Abstract

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 (<i>h²</i> ) 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 (<i>β</i> _OP,<i>h²</i> = 2<i>β</i> _OP/(1 + r_spouse)) and full-sib regression slopes (<i>β</i> _FS, <i>h²</i> = {(1 + 8r_spouse <i>β</i> _FS)^0.05-1}/(2r_spouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples. RESULTS: Quantile-specific <i>h²</i> (± SE) increased with increasing percentiles of the offspring's age- and sex-adjusted adiponectin distribution when estimated from <i>β</i> _OP (<i>P</i> _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 <i>β</i> _FS (<i>P</i> _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 <i>ADIPOQ</i> polymorphisms were modified by adiposity in accordance with its adiponectin-lowering effect; (3) response to rosiglitazone was predicted by the 45T&gt; G <i>ADIPOQ</i> polymorphism; (4) difference by <i>ADIPOQ</i> 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.