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Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations.
Sci Rep. 2020 03 11; 10(1):4486.SR

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 (βOP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h2), estimated by 2βOP/(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, 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).

Authors+Show Affiliations

Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division 1 Cyclotron Road, Berkeley, CA, 94720, USA. ptwilliams@lbl.gov.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

32161301

Citation

Williams, Paul T.. "Gene-environment Interactions Due to Quantile-specific Heritability of Triglyceride and VLDL Concentrations." Scientific Reports, vol. 10, no. 1, 2020, p. 4486.
Williams PT. Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations. Sci Rep. 2020;10(1):4486.
Williams, P. T. (2020). Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations. Scientific Reports, 10(1), 4486. https://doi.org/10.1038/s41598-020-60965-9
Williams PT. Gene-environment Interactions Due to Quantile-specific Heritability of Triglyceride and VLDL Concentrations. Sci Rep. 2020 03 11;10(1):4486. PubMed PMID: 32161301.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations. A1 - Williams,Paul T, Y1 - 2020/03/11/ PY - 2019/10/23/received PY - 2020/02/17/accepted PY - 2020/3/13/entrez PY - 2020/3/13/pubmed PY - 2020/3/13/medline SP - 4486 EP - 4486 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - "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 (βOP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h2), estimated by 2βOP/(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, 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). SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/32161301/Gene_environment_interactions_due_to_quantile_specific_heritability_of_triglyceride_and_VLDL_concentrations_ L2 - http://dx.doi.org/10.1038/s41598-020-60965-9 DB - PRIME DP - Unbound Medicine ER -
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