Quantile-Specific Heritability of Intakes of Alcohol but not Other Macronutrients

Williams, Paul T.

doi:10.1007/s10519-020-10005-z

Cited by 15 publications

(16 citation statements)

References 62 publications

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“…The methods have been described previously [25][26][27][28][29][30][31][32][33] , 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.…”

Section: Methodsmentioning

confidence: 99%

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

Williams

2020

Sci Rep

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Abstract“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (βFS) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed βFS increased significantly with increasing percentiles of the offspring’s age- and sex-adjusted leptin distribution (Plinear = 0.0001), which was accelerated at the higher concentrations (Pquadratic = 0.0003). βFS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, Pdifference = 3.6 × 10−6). Consistent with quantile-dependent expressivity, the βFS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP, LEPR, MnSOD, PPARγ, PPARγ2, and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. βFS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (Plinear = 0.04 and Plinear = 8.5 × 10−6, respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male–female differences in heritability and some gene-environment interactions.

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Section: Methodsmentioning

confidence: 99%

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

Williams

2020

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“…"Quantile-dependent expressivity" postulates that the effects of genetic variants on phenotypes may depend on the whether the phenotype (e.g., CRP concentration) is high or low relative to its distribution. The heritability of adiposity (Williams, 2012(Williams, , 2020a; plasma concentrations of triglyceride (Williams, 2012(Williams, , 2020b, high-density lipoproteins (Williams, 2012(Williams, , 2020c(Williams, , 2020d, total cholesterol (Williams, 2020e), leptin (Williams, 2020f), and adiponection (Williams, 2020g); pulmonary function (Williams, 2020h); and intakes of alcohol (Williams, 2020i) and coffee (Williams, 2020j) are quantile dependent, whereas height and the intakes of other macronutrients are not (Williams, 2012(Williams, , 2020a. Others have also demonstrated increasing genetic effect size with increasing BMI levels (Rokholm et al, 2011;Abadi et al, 2012;Beyerlein et al, 2011;Mitchell et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Quantile-dependent expressivity of serum C-reactive protein concentrations in family sets

Williams¹

2021

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., C-reactive protein, CRP) is high or low relative to its distribution. We have previously shown that the heritabilities (h2) of coffee and alcohol consumption, postprandial lipemia, lipoproteins, leptin, adiponectin, adiposity, and pulmonary function are quantile-specific. Whether CRP heritability is quantile-specific is currently unknown. Methods Serum CRP concentrations from 2,036 sibships and 6,144 offspring-parent pairs were analyzed from the Framingham Heart Study. Quantile-specific heritability from full-sib (βFS, h2 ={(1 + 8rspouseβFS)0.5 − 1}/(2rspouse)) and offspring-parent regression slopes (βOP, h2 = 2βOP/(1 + rspouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples. Results Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted CRP distribution when estimated from βOP (Ptrend = 0.0004): 0.02 ± 0.01 at the 10th, 0.04 ± 0.01 at the 25th, 0.10 ± 0.02 at the 50th, 0.20 ± 0.05 at the 75th, and 0.33 ± 0.10 at the 90th percentile, and when estimated from βFS (Ptrend = 0.0008): 0.03±0.01 at the 10th, 0.06 ± 0.02 at the 25th, 0.14 ± 0.03 at the 50th, 0.24 ± 0.05 at the 75th, and 0.53 ± 0.21 at the 90th percentile. Conclusion Heritability of serum CRP concentration is quantile-specific, which may explain or contribute to the inflated CRP differences between CRP (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), FGB (rs1800787), IL-6 (rs1800795, rs1800796), IL6R (rs8192284), TNF-α (rs1800629) and APOE genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or Staphylococcus aureus bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.

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“…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

Williams

2020

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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.

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Quantile-Specific Heritability of Intakes of Alcohol but not Other Macronutrients

Cited by 15 publications

References 62 publications

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

Quantile-dependent expressivity of serum C-reactive protein concentrations in family sets

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

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