Quantile-specific heritability of serum growth factor concentrations.
Ontology highlight
ABSTRACT: Background
"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low relative to its distribution.Methods
Quantile-regression analysis was applied to family sets from the Framingham Heart Study to determine whether the heritability (h2) of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), angiopoietin-2, and angiopoietin-2 (sTie-2) and VEGFR1 (sFlt-1) receptor concentrations were quantile-specific.Results
Quantile-specific h2 (±SE) increased with increasing percentiles of the age- and sex-adjusted VEGF (Ptrend<10-16), HGF (Ptrend=0.0004), angiopoietin-2 (Ptrend=0.0002), sTie-2 (Ptrend=1.2 × 10-5), and sFlt-1 distributions (Ptrend=0.04).Conclusion
Heritabilities of VEGF, HGF, angiopoitein-2, sTie-2 and sFlt-1 concentrations are quantile dependent. This may explain reported interactions of genetic loci (rs10738760, rs9472159, rs833061, rs3025039, rs2280789, rs1570360, rs2010963) with metabolic syndrome, diet, recurrent miscarriage, hepatocellular carcinoma, erysipelas, diabetic retinopathy, and bevacizumab treatment in their effect on VEGF concentrations.
SUBMITTER: Williams PT
PROVIDER: S-EPMC10101221 | biostudies-literature | 2021 Feb-Jul
REPOSITORIES: biostudies-literature
Publications
Quantile-specific heritability of serum growth factor concentrations.
Growth factors (Chur, Switzerland) 20210201 1-6
<h4>Background</h4>"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low relative to its distribution.<h4>Methods</h4>Quantile-regression analysis was applied to family sets from the Framingham Heart Study to determine whether the heritability (<i>h<sup>2</sup></i>) of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), angiopoietin-2, and angiopoietin-2 (sTie- ...[more]
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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.
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Project description: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.MethodsSerum 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 = 2β OP/(1 + r spouse)) and full-sib regression slopes (β FS, h 2 = {(1 + 8r spouse β FS)0.5 - 1}/(2r spouse)) was robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples.ResultsQuantile-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.ConclusionsHeritability of serum uric acid concentrations is quantile-specific.
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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.MethodsPlasma 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 (β OP,h2 = 2β OP/(1 + rspouse)) and full-sib regression slopes (β FS, h2 = {(1 + 8rspouse β FS)0.05-1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples.ResultsQuantile-specific h2 (± SE) increased with increasing percentiles of the offspring's age- and sex-adjusted adiponectin distribution when estimated from β 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 β 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.ConclusionAdiponectin 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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Project description:Genetic heritability (h2) of alcohol use is reported to be greater in rural dwellers, distressed marriages, low socioeconomic status, in girls who are unmarried or lacking closeness with their parents or religious upbringing, in less-educated men, and in adolescents with peers using alcohol. However, these are all risk factors for heavy drinking, and the greater heritability could be due to quantile-dependent expressivity, i.e., h2 dependent upon whether the phenotype (alcohol intake) is high or low relative to its distribution. Quantile regression showed that h2 estimated from the offspring-parent regression slope increased significantly from lowest to highest gram/day of alcohol consumption (0.006 ± 0.001 per percent, P = 1.1 × 10-7). Heritability at the 90th percentile of the sample distribution (0.557 ± 0.116) was 4.5-fold greater than at the 10th percentile (0.122 ± 0.037). Heritabilities for intakes of other macronutrients were not quantile-dependent. Thus quantile-dependent expressivity may explain the higher estimated heritability associated with risk factors for high alcohol consumption.
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Project description:BackgroundWe 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).ObjectiveEvidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h2) in a larger population (Framingham cohort).MethodsQuantile regression was used to test whether the offspring-parent (βOP) and full-sib (βFS) 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 2βOP/(1 + rspouse) and [(8βFSrspouse + 1)0.5-1]/(2rspouse), where rspouse is the spouse correlation.ResultsHDL cholesterol heritability estimated from βOP increased significantly (P = 4.2 × 10-5) from the 10th (h2 ± SE: 0.44 ± 0.03), 25th (0.45 ± 0.03), 50th (0.47 ± 0.03), and 75th (0.56 ± 0.04) to the 90th percentiles (0.65 ± 0.06) of the offspring's age- and sex-adjusted HDL cholesterol distribution. Heritability estimated from βFS also increased significantly with the percentiles of the offspring's HDL cholesterol (P = .002), apo A1 (P = .006), HDL2 cholesterol (P = .003), and HDL3 cholesterol distribution (P = .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.ConclusionHDL 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.
| S-EPMC7492391 | biostudies-literature
Project description:PurposeHeritability (h2 , the proportion of the phenotypic variance attributable to additive genetic effects) is traditionally assumed to be constant throughout the distribution of the phenotype. However, the heritabilities of circulating C-reactive protein, interleukin-6, plasminogen activator inhibitor type-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) concentrations depend upon whether the phenotype is high or low relative to their distributions (quantile-dependent expressivity), which may account for apparent gene-environment interactions. Whether the heritabilities of other inflammatory biomarkers linked to cardiovascular disease are quantile-dependent remain to be determined.Patients and methodsQuantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted phenotypes of families surveyed as part of the Framingham Heart Study. Quantile-specific heritabilities were calculated as: h2 =2βOP/(1+rspouse) and h2 ={(1+8rspouseβFS)0.5-1}/(2rspouse).ResultsHeritability (h2 ± SE) of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass concentrations increased from 0.11 ± 0.03 at the 10th percentile, 0.08 ± 0.03 at the 25th, 0.12 ± 0.03 at the 50th, 0.20 ± 0.04 at the 75th, and 0.26 ± 0.06 at the 90th percentile, or 0.0023 ± 0.0006 per each one-percent increase in the phenotype distribution (Plinear trend= 0.0004). Similarly, h2 increased 0.0029 ± 0.0011 (Plinear trend= 0.01) for sP-selectin, 0.0032 ± 0.0009 (Plinear trend= 0.0001) for soluble intercellular adhesion molecule 1 (sICAM-1), and 0.0026 ± 0.0006 for tumor necrosis factor receptor 2 (TNFR2) (Plinear trend= 5.0 × 10-6) per each one-percent increase in their distributions when estimated from βOP. Osteoprotegerin and soluble ST2 heritability also increased significantly with increasing percentiles of their distributions when estimated from βFS. Lp-PLA2 activity, CD40 ligand, TNFα, interleukin-18, and myeloperoxidase heritability showed no significant quantile-dependence.ConclusionThe heritabilities of circulating Lp-PLA2-mass, sP-selectin, sICAM-1, TNFR2, osteoprotegerin and soluble ST2 concentrations are quantile-dependent, which may contribute to purported genetic modulations of: 1) sP-selectin's relationships to venous thrombosis, pulmonary hypertension, type 2 diabetes and atorvastatin treatment; 2) sICAM-I's relationships to brain abscess and atorvastatin treatment; and 3) Lp-PLA2's relationships to myocardial infarction and preeclampsia.
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Project description: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 (h 2) 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.MethodsSerum 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, h 2 ={(1 + 8rspouseβFS)0.5 - 1}/(2rspouse)) and offspring-parent regression slopes (βOP, h 2 = 2βOP/(1 + rspouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples.ResultsQuantile-specific h 2 (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted CRP distribution when estimated from βOP (P trend = 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 (P trend = 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.ConclusionHeritability 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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