Abstract
Epistasis has been suggested to underlie part of the missing heritability in genome-wide association studies. In this study, we first report an analysis of gene-gene interactions affecting HDL cholesterol (HDL-C) levels in a candidate gene study of 2,091 individuals with mixed dyslipidemia from a clinical trial. Two additional studies, the Atherosclerosis Risk in Communities study (ARIC; n = 9,713) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,685), were considered for replication. We identified a gene-gene interaction between rs1532085 and rs12980554 (P = 7.1×10−7) in their effect on HDL-C levels, which is significant after Bonferroni correction (P c = 0.017) for the number of SNP pairs tested. The interaction successfully replicated in the ARIC study (P = 7.0×10−4; P c = 0.02). Rs1532085, an expression QTL (eQTL) of LIPC, is one of the two SNPs involved in another, well-replicated gene-gene interaction underlying HDL-C levels. To further investigate the role of this eQTL SNP in gene-gene interactions affecting HDL-C, we tested in the ARIC study for interaction between this SNP and any other SNP genome-wide. We found the eQTL to be involved in a few suggestive interactions, one of which significantly replicated in MESA. Importantly, these gene-gene interactions, involving only rs1532085, explain an additional 1.4% variation of HDL-C, on top of the 0.65% explained by rs1532085 alone. LIPC plays a key role in the lipid metabolism pathway and it, and rs1532085 in particular, has been associated with HDL-C and other lipid levels. Collectively, we discovered several novel gene-gene interactions, all involving an eQTL of LIPC, thus suggesting a hub role of LIPC in the gene-gene interaction network that regulates HDL-C levels, which in turn raises the hypothesis that LIPC's contribution is largely via interactions with other lipid metabolism related genes.
Highlights
Genome-wide association studies (GWAS) have enabled the identification of thousands of single-nucleotide polymorphisms (SNPs) that are associated with complex human diseases and traits [1]
We found it to be nominally associated with the levels of Apolipoprotein A1 (APOA1) (P = 2.261026) and TG (P = 0.01), and almost associated with Apolipoprotein C-3 (APOC3) levels (P = 0.08)
Using a locus-based replication approach [12], we successfully replicated this interaction on High-density lipoprotein cholesterol (HDL-C) levels in an independent European American sample from the Atherosclerosis Risk in Communities study (ARIC) study (P = 7.061024; Pc = 0.02)
Summary
Genome-wide association studies (GWAS) have enabled the identification of thousands of single-nucleotide polymorphisms (SNPs) that are associated with complex human diseases and traits [1]. Most of these associated SNPs exhibit small effect sizes and collectively explain only a minor fraction of heritable variation [2]. Gene-gene interactions, plays an important role underlying the genetic basis of complex diseases and traits [3,4], and has been suggested to underlie some of the ‘‘missing heritability’’ in human GWAS [2,5]. Several recent studies have re-analyzed GWAS datasets and reported a few gene-gene interactions associated with human HDL-C levels [9,12,13,14,15]
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