Cis-epistasis at the LPA locus and risk of coronary artery disease

Abstract

Identification of epistasis affecting complex human traits has been challenging. Focusing on known coronary artery disease (CAD) risk loci, we explore pairwise statistical interactions between 8,068 SNPs from ten CAD genome-wide association studies (n=30,180). We discovered rs1800769 and rs9458001 in the vicinity of the LPA locus to interact in modulating CAD risk (P=1.75×10−13). Specific genotypes (e.g., rs1800769 CT) displayed either significantly decreased or increased risk for CAD in the context of genotypes of the respective other SNP (e.g., rs9458001 GG vs. AA). In the UK Biobank (n=450,112) significant interaction of this SNP pair was replicated for CAD (P=3.09×10−22), and was also found for aortic valve stenosis (P=6.95×10−7) and peripheral arterial disease (P=2.32×10−4). Identical interaction patterns affected circulating lipoprotein(a) (n=5,953; P=8.7×10−32) and hepatic apolipoprotein(a) (apo(a)) expression (n=522, P=2.6×10−11). We further interrogated potential biological implications of the variants and propose a mechanism explaining epistasis that ultimately may translate to substantial cardiovascular risks.

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

“…Three of 12 variants were significantly associated with the expression of one or more genes located in cis in at least one heart tissue (Bonferroni-corrected P < 0.05; Supplementary Data 8). For several of the identified HF loci, extra-cardiac tissues are likely to be relevant; for example, liver is reported to mediate effects of the LPA locus 28 . To further explore these effects, we then analysed results from a large whole-blood eQTL dataset (n = 31,684) and found associations with cis-gene expression (P < 5 × 10 −8 ) for 8 of 12 sentinel variants (Supplementary Table 1) 29 .…”

“…27 Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA. 28 Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. 29 Harvard Medical School, Boston, MA 02115, USA.…”

Genetics of coronary artery disease in the post‐GWAS era

“…In fact, only a small fraction of CAD heritability could be explained by common variations identified to date. Interactions between genes for cardiovascular regulation may account for part of the missing heritability [59], given that the biological mechanisms mediated by genetic effects usually involve multiple genes. Uncovering gene–gene interactions may yield novel insight into biological mechanisms underlying CAD.…”

Lipoprotein(a): Pathophysiology, measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d’Athérosclérose (NSFA)

“…Some single nucleotide polymorphisms (SNPs) within KIV 2 have been reported, and may help to explain why Lp(a) circulating concentrations can vary by 200-fold, even for alleles of the same size [27]. Many additional SNPs in LPA also influence the plasma concentrations of Lp(a), either by increasing them (activating SNPs) [28][29][30][31][32][33][34][35][36][37][38] or by reducing them (inhibiting SNPs) [30,33,37,39] (Table 1). For most of these SNPs, the effect on the plasma concentration of Lp(a) relies on linkage disequilibrium (i.e.…”