Exome-wide association study in 54,698 south Asians identifies novel type 2 diabetes associations with RNF19A, HNF4A, and dissects role of coding variants in GP2 and CDKAL1

Type 2 diabetes (T2D) disproportionately affects individuals of South Asian ancestry, yet the underlying genetic aetiology remains poorly understood and in genetic studies these populations remain underrepresented. We conducted an exome-wide association study (ExWAS) in 13,674 T2D cases and 41,024 controls of British-Bangladeshi and -Pakistani ancestry from the Genes & Health study, focusing on damaging coding variants in single-variant and gene-level analyses. This represents the largest ExWAS of T2D to date. We tested the association of novel genes and variants with metabolic traits in Genes & Health, UK, Madras Diabetes Research Foundation Biobank, India (MDRF), and the UK Biobank. Gene-level analyses revealed novel associations with RNF19A (p = 1.8x10e-14) and HNF4A (p = 2.4x10e-13), a known monogenic diabetes gene. The HNF4A signal was driven by a South Asian-specific gain-of-function variant (rs150776703, Pro437Ser) protective against T2D (OR = 0.48, p = 2.8x10e-14), diabetic eye disease, and gestational diabetes but associated with elevated LDL-cholesterol, plasma PCSK9 upregulation, and increased myocardial infarction risk (HR = 1.62, p = 0.01). In Huh7 cells, Pro437Ser demonstrated similar transactivation of HNF4A target, G6PC, compared to wild-type, partially explaining the protective effect for T2D. Single-variant analyses highlighted a missense variant in CDKAL1 and a T2D risk-increasing South Asian-specific variant, rs78193826 (GP2: Val429Met), linked to CKD risk and beta-cell dysfunction (via stimulated C-peptides). Meta-analysis with UK Biobank highlights a role for plasma GP2 levels as a biomarker for high genetic risk of beta-cell deficiency and low risk for obesity-mediated T2D. These novel findings provide a foundation for drug target development, precision medicine and deeper exploration of metabolic and cardiovascular disease mechanisms in global populations disproportionately affected by T2D.