Quantile-Specific Heritability may Account for Gene–Environment Interactions Involving Coffee Consumption

2020

PLoS ONE

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Purpose "Quantile-dependent expressivity" describes an effect of the genotype that depends upon the level of the phenotype (e.g., whether a subject's triglycerides are high or low relative to its population distribution). Prior analyses suggest that the effect of a genetic risk score (GRS) on fasting plasma triglyceride levels increases with the percentile of the triglyceride distribution. Postprandial lipemia is well suited for testing quantile-dependent expressivity because it exposes each individual's genotype to substantial increases in their plasma triglyceride concentrations. Ninety-seven published papers were identified that plotted mean triglyceride response vs. time and genotype, which were converted into quantitative data. Separately, for each published graph, standard least-squares regression analysis was used to compare the genotype differences at time t (dependent variable) to average triglyceride concentrations at time t (independent variable) to assess whether the genetic effect size increased in association with higher triglyceride concentrations and whether the phenomenon could explain purported genetic interactions with sex, diet, disease, BMI, and drugs. ResultsConsistent with the phenomenon, genetic effect sizes increased (P�0.05) with increasing triglyceride concentrations for polymorphisms associated with

Section: Resultsmentioning

confidence: 99%

Quantile-dependent expressivity of postprandial lipemia

2020

PLoS ONE

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Journal of Clinical Lipidology

2020

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BACKGROUND: We have previously shown that the effect of a high-density lipoprotein (HDL) genetic risk score depends on whether the phenotype (HDL cholesterol) is high or low relative to its distribution (quantile-dependent expressivity). OBJECTIVE: Evidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h 2) in a larger population (Framingham cohort). METHODS: Quantile regression was used to test whether the offspring-parent (b OP) and full-sib (b FS) regression slopes increased with the percentiles of the offspring's HDL distribution in 10,650 parent-offspring pairs and 2130 sibships. Quantile-specific heritability was estimated by 2b OP /(1 1 r spouse) and [(8b FS r spouse 1 1) 0.5 21]/(2r spouse), where r spouse is the spouse correlation. RESULTS: HDL cholesterol heritability estimated from b OP increased significantly (P 5 4.2 ! 10 25) from the 10 th (h 2 6 SE: 0.44 6 0.03), 25 th (0.45 6 0.03), 50 th (0.47 6 0.03), and 75 th (0.56 6 0.04) to the 90 th percentiles (0.65 6 0.06) of the offspring's age-and sex-adjusted HDL cholesterol distribution. Heritability estimated from b FS also increased significantly with the percentiles of the offspring's HDL cholesterol (P 5 .002), apo A1 (P 5 .006), HDL2 cholesterol (P 5 .003), and HDL3 cholesterol distribution (P 5 .02). Consistent with quantile-dependent expressivity, published pharmacologic and nutritional interventions that raised (eg, statin, fibrates, estrogen replacement therapy, efavirenz, and dietary fat) or lowered HDL cholesterol concentrations (tamoxifen, dietary carbohydrate) correspondingly increased and decreased genetic effects. CONCLUSION: : HDL cholesterol heritability increased with increasing percentile of the offspring's HDL distribution. Whereas precision medicine is based on the premise that genetic markers identify patients most likely to benefit from drugs and diet, quantile-dependent expressivity postulates that the strong signals from these genetic markers simply trace the heritability increase with increasing plasma HDL concentrations. Thus, quantile-dependent expressivity provides an alternative interpretation to these genotype-specific effects.

“…This is in contrast to the traditional estimate of a genetic effect size that is assumed to be constant across all population percentiles. Quantile-dependent expressivity has been demonstrated for adiposity ( Williams, 2012 ; Williams, 2020c ), lipoproteins ( Williams, 2012 ; Williams, 2020e ; Williams, 2020a ), pulmonary function ( Williams, 2020g ), coffee intake ( Williams, 2020d ), and alcohol intake ( Williams, 2020f ). Moreover, the genetic effect sizes of single nucleotide polymorphisms (SNPs) affecting triglycerides have been shown to increase and decrease within individuals in accordance with increasing and decreasing postprandial triglyceride concentrations, consistent with quantile-dependent expressivity ( Williams, 2020b ).…”

Section: Introductionmentioning

confidence: 99%

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

2020

PeerJ

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Background “Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. adiponectin) is high or low relative to its distribution. We have previously shown that the heritability (h2) of adiposity, lipoproteins, postprandial lipemia, pulmonary function, and coffee and alcohol consumption are quantile-specific. Whether adiponectin heritability is quantile specific remains to be determined. Methods Plasma adiponectin concentrations from 4,182 offspring-parent pairs and 1,662 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (βOP,h2 = 2βOP/(1 + rspouse)) and full-sib regression slopes (βFS, h2 = {(1 + 8rspouseβFS)0.05-1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples. Results Quantile-specific h2 (± SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted adiponectin distribution when estimated from βOP (Ptrend = 2.2 × 10−6): 0.30 ± 0.03 at the 10th, 0.33 ± 0.04 at the 25th, 0.43 ± 0.04 at the 50th, 0.55 ± 0.05 at the 75th, and 0.57 ± 0.08 at the 90th percentile, and when estimated from βFS (Ptrend = 7.6 × 10−7): 0.42 ± 0.03 at the 10th, 0.44 ± 0.04 at the 25th, 0.56 ± 0.05 at the 50th, 0.73 ± 0.08 at the 75th, and 0.79 ± 0.11 at the 90th percentile. Consistent with quantile-dependent expressivity, adiponectin’s: (1) heritability was greater in women in accordance with their higher adiponection concentrations; (2) relationships to ADIPOQ polymorphisms were modified by adiposity in accordance with its adiponectin-lowering effect; (3) response to rosiglitazone was predicted by the 45T> G ADIPOQ polymorphism; (4) difference by ADIPOQ haplotypes increased linearly with increasing postprandial adiponectin concentrations. Conclusion Adiponectin heritability is quantile dependent, which may explain sex-specific heritability, gene-environment and gene-drug interactions, and postprandial response by haplotypes.