TY - JOUR
T1 - NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke
AU - Regeneron Genetics Center
AU - Business Operations & Administrative Coordinators
AU - Senior Partnerships & Business Operations
AU - Research Program Management & Strategic Initiatives
AU - Therapeutic Area Genetics
AU - Analytical Genetics and Data Science
AU - Genome Informatics & Data Engineering
AU - Clinical Informatics
AU - Sequencing & Lab Operations
AU - RGC Management & Leadership Team
AU - Rodriguez-Flores, Juan Lorenzo
AU - Khalid, Shareef
AU - Parikshak, Neelroop
AU - Rasheed, Asif
AU - Ye, Bin
AU - Kapoor, Manav
AU - Backman, Joshua
AU - Sepehrband, Farshid
AU - Gioia, Silvio Alessandro Di
AU - Gelfman, Sahar
AU - De, Tanima
AU - Banerjee, Nilanjana
AU - Sharma, Deepika
AU - Martinez, Hector
AU - Castaneda, Sofia
AU - D’Ambrosio, David
AU - Zhang, Xingmin A.
AU - Xun, Pengcheng
AU - Tsai, Ellen
AU - Tsai, I. Chun
AU - Siceron, Sunilbe
AU - Pagan, Michelle
AU - Rivera-Picart, Johannie
AU - Solari, Gina
AU - Perez-Beals, Ann
AU - Hart, Samuel
AU - Han, Anna
AU - Hankins, Jody
AU - Schwartz, Randi
AU - Hernandez, Jaimee
AU - Rana, Nadia
AU - Nishtala, Nirupama
AU - Rico-Varela, Jennifer
AU - Mighty, Jason
AU - LeBlanc, Michelle G.
AU - Chen, Esteban
AU - Paulding, Charles
AU - Lin, Nan
AU - Damask, Amy
AU - Choi, Sam
AU - Chen, Lei
AU - Sul, Jae Soon
AU - Zavala, Valentina
AU - Skead, Kimberly
AU - Revez, Joana
AU - Khiabanian, Hossein
AU - He, Jing
AU - Brown, Jessie
AU - Alvarez, Silvia
AU - Kamal, Ayeesha
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85204167263&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-51819-3
DO - 10.1038/s41467-024-51819-3
M3 - Article
C2 - 39271666
AN - SCOPUS:85204167263
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 8029
ER -