes that have been observed to harbor rare damaging genotypes in at least two CHD cases (βS = 0.32, 95% CI 0.08–0.56). These findings add to the evidence linking cytoskeletal genes to CHDs and suggest that, for cytoskeletal genes, common variation may contribute to the risk of CHDs.
Highlights
Congenital heart defects (CHDs) are the most common type of birth defect and are associated with significant morbidity and mortality [1,2,3]
A significant association was identified between the cytoskeletal gene-set and conotruncal heart defects (CTDs) (p = 0.001)
In our analyses based on common variants, we found no evidence for association with the chromatin gene-set (CTDs, p = 0.15; left ventricular outflow tract defects (LVOTDs), p = 0.63; CTDs + LVOTDs, p = 0.57) and only modest evidence for association with the cilia-gene set (CTD only, p = 0.03; LVOTD only, p = 0.09; CTD + LVOTD, p = 0.04)
Summary
Congenital heart defects (CHDs) are the most common type of birth defect and are associated with significant morbidity and mortality [1,2,3]. The majority of individuals with a CHD appear to be non-syndromic [4,5]. Single nucleotide polymorphism (SNP)-level, genome-wide association studies (GWAS) of CHDs and common variants have identified several genomewide significant associations, few of these associations have been independently replicated [8]. Studies using generation sequencing data have revealed enrichment of potentially damaging de novo and rare inherited variants in specific gene classes. Genome-wide significant associations with rare variants have been identified for only a few individual genes. Analysis of whole exome sequence (WES) data from 2871 CHD case-parent trios identified only seven genes with an excess of rare, potentially damaging de novo and inherited variants that exceeded genome-wide significance [9]
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