NOTCH3 p.Arg1231Cys is Markedly Enriched in South Asians and Associated with Stroke

Abstract The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NOTCH3 p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p value = 3.87×10 -9 ), and all strokes (OR [CI] = 2.30 [3.01, 1.77], p value = 7.79×10 -10 ). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95%CI] in SD units = 1.1 [0.61, 1.5], p value = 3.0×10 -6 ). The variant is attributable for approximately 5.5% of hemorrhagic strokes and 1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.