Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits

Abstract

SummaryTraditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age‐related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age‐related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high‐density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large‐scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10−30 for rs693 and β = −1.08, P = 9.8 × 10−42 for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects—protecting against MI risks (β = −0.18, P = 1.1 × 10−5) or increasing MI risks (β = 0.15, P = 2.8 × 10−3) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10−8) that is contrasted with a weak estimate following the traditional, sample‐size‐centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan.

Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities

“…The directions of effects of rs9918162 were opposite in the discovery and replication sets. While genetic variants that have the same direction of effects in multiple independent cohorts are generally of more interest, those with opposite effects can be important as well because they may be indicative of the genetic heterogeneity of the studied trait in different cohorts arising, for example, from the epistasis or differences in LD patterns [59–61].…”

Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes

“…The current study supports this concept by highlighting strong impact of antagonistic heterogeneity, which is counter-intuitive in medical genetics but natural within the evolutionary framework. The antagonistic heterogeneity is also supported by the analyses of alleles from well-known apolipoprotein B and E genes [ 16 , 17 ].…”

“…Accordingly, different, even antagonistic, effects of the same allele on the same phenotype in different population groups are biologically plausible [ 14 , 15 ]. Another challenge in the evolutionary framework is that genetic variants predisposing to a phenotype may not necessarily predispose to another, even causally related, phenotype [ 16 , 17 ] or such genetic variants can predispose to seemingly unrelated phenotypes [ 18 - 20 ].…”

Influence of multiple apolipoprotein A-I and B genetic variations on insulin resistance and metabolic syndrome in obstructive sleep apnea

“…They found APOB rs1042031 confers a moderate risk for CHD [39] and increase the SONFH risk with moderate levels of evidence. APOB rs693 [41], rs2854725 [42] and rs1367117 [43,44] were associated with serum APOB levels, further associated with familial hypercholesterolemia [45] and heart-related traits [46], predicted the risk of CHD [42], maternally-derived effect on BMI [43].There were fewer studies about APOA SNP rs9804646, rs10047462, rs888246 and APOB rs12713956. Data on APOA-I and APOB genetic polymorphisms in insulin resistance and MetS are still lacking.…”