Genotype-covariate interaction-effects and the heritabillity of adult body mass index (BMI), a multifactorial trait

Obesity is a worldwide epidemic, with major health and economic costs. Clearly, obesity is a multifactorial trait –– reflecting the contributions of hundreds if not thousands of genes (DNA sequence differences, the genotype), plus epigenetic effects (DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling), plus environmental adversity of varying amounts. We can view obesity not that much differently than drug efficacy or adverse drug reactions, which are also multifactorial traits.

In the attached report, authors estimate heritability for body mass index (BMI) in ~172,000 sibling-pairs and ~150,832 unrelated individuals and explore the contribution of genotype–covariate interaction-effects at common SNP loci. They found evidence for genotype–age interaction [likelihood ratio test (LRT) = 73.58; degrees of freedom (df) = 1; and P = 4.83 × 10–18], which contributed ~8.1% to BMI variability. Across eight self-reported lifestyle factors –– including diet and exercise –– authors found genotype–environment interaction only for smoking behavior (LRT = 19.70; P = 5.03 × 10–5; LRT = 30.80, P = 1.42 × 10–8), which contributed ~4.0% to BMI variation. Bayesian association analysis suggested that BMI is highly polygenic, with 75% of the SNP heritability attributable to loci that each explain <0.01% of the phenotypic variance. These findings (Peter Visscher is senior author) imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI. The systematic inflation of estimated h2 values for BMI in classical twin studies may simply reflect confounding between shared environ­ment and genetic effects. Alternatively, shared age and environments between twins –– could contribute to the discrepancy in estimates across experimental designs, if there are strong age- or environment-depend­ent genetic effects. If this is the case, heritability estimates from popu­lation studies of unrelated individuals might represent the average genetic effects across ages and environmental or lifestyle factors, resulting in unobserved genetic variation. In the attached report, authors used a large body of data on siblings, plus publicly available phenotype–genotype data sets of unrelated individuals, to estimate the heritability of BMI across a range of experimental designs. And they explored the contribution of age- and environment-specific genetic effects on BMI variation. Nature Genetics Aug 2o17; 49: 1274–1281

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