GENOMIC VARIANTS ASSOCIATED WITH EARLY-ONSET TYPE 2 DIABETES IN SOUTH ASIAN POPULATIONS

Abstract

Type 2 diabetes mellitus (T2D) is more prevalent and of higher burden earlier in South Asian populations, but the underlying genetic mechanisms of early susceptibility to the condition are not fully understood. Open genomic databases offer the possibility to find variants that may have an impact on the manifestation of the disease in the past. The present study aimed to identify genomic variants associated with T2D in South Asians and prioritize those with potential early-onset relevance using a composite scoring framework. A secondary analysis was conducted using variants obtained from the Type 2 Diabetes Knowledge Portal based on a large-scale association dataset. Following initial filtering within the portal, the top 500 variants were analyzed. Variants were evaluated using statistical significance, effect size, functional annotation, and gene mapping. A composite score integrating −log10(p-value), absolute effect size, and functional impact was used to classify variants, with the upper quartile designated as early-onset-associated. Of the 500 variants analyzed, 293 were genome-wide significant, and 125 were classified as early-onset-associated. Strong association signals were concentrated at the TCF7L2 locus, with additional contributions from CDKAL1, IGF2BP2, HHEX, ADCY5, PPARG, UBE2E2, and SLC30A8. Most variants were non-coding, indicating a predominantly regulatory architecture, with selected coding variants suggesting functional relevance. These findings highlight key susceptibility loci in South Asians and demonstrate that composite prioritization can identify variants with potential relevance to early-onset T2D, providing targets for future validation.