Analysis of rare coding variants in 200,000 exome‐sequenced subjects reveals novel genetic risk factors for type 2 diabetes

Abstract Aims The study aimed to elucidate the effects of rare genetic variants on the risk of type 2 diabetes (T2D). Materials and methods Weighted burden analysis of rare variants was applied to a sample of 200,000 exome‐sequenced participants in the UK Biobank project, of whom over 13,000 were identified as having T2D. Variant weights were allocated based on allele frequency and predicted effect, as informed by a previous analysis of hyperlipidaemia. Results There was an exome‐wide significant increased burden of rare, functional variants in three genes, GCK , HNF4A and GIGYF1 . GIGYF1 has not previously been identified as a diabetes risk gene and its product appears to be involved in the modification of insulin signalling. A number of other genes did not attain exome‐wide significance but were highly ranked and potentially of interest, including ALAD , PPARG , GYG1 and GHRL . Loss of function (LOF) variants were associated with T2D in GCK and GIGYF1 whereas nonsynonymous variants annotated as probably damaging were associated in GCK and HNF4A . Overall, fewer than 1% of T2D cases carried one of these variants. In HNF1A and HNF1B there was an excess of LOF variants among cases but the small numbers of these fell short of statistical significance. Conclusions Rare genetic variants make an identifiable contribution to T2D in a small number of cases but these may provide valuable insights into disease mechanisms. As larger samples become available it is likely that additional genetic factors will be identified.