NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke
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<sup>-9</sup>), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p = 7.79 × 10<sup>-10</sup>). 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<sup>-6</sup>). 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.
Authors
- Ellen Tsai (ORCID: https://orcid.org/0000-0002-9032-4011)
- Aris N. Economides (ORCID: https://orcid.org/0000-0002-6508-8942)
- Gannie Tzoneva (ORCID: https://orcid.org/0000-0001-5784-7796)
- Deepika Sharma (ORCID: https://orcid.org/0000-0002-5840-8266)
- Niek Verweij (ORCID: https://orcid.org/0000-0002-4303-7685)
- Alan R. Shuldiner (ORCID: https://orcid.org/0000-0001-9921-4305)
- Manav Kapoor (ORCID: https://orcid.org/0000-0001-6682-940X)
- David D’Ambrosio
- Sahar Gelfman (ORCID: https://orcid.org/0000-0002-4727-7862)
- John D. Overton (ORCID: https://orcid.org/0000-0001-7650-8634)
- Farshid Sepehrband (ORCID: https://orcid.org/0000-0002-4483-5961)
- Muhammad Rehan Mian
- Aris Baras (ORCID: https://orcid.org/0000-0002-6830-3396)
- John Danesh (ORCID: https://orcid.org/0000-0003-1158-6791)
- Muhammad Jahanzaib (ORCID: https://orcid.org/0000-0002-5101-8564)
- Faizan Aslam
- Silvio Alessandro Di Gioia (ORCID: https://orcid.org/0000-0002-7235-5682)
- Luca A. Lotta (ORCID: https://orcid.org/0000-0002-2619-5956)
- Pengcheng Xun (ORCID: https://orcid.org/0000-0002-6245-4505)
- Jonathan Marchini (ORCID: https://orcid.org/0000-0003-0610-8322)
- Nilanjana Banerjee (ORCID: https://orcid.org/0000-0001-8022-8598)
- Tanima De (ORCID: https://orcid.org/0000-0001-9240-3744)
- Jeffrey G. Reid (ORCID: https://orcid.org/0000-0001-8645-4713)
- Michael Cantor (ORCID: https://orcid.org/0000-0002-1074-1203)
- Juan L. Rodríguez-Flores (ORCID: https://orcid.org/0000-0002-0394-8062)
- Giovanni Coppola (ORCID: https://orcid.org/0000-0003-2105-1061)
- Katia Karalis (ORCID: https://orcid.org/0000-0003-3100-2263)
- Wolfgang Liedtke (ORCID: https://orcid.org/0000-0003-4166-5394)
- Sofia Castaneda
- Khalid Mahmood (ORCID: https://orcid.org/0000-0003-0980-3646)
- Thomas R. Coleman
- Neelroop Parikshak (ORCID: https://orcid.org/0000-0003-2027-1871)
- Joshua Backman (ORCID: https://orcid.org/0000-0001-7262-0880)
- Maleeha Khan (ORCID: https://orcid.org/0000-0001-5365-3353)
- Bin Ye (ORCID: https://orcid.org/0000-0002-9544-6907)
- Javed Iqbal (ORCID: https://orcid.org/0000-0002-3005-4785)
- Xingmin Zhang (ORCID: https://orcid.org/0000-0002-7284-3950)
- Asif Rasheed
- Ayeesha Kamran Kamal (ORCID: https://orcid.org/0000-0002-5557-2722)
- Sergio Fazio (ORCID: https://orcid.org/0000-0002-8145-8034)
- Shareef Khalid
- Danish Saleheen
- Philippe Frossard
- I-Chun Tsai
- Muhammad Hussain (ORCID: https://orcid.org/0009-0002-9282-8587)
- Tanvir us Salam
- Muhammad Bilal Liaqat
- Héctor Martínez
Institutions
- Aga Khan University (PK)
- University of California, Los Angeles (US)
- Regeneron (United States) (US)
- University of Cambridge (GB)
- Columbia University Irving Medical Center (US)
- Lahore General Hospital (PK)
- Civil Hospital Karachi (PK)
- Allied Hospital (PK)
- Dow University of Health Sciences (PK)
- Center for Non-Communicable Diseases (PK)
- Columbia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1038/s41467-024-51819-3
- Citations
- 4
- Primary Topic
- Cerebrovascular and genetic disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.48
Funders
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- Biogen
- Alnylam Pharmaceuticals
- Regeneron Pharmaceuticals