ABSTRACT NUMBER: ESOC2026A1903 GENETIC ASSOCIATION STUDY ON WHITE MATTER HYPERINTENSITY BURDEN IN SOUTH ASIANS USING WHOLE GENOME SEQUENCING DATA

Abstract Background and aims White matter hyperintensity burden (WMH) is the most prominent MRI marker of cerebral small vessel disease linked to risk of stroke, cognitive decline, and dementia. Despite high burden, genetic architecture of WMH is understudied in non-European population. We aim to decode the genetic risk architecture of WMH in South Asians using whole-genome sequencing data.​ Methods Whole-genome sequencing data from 906 South Asian individuals in UK Biobank were analyzed for total, deep, and periventricular WMH burden derived from T1- and T2-FLAIR MRI. Association analyses used linear mixed models in REGENIE, adjusting for age, age2, sex, principal components 1–10, assessment center, and total intracranial volume. To enhance discovery, we performed meta-analysis with variants from Sargurupremraj et al., the largest WMH genome-wide association study to date.​ Results Of 27 established European total WMH volume risk loci, 15 showed concordant effects in South Asians, with CALCRL1 being our top hit with p-value of 1.2x10-7. Given the limited sample size, no genome-wide significant hit was detected in South Asians. Moreover, a cross-ancestry meta-analysis identified 2 novel genome-wide significant associations at AMZ2P1 and MCL1.​ Conclusions We report the first genetic association study on WMH volume using whole genome sequencing data in South Asians, identifying 2 novel genome-wide significant hits through cross-ancestry meta-analysis. Our study emphasizes the importance of larger, multi-ancestry genetic investigations to unravel the genetic risk architecture of WMH burden. Conflict of interest JanakiNairM.nothing to disclose