title: Analysis of multiple association studies provides evidence of an expression QTL hub in gene-gene interaction network affecting HDL cholesterol levels.
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.
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Christie
authors.initials: C
authors.lastname: Ballantyne
authors.affiliation: Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America; Department of Medical Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Ariel
authors.initials: A
authors.lastname: Brautbar
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Alon
authors.initials: A
authors.lastname: Keinan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood*; D004843:Epistasis, Genetic; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000453:epidemiology / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D014481:United States / Q000453:epidemiology
chemical_list: D008076:Cholesterol, HDL