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

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10099 ◽  
Author(s):  
Paul T. Williams
Keyword(s):  
Alcohol Consumption ◽  
Genetic Variant ◽  
Postprandial Lipemia ◽  
Specific Response ◽  
Plasma Adiponectin ◽  
Gene Environment ◽  
Heart Study ◽  
Postprandial Response ◽  
Regression Slopes ◽  
Age And Sex

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.

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

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Paul T. Williams
Keyword(s):  
Environmental Effects ◽  
Framingham Heart Study ◽  
Leptin Receptor ◽  
Genetic Variant ◽  
Third Generation ◽  
Gene Environment ◽  
Heart Study ◽  
Soluble Leptin Receptor ◽  
Regression Slopes ◽  
Age And Sex

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.

scholarly journals Quantile-Dependent Expressivity of Serum Uric Acid Concentrations

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Paul T. Williams
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Effect Size ◽  
Genetic Variant ◽  
Genetic Effect ◽  
Obese Patients ◽  
Processed Meats ◽  
Gene Environment ◽  
Heart Study ◽  
Regression Slopes

Objective. “Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., serum uric acid) is high or low relative to its distribution. Analyses were performed to test whether serum uric acid heritability is quantile-specific and whether this could explain some reported gene-environment interactions. Methods. Serum uric acid concentrations were analyzed from 2151 sibships and 12,068 offspring-parent pairs from the Framingham Heart Study. Quantile-specific heritability from offspring-parent regression slopes ( β OP , h 2 = 2 β OP / 1 + r spouse ) and full-sib regression slopes ( β FS , h 2 = 1 + 8 r spouse β FS 0.5 − 1 / 2 r spouse ) was robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results. Quantile-specific h 2 (±SE) increased with increasing percentiles of the offspring’s sex- and age-adjusted uric acid distribution when estimated from β OP   P trend = 0.001 : 0.34 ± 0.03 at the 10th, 0.36 ± 0.03 at the 25th, 0.41 ± 0.03 at the 50th, 0.46 ± 0.04 at the 75th, and 0.49 ± 0.05 at the 90th percentile and when estimated from β FS   P trend = 0.006 . This is consistent with the larger genetic effect size of (1) the SLC2A9 rs11722228 polymorphism in gout patients vs. controls, (2) the ABCG2 rs2231142 polymorphism in men vs. women, (3) the SLC2A9 rs13113918 polymorphism in obese patients prior to bariatric surgery vs. two-year postsurgery following 29 kg weight loss, (4) the ABCG2 rs6855911 polymorphism in obese vs. nonobese women, and (5) the LRP2 rs2544390 polymorphism in heavier drinkers vs. abstainers. Quantile-dependent expressivity may also explain the larger genetic effect size of an SLC2A9/PKD2/ABCG2 haplotype for high vs. low intakes of alcohol, chicken, or processed meats. Conclusions. Heritability of serum uric acid concentrations is quantile-specific.

scholarly journals Quantile-specific heritability of plasma fibrinogen concentrations

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262395
Author(s):  
Paul T. Williams
Keyword(s):  
Smoking Status ◽  
Genetic Effect ◽  
Disease Status ◽  
Plasma Fibrinogen ◽  
Blood Protein ◽  
Fibrinogen Concentration ◽  
Gene Environment ◽  
Heart Study ◽  
Regression Slopes ◽  
Pollution Exposure

Background Fibrinogen is a moderately heritable blood protein showing different genetic effects by sex, race, smoking status, pollution exposure, and disease status. These interactions may be explained in part by “quantile-dependent expressivity”, where the effect size of a genetic variant depends upon whether the phenotype (e.g. plasma fibrinogen concentration) is high or low relative to its distribution. Purpose Determine whether fibrinogen heritability (h2) is quantile-specific, and whether quantile-specific h2 could account for fibrinogen gene-environment interactions. Methods Plasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 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 1000 bootstrap samples. Results Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted fibrinogen distribution when estimated from βOP (Ptrend = 5.5x10-6): 0.30±0.05 at the 10th, 0.37±0.04 at the 25th, 0.48±0.05 at the 50th, 0.61±0.06 at the 75th, and 0.65±0.08 at the 90th percentile, and when estimated from βFS (Ptrend = 0.008): 0.28±0.04 at the 10th, 0.31±0.04 at the 25th, 0.36±0.03 at the 50th, 0.41±0.05 at the 75th, and 0.50±0.06 at the 90th percentile. The larger genetic effect at higher average fibrinogen concentrations may contribute to fibrinogen’s greater heritability in women than men and in Blacks than Whites, and greater increase from smoking and air pollution for the FGB -455G>A A-allele. It may also explain greater fibrinogen differences between: 1) FGB -455G>A genotypes during acute phase reactions than usual conditions, 2) GTSM1 and IL-6 -572C>G genotypes in smokers than nonsmokers, 3) FGB -148C>T genotypes in untreated than treated diabetics, and LPL PvuII genotypes in macroalbuminuric than normoalbuminuric patients. Conclusion Fibrinogen heritability is quantile specific, which may explain or contribute to its gene-environment interactions. The analyses do not disprove the traditional gene-environment interpretations of these examples, rather quantile-dependent expressivity provides an alternative explanation that warrants consideration.

scholarly journals Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin

2021 ◽  
pp. 1-25
Author(s):  
Paul T. Williams
Keyword(s):  
Insulin Resistance ◽  
Fasting Glucose ◽  
Tolerance Test ◽  
Alternative Interpretation ◽  
Model Assessment ◽  
Gene Environment ◽  
Heart Study ◽  
Glucose Ratio ◽  
Homeostatic Model Assessment ◽  
Regression Slopes

<b><i>Background:</i></b> “Quantile-dependent expressivity” is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution. <b><i>Methods:</i></b> Quantile-specific offspring-parent regression slopes (β<sub>OP</sub>) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study. <b><i>Results:</i></b> Quantile-specific heritability (<i>h</i><sup>2</sup>), estimated by 2β<sub>OP</sub>/(1 + <i>r</i><sub>spouse</sub>), increased 0.0045 ± 0.0007 (<i>p</i> = 8.8 × 10<sup>−14</sup>) for each 1% increment in the fasting glucose distribution, that is, <i>h</i><sup>2</sup> ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin (<i>p</i> = 1.2 × 10<sup>−6</sup>), homeostatic model assessment of insulin resistance (HOMA-IR, <i>p</i> = 5.3 × 10<sup>−5</sup>), insulin/glucose ratio (<i>p</i> = 3.9 × 10<sup>−5</sup>), proinsulin (<i>p</i> = 1.4 × 10<sup>−6</sup>), proinsulin/insulin ratio (<i>p</i> = 2.7 × 10<sup>−5</sup>), and glucose concentrations during a glucose tolerance test (<i>p</i> = 0.001), and their logarithmically transformed values. <b><i>Discussion/Conclusion:</i></b> These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between <i>ACE, ADRB3</i>, <i>PPAR-γ2</i>, and <i>TNF-α</i> polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity (<i>APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2</i>), gene-exercise (<i>INS</i>), gene-diet (<i>ACSL1</i>, <i>ELOVL6</i>, <i>IRS-1</i>, <i>PLIN</i>, <i>S100A9</i>), and gene-socioeconomic interactions.

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

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10914
Author(s):  
Paul T. Williams
Keyword(s):  
Acute Exercise ◽  
Postprandial Lipemia ◽  
Arterial Disease ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Coronary Syndrome ◽  
Heart Study ◽  
Regression Slopes ◽  
Peripheral Arterial ◽  
Serum Crp

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.

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

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9145 ◽  
Author(s):  
Paul T. Williams
Keyword(s):  
Quantile Regression ◽  
Population Distribution ◽  
Genetic Effect ◽  
Forced Expiratory Volume ◽  
Gene Environment ◽  
Heart Study ◽  
Significance Levels ◽  
Forced Expiratory Flow ◽  
Expiratory Flow ◽  
Regression Slopes

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 (βOP), offspring-midparent (βOM), and full-sib regression slopes (βFS). Nonparametric significance levels were obtained from 1,000 bootstrap samples. βOPs were used as simple indicators of quantile-specific heritability (i.e., h2 = 2βOP/(1+rspouse), where rspouse was the correlation between spouses). Results βOP ± 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., βOP ± 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.

scholarly journals Evaluating the genetic effects of sex hormone traits on the development of mental traits: a polygenic score analysis and gene-environment-wide interaction study in UK Biobank cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xiao Liang ◽  
ShiQiang Cheng ◽  
Jing Ye ◽  
XiaoMeng Chu ◽  
Yan Wen ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Fluid Intelligence ◽  
Genetic Effects ◽  
Sex Hormone ◽  
Uk Biobank ◽  
Interaction Study ◽  
Middle Aged ◽  
Bioavailable Testosterone ◽  
Gene Environment ◽  
Middle Aged Adults

Abstract Objective To evaluate the genetic effects of sex hormone traits on the development of mental traits in middle-aged adults. Methods The SNPs associated with sex hormone traits were derived from a two-stage genome-wide association study (GWAS). Four sex hormone traits were selected in the current study, including sex hormone-binding globulin (SHBG), testosterone, bioavailable testosterone and estradiol. The polygenic risk score (PRS) of sex hormone traits were calculated from individual-level genotype data of the United Kingdom (UK) Biobank cohort. We then used logistic and linear regression models to assess the associations between individual PRS of sex hormone traits and the frequency of alcohol consumption, anxiety, intelligence and so on. Finally, gene-environment-wide interaction study (GEWIS) was performed to detect novel candidate genes interacting with the sex hormone traits on the development of fluid intelligence and the frequency of smoking and alcohol consumption by PLINK2.0. Results We observed positive association between SHBG and the frequency of alcohol consumption (b = 0.0101, p = 3.84 × 10–11) in middle-aged males and females. In addition, estradiol was positively associated with the frequency of alcohol consumption (b = 0.0128, p = 1.96 × 10–8) in middle-aged males. Moreover, bioavailable testosterone was associated with the fluid intelligence (b = − 0.0136, p = 5.74 × 10–5) in middle-aged females. Finally, GEWIS identified one significant loci, Tenascin R (TNR) (rs34633780, p = 3.45 × 10–8) interacting with total testosterone for fluid intelligence. Conclusion Our study results support the genetic effects of sex hormone traits on the development of intelligence and the frequency of alcohol consumption in middle-aged adults in UK.

Abstract P099: The Relation of Kidney Disease to Measures of Digital Arterial Tonometry in the Jackson Heart Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Eric McClendon ◽  
Solomon Musani ◽  
Sushante Khaire ◽  
Herman Taylor ◽  
Ervin Fox
Keyword(s):  
Chronic Kidney Disease ◽  
African Americans ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Least Square ◽  
Jackson Heart Study ◽  
Pulse Wave Amplitude ◽  
Arterial Tonometry ◽  
Heart Study ◽  
Age And Sex

Background: The presence of chronic kidney disease is greater in African Americans than in non-Hispanic whites. Though there is data to show a relation between endothelial dysfunction and end-stage kidney disease, the relation to mild and moderate chronic kidney disease (particularly in African Americans) is unclear. Methods and Results: Digital arterial tonometry was performed during Exam 2 and 3 of the Jackson Heart Study using the endoPAT2000. Data from digital arterial tonometry included baseline pulse wave amplitude (BPA) as a measure of endothelial tone and reactive hyperemic index (F-RHI) as a measure of endothelial function. For this study, the estimated glomerular filtration rate (eGFR) was calculated using the MDRD equation. Those participants with eGFR < 60 ml/min/1.73m2 were defined as having CKD. Participants with eGFR < 15 ml/min/1.73m2 were excluded from the analysis. Microalbuminuria in this study was defined as a urinary albumin:creatinine ratio ≥ 17mg/g in men and ≥ 25 mg/g in women. We compared the differences in least square means adjusted for age and sex, and adjusted for multiple traditional clinical covariates using a generalized linear model. Results: There were 834 participants in the study population (mean age 58.5 years, 61% women); 87 (10.4%) participants with CKD and 108 (13.0%) with microalbuminuria. In age and sex adjusted samples, we found that both BPA and F-RHI were significantly associated with CKD in the pooled samples. However in multivariable adjusted analysis the relation was no longer significant in either the pooled or sex-specific samples. In the multivariable adusted analysis,BPA was significantly (P=0.036) associated with microalbuminuria in men and F-RHI was weakly significantly (P=0.08) associated with microalbuminuria in women. Conclusion: We found that endothelial dysfunction as measured by digital arterial tonometry is not significantly associated with chronic kidney disease. There is an association of endothelial tone in men and endothelial dysfunction in women with microalbuminuria.

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