Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations.

ABSTRACT: "Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., triglycerides) is high or low relative to its distribution in the population. Quantile-specific offspring-parent regression slopes (?OP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h2), estimated by 2?OP/(1 + rspouse), decreased 0.0047?±?0.0007 (P?=?2.9?×?10-14) for each one-percent decrement in fasting triglyceride concentrations, i.e., h2?±?SE were: 0.428?±?0.059, 0.230?±?0.030, 0.111?±?0.015, 0.050?±?0.016, and 0.033?±?0.010 at the 90th, 75th, 50th, 25th, and 10th percentiles of the triglyceride distribution, respectively. Consistent with quantile-dependent expressivity, 11 drug studies report smaller genotype differences at lower (post-treatment) than higher (pre-treatment) triglyceride concentrations. This meant genotype-specific triglyceride changes could not move in parallel when triglycerides were decreased pharmacologically, so that subtracting pre-treatment from post-treatment triglyceride levels necessarily created a greater triglyceride decrease for the genotype with a higher pre-treatment value (purported precision-medicine genetic markers). In addition, sixty-five purported gene-environment interactions were found to be potentially attributable to triglyceride's quantile-dependent expressivity, including gene-adiposity (APOA5, APOB, APOE, GCKR, IRS-1, LPL, MTHFR, PCSK9, PNPLA3, PPAR?2), gene-exercise (APOA1, APOA2, LPL), gene-diet (APOA5, APOE, INSIG2, LPL, MYB, NXPH1, PER2, TNFA), gene-alcohol (ALDH2, APOA5, APOC3, CETP, LPL), gene-smoking (APOC3, CYBA, LPL, USF1), gene-pregnancy (LPL), and gene-insulin resistance interactions (APOE, LPL).

SUBMITTER: Williams PT 

PROVIDER: S-EPMC7066156 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature