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Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution.

ABSTRACT: Background:"Quantile-dependent expressivity" refers to a genetic effect that is dependent upon whether the phenotype (e.g., spirometric data) is high or low relative to its population distribution. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and the FEV1/FVC ratio are moderately heritable spirometric traits. The aim of the analyses is to test whether their heritability (h2 ) is constant over all quantiles of their distribution. Methods:Quantile regression was applied to the mean age, sex, height and smoking-adjusted spirometric data over multiple visits in 9,993 offspring-parent pairs and 1,930 sibships from the Framingham Heart Study to obtain robust estimates of offspring-parent (?OP), offspring-midparent (?OM), and full-sib regression slopes (?FS). Nonparametric significance levels were obtained from 1,000 bootstrap samples. ?OPs were used as simple indicators of quantile-specific heritability (i.e., h 2 = 2?OP/(1+rspouse), where rspouse was the correlation between spouses). Results:?OP ± standard error (SE) decreased by 0.0009 ± 0.0003 (P = 0.003) with every one-percent increment in the population distribution of FEV1/FVC, i.e., ?OP ± SE were: 0.182 ± 0.031, 0.152 ± 0.015; 0.136 ± 0.011; 0.121 ± 0.013; and 0.099 ± 0.013 at the 10th, 25th, 50th, 75th, and 90th percentiles of the FEV1/FVC distribution, respectively. These correspond to h2 ± SEs of 0.350 ± 0.060 at the 10th, 0.292 ± 0.029 at the 25th, 0.262 ± 0.020 at the 50th, 0.234 ± 0.025 at the 75th, and 0.191 ± 0.025 at the 90th percentiles of the FEV1/FVC ratio. Maximum mid-expiratory flow (MMEF) h2 ± SEs increased 0.0025 ± 0.0007 (P = 0.0004) with every one-percent increment in its distribution, i.e.: 0.467 ± 0.046, 0.467 ± 0.033, 0.554 ± 0.038, 0.615 ± 0.042, and 0.675 ± 0.060 at the 10th, 25th, 50th, 75th, and 90th percentiles of its distribution. This was due to forced expiratory flow at 75% of FVC (FEF75%), whose quantile-specific h2 increased an average of 0.0042 ± 0.0008 for every one-percent increment in its distribution. It is speculated that previously reported gene-environment interactions may be partially attributable to quantile-specific h2 , i.e., greater heritability in individuals with lower FEV1/FVC due to smoking or airborne particles exposure vs. nonsmoking, unexposed individuals. Conclusion:Heritabilities of FEV1/FVC, MMEF, and FEF75% from quantile-regression of offspring-parent and sibling spirometric data suggest their quantile-dependent expressivity.

SUBMITTER: Williams PT

PROVIDER: S-EPMC7233273 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution.

Williams Paul T PT

PeerJ 20200515

<h4>Background</h4>"Quantile-dependent expressivity" refers to a genetic effect that is dependent upon whether the phenotype (e.g., spirometric data) is high or low relative to its population distribution. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV<sub>1</sub>), and the FEV<sub>1</sub>/FVC ratio are moderately heritable spirometric traits. The aim of the analyses is to test whether their heritability (<i>h<sup>2</sup></i> ) is constant over all quantiles of their dist ...[more]

PMID: 32461834

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Project description:"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.

Project description:BackgroundUrinary 8-isoprostane provides a significantly heritable measure of oxidative stress. Prior reports suggest that genetic variants may modulate oxidative stress due to smoking, other environmental factors, and disease. Alternatively, these apparent modulations may reflect a dependence of genetic effects on 8-isoprostane concentrations.MethodTo test whether genetic effects on 8-isoprostane concentrations are quantile-dependent, quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted creatinine-standardized urinary 8-isoprostane concentrations of Framingham Heart Study families. Quantile-specific heritabilities were calculated as h2 = 2βOP/(1+rspouse) and h2 = {(1+8rspouseβFS)0.5-1}/(2rspouse)).ResultsSpouse 8-isoprostane concentrations were weakly concordant (rspouse = 0.06). 8-isoprostane heritability (h2±SE) increased significantly with increasing percentiles of its distribution (Plinear trend = 0.0009, Pquadratic trend = 0.0007, Pcubic trend = 0.003) when estimated from βOP, and when estimated from βFS (Plinear trend = 0.005, Pquadratic trend = 0.09, Pcubic trend = 0.06). Compared to the 10th percentile, βOP-estimated h2 was over 22-fold greater at the 90th percentile (Pdifference = 9.2 × 10-5), and 5.3-fold greater when estimated from βFS (Pdifference = 0.004). Significantly higher 8-isoprostane heritability in smokers than nonsmokers (0.352 ± 0.147 vs. 0.061 ± 0.036, Pdifference = 0.01), and heavier than lighter drinkers (0.449 ± 0.216 vs. 0.078 ± 0.037, Pdifference = 0.01) were eliminated when corrected for the higher 8-isoprostane concentrations of the smokers and heavier drinkers.ConclusionHeritability of oxidative stress as measured by 8-isoprostane is quantile-dependent, which may contribute to the larger reported effects on oxidative stress by UCP2 -866G > A, IL6 -572C > G and LTA 252A > G polymorphisms in smokers than nonsmokers, by the UCP2 -866G > A polymorphism in coronary heart disease patients, by the ESRRG rs1890552 A > G polymorphism in type 2 diabetics, by the CYBA 242C > T polymorphism after exercise training, by the PLIN 11482G > A/14995A > T haplotype before weight loss, and by the CYBA -930A > G and GSTP1 I105V haplotypes in patients with pulmonary edema.

Project description: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 (? OP,h2 = 2? OP/(1 + rspouse)) and full-sib regression slopes (? FS, h2 = {(1 + 8rspouse ? FS)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 ? OP (P trend = 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 ? FS (P trend = 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.

Project description:BackgroundMonocyte chemoattractant protein-1 (MCP-1) concentrations are 34% to 47% heritable. Larger -2518 G/A (rs1024611) genotypes differences are reported for: 1) MCP-1 production in stimulated vs. basal cells; and 2) MCP-1 concentrations in diseased (sepsis, brain abscess, hepatitis B virus, Alzheimer's disease, Behcet's disease, and systemic lupus erythematosus) vs. healthy patients. Those results suggest that the -2518 G/A effect size may depend on whether the phenotype is high or low relative to its distribution (quantile-dependent expressivity).MethodTo test whether quantile-dependent expressivity applies more broadly to genetic influences on MCP-1 concentrations, quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted serum MCP-1 concentrations of Framingham Heart Study families. Quantile-specific heritabilities were calculated as h2 = 2βOP/(1 + rspouse) and h2={(1 + 8rspouseβFS)0.5-1}/(2rspouse)).ResultsHeritability (h2 ± SE) of MCP-1 concentrations increased from 0.15 ± 0.05 at the 10th percentile of the MCP-1 distribution, 0.23 ± 0.04 at the 25th, 0.32 ± 0.05 at the 50th, 0.43 ± 0.07 at the 75th, and 0.44 ± 0.07 at the 90th percentile, or an 0.0041 ± 0.0009 increase for each one-percent increment in the MCP-1 distribution (Plinear trend = 2.4 × 10-5) when estimated from βOP, and (Plinear trend = 7.7 × 10-9) when estimated from βFS. Compared to the 10th percentile, βOP-estimated h2 was 3-fold greater at the 90th percentile (Pdifference = 0.0003), and 6.9-fold greater when estimated from βFS (Pdifference = 3.3 × 10-6). Re-analysis of in vivo comparison of MCP-1 concentrations in controls vs. patients with MCP-1-elevating conditions, and in vitro studies of MCP-1 production in basal vs. stimulated cells, show rs1024611 genotypes differences that were consistent with quantile-dependent expressivity.ConclusionThe heritability of circulating MCP-1 concentrations is quantile-dependent.

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Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution.

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Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution.

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