Weighted Burden Analysis of Rare Genetic Variants Identifies Novel Genes with Effects on BMI

INTRODUCTION: A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and BMI had implicated two genes, MC4R and PCSK1, at exome-wide significance. In addition, further 66 genes were significant with an uncorrected p value of <0.001. METHODS: Exome sequence data have become available for further 270,000 participants, and weighted burden analyses to test for association with BMI were carried out in this sample for all the 68 genes highlighted by the previous study. RESULTS: Three novel genes, in addition to MC4R and PCSK1, were significant after correction for multiple testing: PTOV1, GALNT9, and ATP8B2. All five genes were exome-wide significant in the whole sample of 470,000 participants. Rare coding variants impairing gene function were associated with reduced BMI for ATP8B2 but increased BMI for the other genes, and for all genes, loss of function variants had larger effect sizes than nonsynonymous variants. CONCLUSION: The biological mechanisms whereby the novel genes might affect BMI are not clear, although impairment of ATP8B2 might possibly have an effect on insulin secretion. Functional studies might throw further light on how these genes are involved in regulation of body weight. Collectively, the identified variants are very rare and do not make a major contribution to variation in BMI in the population. This research has been conducted using the UK Biobank Resource.