NOTCH3p.Arg1231Cys is Markedly Enriched in South Asians and Associated with Stroke
Author:
Rodriguez-Flores Juan L., Khalid Shareef, Parikshak Neelroop, Rasheed Asif, Ye Bin, Kapoor Manav, Backman Joshua, Sepehrband Farshid, DiGioia Silvio Alessandro, Gelfman Sahar, De Tanima, Banerjee Nilanjana, Sharma Deepika, Martinez Hector, Castaneda Sofia, D’Ambrosio David, Zhang Xingmin A., Xun Pengcheng, Tsai Ellen, Tsai I-Chun, Center Regeneron Genetics, Jahanzaib Muhammad, Khan Maleeha Zaman, Mian Muhammad Rehan, Liaqat Muhammad Bilal, Mahmood Khalid, Salam Tanvir Us, Hussain Muhammad, Iqbal Javed, Aslam Faizan, Cantor Michael N., Tzoneva Gannie, Overton John, Marchini JonathanORCID, Reid JeffORCID, Baras Aris, Verweij Niek, Lotta Luca A., Coppola GiovanniORCID, Karalis Katia, Economides Aris, Fazio Sergio, Liedtke Wolfgang, Danesh John, Kamal Ayeesha, Frossard Philippe, Coleman Thomas, Shuldiner Alan R., Saleheen Danish
Abstract
AbstractThe genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identifiedNOTCH3p.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).NOTCH3p.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.
Publisher
Cold Spring Harbor Laboratory
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