| Title: | NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke |
| Journal: | Nature Communications |
| Published: | 13 Sep 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39271666/ |
| DOI: | https://doi.org/10.1038/s41467-024-51819-3 |
Publication 13495
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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.</p>
17 Keywords
- Aged
- Exome Sequencing
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Mutation, Missense
- Pakistan
- Polymorphism, Single Nucleotide
- Receptor, Notch3
- South Asian People
- Stroke
- UK Biobank
- United Kingdom
164 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
Enabling scientific discoveries that improve human health