Evidence from multiple genome-wide association studies of a hub of gene-gene interactions affecting human HDL cholesterol levels. L. Ma1,2, C. Ballantyne3, A. Brautbar4, A. Keinan1 1) Biological Statistics and Computational Biology, Cornell University, Ithaca, NY; 2) Department of Animal and Avian Sciences, University of Maryland, College Park, MD; 3) Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX; 4) Department of Medical Genetics, Marshfield Clinic, Marshfield, WI.

   Epistasis, an important genetic component underlying the basis of complex traits in many species, has been suggested to underlie some of missing heritability in genome-wide association studies. In this study, we first sought to identify gene-gene interactions affecting HDL cholesterol (HDL-C) levels between a focused set of SNPs in a sample of 2,091 European American (EA) individuals in a candidate gene study. Two additional EA samples from the Atherosclerosis Risk in Communities study (ARIC; n = 9,713) and from 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 = 7.110-7) in their effect on HDL-C levels, which is significant after Bonferroni correction (Pc = 0.017) for the number of SNP pairs tested. It successfully replicated in the ARIC study (P = 7.010-4; Pc = 0.02). Rs1532085, an eQTL of LIPC, has been involved in another, well-replicated interaction affecting HDL-C that we recently published. To further investigate the role of this SNP in gene-gene interactions, we additionally tested for gene-gene interaction between this SNP and any other SNP in the ARIC study and found it to be involved in a few additional suggestive interactions (FDR = 0.25), one of which significantly replicated in MESA (P = 0.03). LIPC is known to play a key role in the lipid and lipoprotein metabolism pathway. LIPC, and rs1532085 in particular, has also been previously associated by itself with the level of HDL-C, as well as with other lipid traits and metabolic syndrome. Collectively, we discovered several novel gene-gene interactions on HDL-C levels, all involving an eQTL of LIPC, thus suggesting a hub role of this SNP and LIPC in general in the interaction network regulating HDL-C.

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