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

Williams, Paul T.

doi:10.1038/s41598-020-60965-9

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

Journal Article · Wed Mar 11 00:00:00 EDT 2020 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-020-60965-9· OSTI ID:1615321

Williams, Paul T. ^[1]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics & Integrated Bioimaging Division

"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 (β_OP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h²), estimated by 2β_OP/(1 + $$\Gamma$$ _spouse), 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, PPARγ2), 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).

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Heart, Lung, and Blood Institute (NHLBI); Boston University; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231; N01-HC-25195; HHSN268201500001I; R21ES020700

OSTI ID:: 1615321

Journal Information:: Scientific Reports, Vol. 10, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 23 works

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