Identifying loci affecting trait variability and detecting interactions in genome-wide association studies

Identification of genetic variants with effects on trait variability can provide insights into the biological mechanisms that control variation and can identify potential interactions. We propose a two-degree-of-freedom test for jointly testing mean and variance effects to identify such variants. We implement the test in a linear mixed model, for which we provide an efficient algorithm and software. To focus on biologically interesting settings, we develop a test for dispersion effects, that is, variance effects not driven solely by mean effects when the trait distribution is non-normal. We apply our approach to body mass index in the subsample of the UK Biobank population with British ancestry (n ~408,000) and show that our approach can increase the power to detect associated loci. We identify and replicate novel associations with significant variance effects that cannot be explained by the non-normality of body mass index, and we provide suggestive evidence for a connection between leptin levels and body mass index variability.