Stroke genetics informs drug discovery and risk prediction across ancestries

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. Georgakis, Ilana Caro, Kristi Krebs, Yi Ching Liaw, Felix C. Vaura, Kuang Lin, Bendik Slagsvold Winsvold, Vinodh Srinivasasainagendra, Livia ParodiHee Joon Bae, Ganesh Chauhan, Michael R. Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V. Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel-Márquez, Marianne Nygaard, Hampton L. Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J. Knol, Adam J. Lewis, Renae L. Judy, Tetsuro Ago, Philippe Amouyel, Nicole D. Armstrong, Mark K. Bakker, Traci M. Bartz, David A. Bennett, Joshua C. Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M. Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W. Cole, Phil L. de Jager, Rafael de Cid, Matthias Endres, Leslie E. Ferreira, Mirjam I. Geerlings, Natalie C. Gasca, Vilmundur Gudnason, Jun Hata, Jing He, Alicia K. Heath, Yuk Lam Ho, Aki S. Havulinna, Jemma C. Hopewell, Hyacinth I. Hyacinth, Michael Inouye, Mina A. Jacob, Christina E. Jeon, Christina Jern, Masahiro Kamouchi, Keith L. Keene, Takanari Kitazono, Steven J. Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J. Launer, Keon Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S. Markus, Nicholas A. Marston, Thomas Meitinger, Braxton D. Mitchell, Felipe A. Montellano, Takayuki Morisaki, Thomas H. Mosley, Mike A. Nalls, Børge G. Nordestgaard, Martin J. O'Donnell, Yukinori Okada, N. Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M. Psaty, Stephen S. Rich, Jonathan Rosand, Marc S. Sabatine, Ralph L. Sacco, Danish Saleheen, Else Charlotte Sandset, Veikko Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia L. Satizabal, Carsten O. Schmidt, Atsushi Shimizu, Nicholas L. Smith, Kelly L. Sloane, Yoichi Sutoh, Yan V. Sun, Kozo Tanno, Steffen Tiedt, Turgut Tatlisumak, Nuria P. Torres-Aguila, Hemant K. Tiwari, David Alexandre Trégouët, Stella Trompet, Anil Man Tuladhar, Anne Tybjærg-Hansen, Marion van Vugt, Riina Vibo, Shefali S. Verma, Kerri L. Wiggins, Patrik Wennberg, Daniel Woo, Peter W.F. Wilson, Huichun Xu, Qiong Yang, Kyungheon Yoon, Iona Y. Millwood, Christian Gieger, Toshiharu Ninomiya, Hans J. Grabe, J. Wouter Jukema, Ina L. Rissanen, Daniel Strbian, Young Jin Kim, Pei Hsin Chen, Ernst Mayerhofer, Joanna M.M. Howson, Marguerite R. Irvin, Hieab Adams, Sylvia Wassertheil-Smoller, Kaare Christensen, Mohammad A. Ikram, Tatjana Rundek, Bradford B. Worrall, G. Mark Lathrop, Moeen Riaz, Eleanor M. Simonsick, Janika Kõrv, Paulo H.C. França, Ramin Zand, Kameshwar Prasad, Ruth Frikke-Schmidt, Frank Erik de Leeuw, Thomas Liman, Karl Georg Haeusler, Ynte M. Ruigrok, Peter Ulrich Heuschmann, W. T. Longstreth, Keum Ji Jung, Lisa Bastarache, Guillaume Paré, Scott M. Damrauer, Daniel I. Chasman, Jerome I. Rotter, Christopher D. Anderson, John Anker Zwart, Teemu J. Niiranen, Myriam Fornage, Yung Po Liaw, Sudha Seshadri, Israel Fernández-Cadenas, Robin G. Walters, Christian T. Ruff, Mayowa O. Owolabi, Jennifer E. Huffman, Lili Milani, Yoichiro Kamatani, Martin Dichgans, Stephanie Debette, The PRECISE4Q Consortium, The FinnGen Consortium, The NINDS Stroke Genetics Network (SiGN), The MEGASTROKE Consortium, The SIREN Consortium, China Kadoorie Biobank Collaborative Group, The VA Million Veteran Program, The International Stroke Genetics Consortium (ISGC), The Biobank Japan, The CHARGE Consortium, The GIGASTROKE Consortium, The COMPASS Consortium, The INVENT Consortium, The Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, The Estonian Biobank

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Abstract

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.

Original languageEnglish
Pages (from-to)115-123
Number of pages9
JournalNature
Volume611
Issue number7934
DOIs
Publication statusPublished - 3 Nov 2022
  • Erratum: Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries (Nature (2022) 611 7934 (115-123))

    Mishra, A., Malik, R., Hachiya, T., Jürgenson, T., Namba, S., Posner, D. C., Kamanu, F. K., Koido, M., Le Grand, Q., Shi, M., He, Y., Georgakis, M. K., Caro, I., Krebs, K., Liaw, Y. C., Vaura, F. C., Lin, K., Winsvold, B. S., Srinivasasainagendra, V., Parodi, L., & 182 othersBae, H. J., Chauhan, G., Chong, M. R., Tomppo, L., Akinyemi, R., Roshchupkin, G. V., Habib, N., Jee, Y. H., Thomassen, J. Q., Abedi, V., Cárcel-Márquez, J., Nygaard, M., Leonard, H. L., Yang, C., Yonova-Doing, E., Knol, M. J., Lewis, A. J., Judy, R. L., Ago, T., Amouyel, P., Armstrong, N. D., Bakker, M. K., Bartz, T. M., Bennett, D. A., Bis, J. C., Bordes, C., Børte, S., Cain, A., Ridker, P. M., Cho, K., Chen, Z., Cruchaga, C., Cole, J. W., de Jager, P. L., de Cid, R., Endres, M., Ferreira, L. E., Geerlings, M. I., Gasca, N. C., Gudnason, V., Hata, J., He, J., Heath, A. K., Ho, Y. L., Havulinna, A. S., Hopewell, J. C., Hyacinth, H. I., Inouye, M., Jacob, M. A., Jeon, C. E., Jern, C., Kamouchi, M., Keene, K. L., Kitazono, T., Kittner, S. J., Konuma, T., Kumar, A., Lacaze, P., Launer, L. J., Lee, K. J., Lepik, K., Li, J., Li, L., Manichaikul, A., Markus, H. S., Marston, N. A., Meitinger, T., Mitchell, B. D., Montellano, F. A., Morisaki, T., Mosley, T. H., Nalls, M. A., Nordestgaard, B. G., O'Donnell, M. J., Okada, Y., Onland-Moret, N. C., Ovbiagele, B., Peters, A., Psaty, B. M., Rich, S. S., Rosand, J., Sabatine, M. S., Sacco, R. L., Saleheen, D., Sandset, E. C., Salomaa, V., Sargurupremraj, M., Sasaki, M., Satizabal, C. L., Schmidt, C. O., Shimizu, A., Smith, N. L., Sloane, K. L., Sutoh, Y., Sun, Y. V., Tanno, K., Tiedt, S., Tatlisumak, T., Torres-Aguila, N. P., Tiwari, H. K., Trégouët, D. A., Trompet, S., Tuladhar, A. M., Tybjærg-Hansen, A., van Vugt, M., Vibo, R., Verma, S. S., Wiggins, K. L., Wennberg, P., Woo, D., Wilson, P. W. F., Xu, H., Yang, Q., Yoon, K., Millwood, I. Y., Gieger, C., Ninomiya, T., Grabe, H. J., Jukema, J. W., Rissanen, I. L., Strbian, D., Kim, Y. J., Chen, P. H., Mayerhofer, E., Howson, J. M. M., Irvin, M. R., Adams, H., Wassertheil-Smoller, S., Christensen, K., Ikram, M. A., Rundek, T., Worrall, B. B., Lathrop, G. M., Riaz, M., Simonsick, E. M., Kõrv, J., França, P. H. C., Zand, R., Prasad, K., Frikke-Schmidt, R., de Leeuw, F. E., Liman, T., Haeusler, K. G., Ruigrok, Y. M., Heuschmann, P. U., Longstreth, W. T., Jung, K. J., Bastarache, L., Paré, G., Damrauer, S. M., Chasman, D. I., Rotter, J. I., Anderson, C. D., Zwart, J. A., Niiranen, T. J., Fornage, M., Liaw, Y. P., Seshadri, S., Fernández-Cadenas, I., Walters, R. G., Ruff, C. T., Owolabi, M. O., Huffman, J. E., Milani, L., Kamatani, Y., Dichgans, M., Debette, S., The PRECISE4Q Consortium, The FinnGen Consortium, The NINDS Stroke Genetics Network (SiGN), The MEGASTROKE Consortium, The SIREN Consortium, China Kadoorie Biobank Collaborative Group, The VA Million Veteran Program, The International Stroke Genetics Consortium (ISGC), The Biobank Japan, The CHARGE Consortium, The GIGASTROKE Consortium, The COMPASS Consortium, The INVENT Consortium, The Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group & The Estonian Biobank, 1 Dec 2022, In: Nature. 612, 7938, p. e7 1 p.

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