Abstract

BACKGROUND/OBJECTIVES: Quantile-dependent expressivity occurs when a gene's phenotypic expression depends upon whether the trait (e.g., BMI) is high or low relative to its distribution. We have previously shown that the obesity effects of a genetic risk score (GRS_BMI) increased significantly with increasing quantiles of BMI. However, BMI is an inexact adiposity measure and GRS_BMI explains <3% of the BMI variance. The purpose of this paper is to test BMI for quantile-dependent expressivity using a more inclusive genetic measure (h², heritability in the narrow sense), extend the result to other adiposity measures, and demonstrate its consistency with purported gene-environment interactions. SUBJECTS/METHODS: Quantile-specific offspring-parent regression slopes (β_OP) were obtained from quantile regression for height (ht) and computed tomography (CT), dual-energy x-ray absorptiometry (DXA), anthropometric, and bioelectrical impedance (BIA) adiposity measures. Heritability was estimated by 2β_OP/(1 + r_spouse) in 6227 offspring-parent pairs from the Framingham Heart Study, where r_spouse is the spouse correlation. RESULTS: Compared to h² at the 10th percentile, genetic heritability was significantly greater at the 90th population percentile for BMI (3.14-fold greater, P < 10^-15), waist girth/ht (3.27-fold, P < 10^-15), hip girth/ht (3.12-fold, P = 6.3 × 10^-14), waist-to-hip ratio (1.75-fold, P = 0.01), sagittal diameter/ht (3.89-fold, P = 3.7 × 10^-7), DXA total fat/ht² (3.62-fold, P = 0.0002), DXA leg fat/ht² (3.29-fold, P = 2.0 × 10^-11), DXA arm fat/ht² (4.02-fold, P = 0.001), CT-visceral fat/ht² (3.03-fold, P = 0.002), and CT-subcutaneous fat/ht² (3.54-fold, P = 0.0004). External validity was suggested by the phenomenon's consistency with numerous published reports. Quantile-dependent expressivity potentially explains precision medicine markers for weight gain from overfeeding or antipsychotic medications, and the modifying effects of physical activity, sleep, diet, polycystic ovary syndrome, socioeconomic status, and depression on gene-BMI relationships. CONCLUSIONS: Genetic heritabilities of anthropometric, CT, and DXA adiposity measures increase with increasing adiposity. Some gene-environment interactions may arise from analyzing subjects by characteristics that distinguish high vs. low adiposity rather than the effects of environmental stimuli on transcriptional and epigenetic processes.