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

Abstract

Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations paul t. Williams "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 offspringparent regression slopes (β op) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h 2), estimated by 2β op /(1 + r spouse), decreased 0.0047 ± 0.0007 (P = 2.9 × 10 −14) for each one-percent decrement in fasting triglyceride concentrations, i.e., h 2 ± 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 (posttreatment) 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

Quantile-dependent expressivity of plasma adiponectin concentrations may explain its sex-specific heritability, gene-environment interactions, and genotype-specific response to postprandial lipemia

“…1 suggests that the transformation accentuates the genetic effect at low concentrations (where the genetic effects are weakest) and diminishes the genetic effect at higher values concentrations (where the genetic effects are strongest). Our previous analyses (Williams, 2012;Williams, 2020c;Williams, 2020e;Williams, 2020a;Williams, 2020b) suggest this concern is also apropos to lipoproteins and adiposity GWAS.…”

“…The methods have been described previously (Williams, 2020c;Williams, 2020e;Williams, 2020a;Williams, 2020g), but are repeated here for completeness. The data were obtained from the National Institutes of Health FRAMCOHORT, GEN3, FRAMOFFSPRING Research Materials obtained from the National Heart Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center.…”

Quantile-specific heritability of high-density lipoproteins with implications for precision medicine

“…The competing effects of HDL and triglyceride quantile-dependent expressivity in the context of their inverse relationship are complicated and warrant further investigation. 11,12 We also caution that HDL cholesterol levels are not an adequate surrogate measure of the HDL particle metabolism, physiology, or functionality. Functional properties of HDL are more important physiologically than their cholesterol-carrying capacity, and on occasion very large, cholesterol-rich, HDL particles are dysfunctional.…”

“…We refer to this phenomenon as quantile-dependent expressivity (AKA quantile-dependent penetrance). [10][11][12][13][14] Quantile-dependent expressivity represents an alternative perspective to precision medicine. It postulates that pharmacogenetic or nutrigenetic genetic markers simply trace the heritability increase with increasing plasma HDL cholesterol concentrations.…”

“…For example, a smaller genetic effect size at a lower (pretreatment) than higher (posttreatment) HDL concentrations requires that the effects of the genotypes do not move in parallel when pharmacologically treated. 11,12 In this case, subtracting pretreatment from the posttreatment HDL levels will necessarily create a relatively greater HDL increase for the genotype with the higher pretreatment HDL.…”