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
Hodgson, S.; Bui, V.; Bigossi, M.; Stow, D.; Maroteau, C.; Williamson, A.; Hu, S.; Blee, A. M.; Dawed, A. Y.; Carrasco-Zanini-Sanchez, J.; Baskar, V.; Saravanan, J.; Jacobs, B. M.; Kalantzis, G.; Rison, S.; Walter, K.; Pennarun, E.; Genes& Health Research Team, ; Martin, H. C.; Barroso, I.; Radha, V.; Rajendra, P.; Langenberg, C.; Viswanathan, M.; Ranjit Mohan, A.; van Heel, D. A.; Majithia, A.; Jamshidi, Y.; Finer, S.; Siddiqui, M. K.
Show abstract
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 = 2.8x10-{superscript 1}{square}), 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 = 5.14x10-6), 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.
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