Quantile-specific heritability of total cholesterol and its pharmacogenetic and nutrigenetic implications.

Pubmed ID: 33296721

Pubmed Central ID: PMC7897293

Journal: International journal of cardiology

Publication Date: March 15, 2021

MeSH Terms: Genotype, Cholesterol, Phenotype, Pharmacogenetics, Nutrigenomics

Grants: N01HC25195, HHSN268201500001I, R21 ES020700, HHSN268201500001C

Authors: Williams PT

Cite As: Williams PT. Quantile-specific heritability of total cholesterol and its pharmacogenetic and nutrigenetic implications. Int J Cardiol 2021 Mar 15;327:185-192. Epub 2020 Dec 6.

Studies:

Abstract

BACKGROUND: "Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. cholesterol) is high or low relative to its distribution. We have previously shown that the effect of a 52-SNP genetic-risk score was 3-fold larger at the 90th percentile of the total cholesterol distribution than at its 10th percentile. The objective of this study is to assess quantile-dependent expressivity for total cholesterol in 7006 offspring with parents and 2112 sibships from Framingham Heart Study. METHODS: Quantile-specific heritability (h<sup>2</sup>) was estimated as twice the offspring-parent regression slope as robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. RESULTS: Quantile-specific h<sup>2</sup> increased linearly with increasing percentiles of the offspring's cholesterol distribution (P = 3.0 × 10<sup>-9</sup>), i.e. h<sup>2</sup> = 0.38 at the 10th percentile, h<sup>2</sup> = 0.45 at the 25th percentile, h<sup>2</sup> = 0.52 at the 50th, h<sup>2</sup> = 0.61 at the 75th percentile, and h<sup>2</sup> = 0.65 at the 90th percentile of the total cholesterol distribution. Average h<sup>2</sup> decreased from 0.55 to 0.34 in 3564 offspring who started cholesterol-lowering medications, but this was attributable to quantile-dependent expressivity and the offspring's 0.94 mmol/L average drop in total cholesterol. Quantile-dependent expressivity likely explains the reported effect of the CELSR2/PSRC1/SORT1 rs646776 and APOE rs7412 gene loci on statin efficacy. Specifically, a smaller genetic effect size at the lower (post-treatment) than higher (pre-treatment) cholesterol concentrations mandates that the trajectories of the genotypes cannot move in parallel when cholesterol is decreased pharmacologically. CONCLUSION: Cholesterol concentrations exhibit quantile-dependent expressivity, which may provide an alternative interpretation to pharmacogenetic and nutrigenetic interactions.