An Ancestry-Enriched HNF4A Variant and GP2 Reveal Distinct Mechanisms of Type 2 Diabetes in Exome-Wide Study of 13,674 Cases and 41,024 Controls.

Type 2 diabetes (T2D) is a common and complex metabolic condition with significant heterogeneity within and across ancestries 1-4 . Compared with individuals of European ancestry (EUR), people of south Asian ancestry (SAS) have two to four-fold higher risk of T2D, develop the disease at younger ages and lower body mass index (BMI), and experience more rapid progression to complications 5-10 . Understanding the genetic basis of this is hindered by low representation of south Asians in genetic studies. Here, we perform an exome-wide association study of T2D in 13,674 cases and 41,024 controls from the Genes & Health study of British Pakistani and Bangladeshi individuals. We identify a novel rare variant in HNF4A - a canonical monogenic diabetes / MODY gene, in which missense variants would be expected to increase T2D risk. Surprisingly, HNF4A Pro437Ser is associated with a halved risk of T2D and reduced risk of diabetes-related complications but increased non-HDL cholesterol. We additionally characterise a T2D risk-increasing variant which is common only in South and East Asian ancestral groups ( GP2 Val429Met), which is associated with lower BMI and phenotypic and genetic markers of insulin deficiency. We validate our findings through replication in independent multi-ancestry cohorts, in vitro functional assays, and integration of proteogenomic analysis. These findings highlight how the study of under-represented populations can identify biological mechanisms associated with disease phenotypes enriched in those populations.