Abstract
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 (βOP, h2 = 2βOP/(1 + rspouse)) and full-sib regression slopes (βFS, h2 = {(1 + 8rspouseβFS)0.5 − 1}/(2rspouse)) was 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 sex- and age-adjusted uric acid distribution when estimated from βOP (Ptrend = 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 βFS (Ptrend = 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.
Highlights
Serum uric acid concentrations reflect the equilibrium between renal clearance and endogenous uric acid produced from food-derived purines [1]
Our analyses of offspring-parent and full-sib pairs from the Framingham Heart Study suggest that serum uric acid concentrations exhibit quantile-dependent expressivity
Whereas genetic analyses traditionally assume that effect size is constant throughout the phenotype distribution, our analysis showed that heritability at the 90th percentile of the offspring distribution was 47% larger than that at the 10th percentile when estimated from offspring-parent regression and 53% larger when estimated from the full-sib regres
Summary
Serum uric acid concentrations reflect the equilibrium between renal clearance and endogenous uric acid produced from food-derived purines [1]. Hyperuricaemia, defined as uric acid > 404 or >417 μmol/L (>6.8 or >7 mg/dL) [2], occurs when renal excretion is inadequate or uric acid is overproduced, for example, due to excessive intake of sugar-sweetened beverages and purine-rich foods [2]. Inadequate excretion is mainly due to the high reabsorption of filtered urate in the renal proximal tubules [3]. Hyperuricaemia can lead to gout, i.e., an inflammatory response within joints and tissues due to the deposition of urate crystals [2]. Male sex, obesity, alcohol consumption, and insulin resistance are associated with increased hyperuricaemia and gout risk [2]. Hyperuricaemia is a risk factor for diabetes, hypertension, cardiovascular disease, and chronic kidney disease [2]
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