NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke

Disease areas:

brain

Last updated:: 19 November 2025

Author(s):: Gonçalo Abecasis, Adolfo Ferrando, Michael Cantor, Andrew Deubler, John D. Overton, Katherine Siminovitch, Jason Portnoy, Marcus B. Jones, Lyndon Mitnaul, Alison Fenney, Manuel Allen Revez Ferreira, Maya Ghoussaini, Mona Nafde, William Salerno, Christina Beechert, Erin D. Brian, Laura M. Cremona, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Alexander Lopez, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E. Wolf, Amelia Averitt, Dadong Li, Sameer Malhotra, Justin Mower, Mudasar Sarwar, Sean Yu, Xingmin Aaron Zhang, Muhammad Aqeel, Manan Goyal, George Mitra, Sanjay Sreeram, Rouel Lanche, Vrushali Mahajan, Sai Lakshmi Vasireddy, Gisu Eom, Krishna Pawan Punuru, Sujit Gokhale, Benjamin Sultan, Pooja Mule, Eliot Austin, Xiaodong Bai, Lance Zhang, Sean O'Keeffe, Razvan Panea, Evan Edelstein, Ayesha Rasool, Evan K. Maxwell, Boris Boutkov, Alexander Gorovits, Ju Guan, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Samantha Zarate, Adam J. Mansfield, Kathy Burch, Adrian Campos, Liron Ganel, Sheila Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Salvador Romero Martinez, Christopher Gillies, Lauren Gurski, Joseph Herman, Eric Jorgenson, Tyler Joseph, Michael Kessler, Jack Kosmicki, Adam Locke, Priyanka Nakka, Karl Landheer, Olivier Delaneau, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Aditeya Pandey, Anita Pandit, Jonathan Ross, Carlo Sidore, Eli Stahl, Timothy Thornton, Peter VandeHaar, Sailaja Vedantam, Rujin Wang, Kuan-Han Wu, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Yuxin Zou, Jingning Zhang, Kyoko Watanabe, Mira Tang, Frank Wendt, Suganthi Balasubramanian, Suying Bao, Kathie Sun, Chuanyi Zhang, Brian Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit Joshi, Antoine Baldassari, Cristen Willer, Sarah Graham, Ernst Mayerhofer, Mary Haas, George Hindy, Jonas Bovijn, Parsa Akbari, Luanluan Sun, Olukayode Sosina, Arthur Gilly, Peter Dornbos, Moeen Riaz, Momodou W. Jallow, Anna Alkelai, Ariane Ayer, Veera Rajagopal, Vijay Kumar, Jacqueline Otto, Aysegul Guvenek, Jose Bras, Silvia Alvarez, Jessie Brown, Jing He, Hossein Khiabanian, Joana Revez, Kimberly Skead, Valentina Zavala, Jae Soon Sul, Lei Chen, Sam Choi, Amy Damask, Nan Lin, Charles Paulding, Esteban Chen, Michelle G. LeBlanc, Jason Mighty, Jennifer Rico-Varela, Nirupama Nishtala, Nadia Rana, Jaimee Hernandez, Randi Schwartz, Jody Hankins, Anna Han, Samuel Hart, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron
Publish date:: 13 September 2024
Journal:: Nature Communications
PubMed ID:: 39271666
DOI:: 10.1038/s41467-024-51819-3

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.