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

作者：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, Héctor Martínez, Sofia Castaneda, David D’Ambrosio, Xingmin Zhang, Pengcheng Xun, Ellen Tsai, I-Chun Tsai, RGC Management & Leadership Team, 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, Sequencing & Lab Operations, 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, Genome Informatics & Data Engineering, 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, Analytical Genetics and Data Science, 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, Therapeutic Area Genetics, 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, Senior Partnerships & Business Operations, Randi Schwartz, Jody Hankins, Anna Han, Samuel Hart, Business Operations & Administrative Coordinators, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron, Maleeha Khan, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Khalid Mahmood, Tanvir us Salam, Muhammad Hussain, Javed Iqbal, Faizan Aslam, Michael Cantor, Gannie Tzoneva, John D. Overton, Jonathan Marchini, Jeffrey G. Reid, Aris Baras, Niek Verweij, Luca A. Lotta, Giovanni Coppola, Katia Karalis, Aris N. Economides, Sergio Fazio, Wolfgang Liedtke, John Danesh, Ayeesha Kamran Kamal, Philippe Frossard, Thomas R. Coleman, Alan R. Shuldiner, Danish Saleheen · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-51819-3 · 被引用次数：8 · 研究领域：Cerebrovascular and genetic disorders、Cell Adhesion Molecules Research、S100 Proteins and Annexins

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. Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.