1. NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke
- Author
-
Juan Lorenzo Rodriguez-Flores, Shareef Khalid, Neelroop Parikshak, Asif Rasheed, Bin Ye, Manav Kapoor, Joshua Backman, Farshid Sepehrband, Silvio Alessandro Di Gioia, Sahar Gelfman, Tanima De, Nilanjana Banerjee, Deepika Sharma, Hector Martinez, Sofia Castaneda, David D’Ambrosio, Xingmin A. Zhang, Pengcheng Xun, Ellen Tsai, I-Chun Tsai, Regeneron Genetics Center, Maleeha Zaman Khan, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Khalid Mahmood, Tanvir Us Salam, Muhammad Hussain, Javed Iqbal, Faizan Aslam, Michael N. Cantor, Gannie Tzoneva, John Overton, Jonathan Marchini, Jeffrey G. Reid, Aris Baras, Niek Verweij, Luca A. Lotta, Giovanni Coppola, Katia Karalis, Aris Economides, Sergio Fazio, Wolfgang Liedtke, John Danesh, Ayeesha Kamal, Philippe Frossard, Thomas Coleman, Alan R. Shuldiner, and Danish Saleheen
- Subjects
Science - Abstract
Abstract The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691 C > T, encoding the missense amino acid substitution 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 = 3.87 × 10−9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p = 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 = 3.0 × 10−6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% 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.
- Published
- 2024
- Full Text
- View/download PDF