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

Juan L. Rodríguez-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 Zhang; Pengcheng Xun; Ellen A. Tsai; I-Chun Tsai; Maleeha Zaman Khan; Muhammad Jahanzaib; Muhammad Rehan Mian; Muhammad Bilal Liaqat; Khalid Mahmood; Tanvir us Salam; Muhammad Shakhawat Hussain; Javed Iqbal; Faizan Aslam; Michael N Cantor

doi:10.1101/2023.10.05.23296511

Genetic & Genomic MedicinemedRxivOct 5, 2023

Preprint

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

Juan L. Rodríguez-Flores iD, Shareef Khalid, Neelroop Parikshak iD, Asif Rasheed, Bin Ye iD, Manav Kapoor iD, Joshua Backman iD, Farshid Sepehrband iD, Silvio Alessandro Di Gioia iD, Sahar Gelfman iD, Tanima De iD, Nilanjana Banerjee iD, Deepika Sharma iD, Hector Martinez, Sofia Castaneda, David D’Ambrosio, Xingmin Zhang iD, Pengcheng Xun iD, Ellen A. Tsai iD, I-Chun Tsai, Maleeha Zaman Khan iD, Muhammad Jahanzaib iD, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Khalid Mahmood iD, , Danish Saleheen iD

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.3691C>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 value = 3.87x10-9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p value = 7.79x10-10). 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 = 3.0x10-6). 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.

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