Nature Communications (Sep 2024)
NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke
- 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,
- Danish Saleheen
Affiliations
- Juan Lorenzo Rodriguez-Flores
- Regeneron Genetics Center
- Shareef Khalid
- Columbia University
- Neelroop Parikshak
- Regeneron Genetics Center
- Asif Rasheed
- Center for Non-Communicable Diseases
- Bin Ye
- Regeneron Genetics Center
- Manav Kapoor
- Regeneron Genetics Center
- Joshua Backman
- Regeneron Genetics Center
- Farshid Sepehrband
- Regeneron Genetics Center
- Silvio Alessandro Di Gioia
- Regeneron Pharmaceuticals Inc
- Sahar Gelfman
- Regeneron Genetics Center
- Tanima De
- Regeneron Genetics Center
- Nilanjana Banerjee
- Regeneron Genetics Center
- Deepika Sharma
- Regeneron Genetics Center
- Hector Martinez
- Regeneron Pharmaceuticals Inc
- Sofia Castaneda
- Rye Country Day School
- David D’Ambrosio
- Regeneron Pharmaceuticals Inc
- Xingmin A. Zhang
- Regeneron Genetics Center
- Pengcheng Xun
- Regeneron Pharmaceuticals Inc
- Ellen Tsai
- University of California at Los Angeles
- I-Chun Tsai
- Regeneron Pharmaceuticals Inc
- Regeneron Genetics Center
- Maleeha Zaman Khan
- Center for Non-Communicable Diseases
- Muhammad Jahanzaib
- Center for Non-Communicable Diseases
- Muhammad Rehan Mian
- Center for Non-Communicable Diseases
- Muhammad Bilal Liaqat
- Center for Non-Communicable Diseases
- Khalid Mahmood
- Dow University of Health Sciences and Civil Hospital
- Tanvir Us Salam
- Lahore General Hospital
- Muhammad Hussain
- Lahore General Hospital
- Javed Iqbal
- Department of Neurology, Allied Hospital
- Faizan Aslam
- Department of Neurology, Aziz Fatima Hospital
- Michael N. Cantor
- Regeneron Genetics Center
- Gannie Tzoneva
- Regeneron Genetics Center
- John Overton
- Regeneron Genetics Center
- Jonathan Marchini
- Regeneron Genetics Center
- Jeffrey G. Reid
- Regeneron Genetics Center
- Aris Baras
- Regeneron Genetics Center
- Niek Verweij
- Regeneron Genetics Center
- Luca A. Lotta
- Regeneron Genetics Center
- Giovanni Coppola
- Regeneron Genetics Center
- Katia Karalis
- Regeneron Genetics Center
- Aris Economides
- Regeneron Genetics Center
- Sergio Fazio
- Regeneron Pharmaceuticals Inc
- Wolfgang Liedtke
- Regeneron Pharmaceuticals Inc
- John Danesh
- Department of Public Health and Primary Care, University of Cambridge
- Ayeesha Kamal
- Section of Neurology, Department of Medicine, Aga Khan University
- Philippe Frossard
- Center for Non-Communicable Diseases
- Thomas Coleman
- Regeneron Genetics Center
- Alan R. Shuldiner
- Regeneron Genetics Center
- Danish Saleheen
- Columbia University
- DOI
- https://doi.org/10.1038/s41467-024-51819-3
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 14
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.
