Three Loci Affecting Variance of Body Mass Index in African Americans and Sub-Saharan Africans

Conventional genome-wide association studies (GWAS) are designed to assess the effect of a genetic locus on phenotypic mean by genotype. Such loci explain a proportion of phenotypic variance known as narrow-sense heritability. In contrast, variance quantitative trait loci (vQTL) are associated with the phenotypic variance by genotype. These loci explain an additional proportion of phenotypic variance and contribute to broad-sense heritability but not to narrow-sense heritability. Here, a genome-wide vQTL analysis in 22,805 African Americans yielded eight loci for body mass index (BMI). Of these loci, three were replicated in 6002 sub-Saharan Africans. No locus reached genome-wide significance using the standard additive model. Furthermore, no locus showed evidence for natural selection, haplotype effects, or gene × sex or gene × study interactions. Two loci showed evidence for an effect of locus-specific ancestry resulting from admixture and for a gene × gene interaction. One locus showed evidence for interaction with diastolic blood pressure, consistent with this vQTL capturing an unmodeled gene × covariate interaction. These analyses demonstrate that relevant BMI loci can be detected by evaluating vQTL and that these loci contribute to the underexplored broad-sense heritability for this trait.