Selection-guided discovery in South Asians implicates the MAPT locus in insulin resistance.

Authors

Erwan Pennarun, Borbala Banfalvi, Yuemin Li, Sam Hodgson, Vi Bui, Margherita Bigossi, Miriam Samuel, Sandipan Arnab, Tayyibah Naimah, Stuart Rison, Daniel Stow, Benjamin Jacobs, Viswanathan Baskar, Jebarani Saravanan, Venkatesan Radha, David van Heel, MDRF research team, Genes & Health research team, Viswanathan Mohan, Sarah Finer, Michael DeGiorgio, Ranjit Mohan Anjana, Matteo Fumagalli, Moneeza K Siddiqui

Published in

medRxiv : the preprint server for health sciences. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

South Asians constitute 25% of the global population yet account for 33% of individuals living with type 2 diabetes (T2D) (1). Despite this burden, they remain substantially underrepresented in genome-wide association studies (GWAS), limiting discovery of ancestry-relevant disease biology (2). This limits biological insight and hampers genomic discovery. Here we integrated genome-wide signatures of recent positive selection across 13 South Asian populations (3,4) with cross-trait genetic association data (3,4). We identified 1,797 genes residing within regions under recent positive selection and prioritised 65 shared across South Asia. Selection-prioritised loci were enriched for credible sets from the largest trans-ancestry T2D GWAS and for partitioned polygenic score clusters implicated in lipodystrophy-like fat distribution, obesity and proinsulin biology. Multi-trait fine-mapping recovered established T2D loci, including RBM6 and PEPD , and identified a signal at MAPT associated with hepatic insulin resistance, erythrocytic traits and HbA1c in two independent south Asian cohorts (5-7). These findings demonstrate that signatures of recent positive selection can be integrated with genetic association data to prioritise metabolically relevant loci and provide a complementary route to genetic discovery in underrepresented populations.

PMID:
42396317
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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