Exome-wide association study in 54,698 south Asians identifies novel type 2 diabetes associations with HNF4A and GP2

Type 2 diabetes (T2D) disproportionately affects individuals of South Asian ancestry (SAS), yet they remain underrepresented in genetic studies. We performed an exome-wide association study in 54,698 SAS T2D case: controls and follow-up metabolic trait evaluation. We identified ancestry-specific genes and protein-coding variants, including a SAS-specific variant in the known monogenic diabetes gene HNF4A (rs150776703, Pro437Ser), which was associated with protection from T2D (OR = 0.48, p = 2.8×10⁻¹□), diabetic eye disease, and gestational diabetes. Experimental interrogation of HNF4A Pro437Ser revealed context-dependent enhancement of HNF4A transcriptional activity, suggesting gain-of-function. We additionally describe a T2D risk increasing variant in GP2 (rs78193826, Val429Met, OR = 1.21, p = 5.14×10 ^-6 ), which was also associated with beta-cell dysfunction. These findings underscore how studying ancestrally distinct populations disproportionately affected by T2D can reveal novel disease genes, therapeutic hypotheses, and biological insight.