IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-51819-3.html
   My bibliography  Save this article

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

Author

Listed:
  • Juan Lorenzo Rodriguez-Flores

    (Regeneron Genetics Center)

  • Shareef Khalid

    (Columbia University
    Center for Non-Communicable Diseases)

  • 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)

  • 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

    (Allied Hospital)

  • Faizan Aslam

    (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

    (University of Cambridge)

  • Ayeesha Kamal

    (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
    Center for Non-Communicable Diseases)

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.

Suggested Citation

  • 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 D, 2024. "NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51819-3
    DOI: 10.1038/s41467-024-51819-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-51819-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-51819-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Lloyd T. Elliott & Kevin Sharp & Fidel Alfaro-Almagro & Sinan Shi & Karla L. Miller & Gwenaëlle Douaud & Jonathan Marchini & Stephen M. Smith, 2018. "Genome-wide association studies of brain imaging phenotypes in UK Biobank," Nature, Nature, vol. 562(7726), pages 210-216, October.
    2. Danish Saleheen & Pradeep Natarajan & Irina M. Armean & Wei Zhao & Asif Rasheed & Sumeet A. Khetarpal & Hong-Hee Won & Konrad J. Karczewski & Anne H. O’Donnell-Luria & Kaitlin E. Samocha & Benjamin We, 2017. "Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity," Nature, Nature, vol. 544(7649), pages 235-239, April.
    3. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    4. Aniket Mishra & Rainer Malik & Tsuyoshi Hachiya & Tuuli Jürgenson & Shinichi Namba & Daniel C. Posner & Frederick K. Kamanu & Masaru Koido & Quentin Le Grand & Mingyang Shi & Yunye He & Marios K. Geor, 2022. "Stroke genetics informs drug discovery and risk prediction across ancestries," Nature, Nature, vol. 611(7934), pages 115-123, November.
    5. Aniket Mishra & Rainer Malik & Tsuyoshi Hachiya & Tuuli Jürgenson & Shinichi Namba & Daniel C. Posner & Frederick K. Kamanu & Masaru Koido & Quentin Le Grand & Mingyang Shi & Yunye He & Marios K. Geor, 2022. "Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries," Nature, Nature, vol. 612(7938), pages 7-7, December.
    6. Joshua D. Backman & Alexander H. Li & Anthony Marcketta & Dylan Sun & Joelle Mbatchou & Michael D. Kessler & Christian Benner & Daren Liu & Adam E. Locke & Suganthi Balasubramanian & Ashish Yadav & Ni, 2021. "Exome sequencing and analysis of 454,787 UK Biobank participants," Nature, Nature, vol. 599(7886), pages 628-634, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Michael Wainberg & Natalie J. Forde & Salim Mansour & Isabel Kerrebijn & Sarah E. Medland & Colin Hawco & Shreejoy J. Tripathy, 2024. "Genetic architecture of the structural connectome," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Marcin Kierczak & Nima Rafati & Julia Höglund & Hadrien Gourlé & Valeria Lo Faro & Daniel Schmitz & Weronica E. Ek & Ulf Gyllensten & Stefan Enroth & Diana Ekman & Björn Nystedt & Torgny Karlsson & Ås, 2022. "Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Matthias Wuttke & Eva König & Maria-Alexandra Katsara & Holger Kirsten & Saeed Khomeijani Farahani & Alexander Teumer & Yong Li & Martin Lang & Burulca Göcmen & Cristian Pattaro & Dorothee Günzel & An, 2023. "Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Derek W. Brown & Liam D. Cato & Yajie Zhao & Satish K. Nandakumar & Erik L. Bao & Eugene J. Gardner & Aubrey K. Hubbard & Alexander DePaulis & Thomas Rehling & Lei Song & Kai Yu & Stephen J. Chanock &, 2023. "Shared and distinct genetic etiologies for different types of clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. M. Kelemen & J. Danesh & E. Angelantonio & M. Inouye & J. O’Sullivan & L. Pennells & T. Roychowdhury & M. J. Sweeting & A. M. Wood & S. Harrison & L. G. Kim, 2024. "Evaluating the cost-effectiveness of polygenic risk score-stratified screening for abdominal aortic aneurysm," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    7. Benjamin B. Sun & Stephanie J. Loomis & Fabrizio Pizzagalli & Natalia Shatokhina & Jodie N. Painter & Christopher N. Foley & Megan E. Jensen & Donald G. McLaren & Sai Spandana Chintapalli & Alyssa H. , 2022. "Genetic map of regional sulcal morphology in the human brain from UK biobank data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Asmundur Oddsson & Patrick Sulem & Gardar Sveinbjornsson & Gudny A. Arnadottir & Valgerdur Steinthorsdottir & Gisli H. Halldorsson & Bjarni A. Atlason & Gudjon R. Oskarsson & Hannes Helgason & Henriet, 2023. "Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Matthew Tegtmeyer & Jatin Arora & Samira Asgari & Beth A. Cimini & Ajay Nadig & Emily Peirent & Dhara Liyanage & Gregory P. Way & Erin Weisbart & Aparna Nathan & Tiffany Amariuta & Kevin Eggan & Marzi, 2024. "High-dimensional phenotyping to define the genetic basis of cellular morphology," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    10. Erik Schoenmakers & Federica Marelli & Helle F. Jørgensen & W. Edward Visser & Carla Moran & Stefan Groeneweg & Carolina Avalos & Sean J. Jurgens & Nichola Figg & Alison Finigan & Neha Wali & Maura Ag, 2023. "Selenoprotein deficiency disorder predisposes to aortic aneurysm formation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    11. Xiaoyi Raymond Gao & Marion Chiariglione & Alexander J. Arch, 2022. "Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    12. Nazia Pathan & Wei Q. Deng & Matteo Di Scipio & Mohammad Khan & Shihong Mao & Robert W. Morton & Ricky Lali & Marie Pigeyre & Michael R. Chong & Guillaume Paré, 2024. "A method to estimate the contribution of rare coding variants to complex trait heritability," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    13. Jingning Zhang & Jianan Zhan & Jin Jin & Cheng Ma & Ruzhang Zhao & Jared O’Connell & Yunxuan Jiang & Bertram L. Koelsch & Haoyu Zhang & Nilanjan Chatterjee, 2024. "An ensemble penalized regression method for multi-ancestry polygenic risk prediction," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Aimee M. Deaton & Aditi Dubey & Lucas D. Ward & Peter Dornbos & Jason Flannick & Elaine Yee & Simina Ticau & Leila Noetzli & Margaret M. Parker & Rachel A. Hoffing & Carissa Willis & Mollie E. Plekan , 2022. "Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    15. Diana Dunca & Sandesh Chopade & María Gordillo-Marañón & Aroon D. Hingorani & Karoline Kuchenbaecker & Chris Finan & Amand F. Schmidt, 2024. "Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    16. Young Jin Kim & Sanghoon Moon & Mi Yeong Hwang & Sohee Han & Hye-Mi Jang & Jinhwa Kong & Dong Mun Shin & Kyungheon Yoon & Sung Min Kim & Jong-Eun Lee & Anubha Mahajan & Hyun-Young Park & Mark I. McCar, 2022. "The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    17. Remo Monti & Pia Rautenstrauch & Mahsa Ghanbari & Alva Rani James & Matthias Kirchler & Uwe Ohler & Stefan Konigorski & Christoph Lippert, 2022. "Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    19. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    20. Junjiao Feng & Liang Zhang & Chunhui Chen & Jintao Sheng & Zhifang Ye & Kanyin Feng & Jing Liu & Ying Cai & Bi Zhu & Zhaoxia Yu & Chuansheng Chen & Qi Dong & Gui Xue, 2022. "A cognitive neurogenetic approach to uncovering the structure of executive functions," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51819-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.