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

Abstract / Introductory Paragraph 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…