TY - JOUR

T1 - Stroke genetics informs drug discovery and risk prediction across ancestries

AU - Mishra, Aniket

AU - Malik, Rainer

AU - Hachiya, Tsuyoshi

AU - Jürgenson, Tuuli

AU - Namba, Shinichi

AU - Posner, Daniel C.

AU - Kamanu, Frederick K.

AU - Koido, Masaru

AU - Le Grand, Quentin

AU - Shi, Mingyang

AU - He, Yunye

AU - Georgakis, Marios K.

AU - Caro, Ilana

AU - Krebs, Kristi

AU - Liaw, Yi Ching

AU - Vaura, Felix C.

AU - Lin, Kuang

AU - Winsvold, Bendik Slagsvold

AU - Srinivasasainagendra, Vinodh

AU - Parodi, Livia

AU - Bae, Hee Joon

AU - Chauhan, Ganesh

AU - Chong, Michael R.

AU - Tomppo, Liisa

AU - Akinyemi, Rufus

AU - Roshchupkin, Gennady V.

AU - Habib, Naomi

AU - Jee, Yon Ho

AU - Thomassen, Jesper Qvist

AU - Abedi, Vida

AU - Cárcel-Márquez, Jara

AU - Nygaard, Marianne

AU - Leonard, Hampton L.

AU - Yang, Chaojie

AU - Yonova-Doing, Ekaterina

AU - Knol, Maria J.

AU - Lewis, Adam J.

AU - Judy, Renae L.

AU - Ago, Tetsuro

AU - Amouyel, Philippe

AU - Armstrong, Nicole D.

AU - Bakker, Mark K.

AU - Bartz, Traci M.

AU - Bennett, David A.

AU - Bis, Joshua C.

AU - Bordes, Constance

AU - Børte, Sigrid

AU - Nordestgaard, Børge G.

AU - Tybjærg-Hansen, Anne

AU - Frikke-Schmidt, Ruth

AU - PRECISEQ Consortium

AU - FinnGen Consortium

AU - NINDS Stroke Genetics Network (SiGN)

AU - MEGASTROKE Consortium

AU - SIREN Consortium

AU - China Kadoorie Biobank Collaborative Group

AU - VA Million Veteran Program

AU - International Stroke Genetics Consortium (ISGC)

AU - BioBank Japan

AU - CHARGE Consortium

AU - GIGASTROKE Consortium

AU - COMPASS Consortium

AU - INVENT Consortium

AU - Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group

AU - Estonian Biobank

N1 - Publisher Copyright: © 2022. The Author(s).

PY - 2022

Y1 - 2022

N2 - Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

AB - Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

U2 - 10.1038/s41586-022-05165-3

DO - 10.1038/s41586-022-05165-3

M3 - Journal article

C2 - 36180795

AN - SCOPUS:85141853404

VL - 611

SP - 115

EP - 123

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7934

ER -