Abstract
AimsCoronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic effects might be responsible for part of the unaccounted genetic variance. Here, we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.Methods and resultsWe tested for epistatic interactions in 10 CAD case–control studies and UK Biobank with focus on 8068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD [odds ratio (OR) = 1.37, P = 1.07 × 10−11], peripheral arterial disease (OR = 1.22, P = 2.32 × 10−4), aortic stenosis (OR = 1.47, P = 6.95 × 10−7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, P = 1.41 × 10−8), and Lp(a) serum levels (beta = 0.58, P = 8.7 × 10−32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, P = 9.97 × 10−32) and individuals homozygous for the minor allele (relative OR = 1.77, P = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.ConclusionsThese results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.
Highlights
Coronary artery disease (CAD) is one of the largest contributors to morbidity and mortality worldwide[1]
4.1 Discovery of SNP pairs associated with CAD risk We identified 56 previously known CAD risk loci from two previous GWAS20,25 (Supplementaty Table 14)
The interaction term displayed a strong association (ORint=1.42, p=1.75×10-13 for the rs1800769[T] ×rs9458001[A] interaction term). As both SNP were encoded in the additive genetic model, the OR can be interpreted as the increase in likeliness to suffer from CAD associated with an increase of one unit in the product between the number of minor alleles at each of the interacting SNPs
Summary
Coronary artery disease (CAD) is one of the largest contributors to morbidity and mortality worldwide[1]. A fundamental aspect of CAD is its complex and multifactorial aetiology, which includes numerous environmental risk factors, such as obesity and smoking[2], as well as a strong genetic predisposition. A decade of genome-wide association studies (GWAS) shed light on the genetic architecture of the disease, discovering 163 genetic loci associated with CAD risk[4,5]. About a quarter of CAD heritability can be explained by additive effects of these and other common genetic variants[4,5]. More complex models involving gene regulatory networks[6] may help to better explain the heritability of the disease. Until now non-additive genetic effects, such as epistatic interactions, are largely neglected for explaining the heritability of CAD. Epistasis has been postulated by some to account for part of this “missing heritability”[8] and has been found to act alongside additive effects to influence complex phenotypes.[9,10]
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