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 (<i>β</i> _OP, <i>h</i> ² = 2<i>β</i> _OP/(1 + <i>r</i> _spouse)) and full-sib regression slopes (<i>β</i> _FS, <i>h</i> ² = {(1 + 8<i>r</i> _spouse <i>β</i> _FS)^0.5 - 1}/(2<i>r</i> _spouse)) was robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. RESULTS: Quantile-specific <i>h</i> ² (±SE) increased with increasing percentiles of the offspring's sex- and age-adjusted uric acid distribution when estimated from <i>β</i> _OP (<i>P</i> _trend = 0.001): 0.34 ± 0.03 at the 10^th, 0.36 ± 0.03 at the 25^th, 0.41 ± 0.03 at the 50^th, 0.46 ± 0.04 at the 75^th, and 0.49 ± 0.05 at the 90^th percentile and when estimated from <i>β</i> _FS (<i>P</i> _trend = 0.006). This is consistent with the larger genetic effect size of (1) the <i>SLC2A9</i> rs11722228 polymorphism in gout patients vs. controls, (2) the <i>ABCG2</i> rs2231142 polymorphism in men vs. women, (3) the <i>SLC2A9</i> rs13113918 polymorphism in obese patients prior to bariatric surgery vs. two-year postsurgery following 29 kg weight loss, (4) the <i>ABCG2</i> rs6855911 polymorphism in obese vs. nonobese women, and (5) the <i>LRP2</i> rs2544390 polymorphism in heavier drinkers vs. abstainers. Quantile-dependent expressivity may also explain the larger genetic effect size of an <i>SLC2A9</i>/<i>PKD2</i>/<i>ABCG2</i> haplotype for high vs. low intakes of alcohol, chicken, or processed meats. CONCLUSIONS: Heritability of serum uric acid concentrations is quantile-specific.