Stroke genetics informs drug discovery and risk prediction across ancestries

Autor: Stéphanie Debette, Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Masaru Koido, Quentin Le Grand, Frederick Kamanu, Mingyang Shi, Yunye He, Marios Georgakis, Ilana Caro, Kristi Krebs, Felix Vaura, Naomi Habib, Bendik Winsvold, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel-Márquez, Kuang Lin, Marianne Nygaard, Ganesh Chauhan, Hampton Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria Knol, Tetsuro Ago, Philippe Amouyel, Christopher Anderson, Nicole Armstrong, Mark Bakker, Traci Bartz, Joshua Bis, Constance Bordes, Sigrid Borte, Anael Cain, Paul Ridker, Zhengming Chen, Michael Chong, John Cole, Rafael de Cid, Matthias Endres, Leslie Ferreira, Natalie Gasca, Vilmundur Gudnason, Jun Hata, Aki Havulinna, Jemma Hopewell, Hyacinth Hyacinth, Michael Inouye, Mina Jacob, Christina Jeon, Christina Jern, Masahiro Kamouchi, Keith Keene, Takanari Kitazono, Steven Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore Launer, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh Markus, Nicholas Marston, Thomas Meitinger, Braxton Mitchell, Felipe Montellano, Takayuki Morisaki, Thomas Mosley, Mike Nalls, Børge Nordestgaard, Martin O'Donnell, Yukinori Okada, Guillaume Pare, Annette Peters, Bruce Psaty, Stephen Rich, Jonathan Rosand, Marc Sabatine, Ralph Sacco, Danish Saleheen, Else Charlotte Sandset, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia Satizabal, Carsten Schmidt, Atsushi Shimizu, Nicholas Smith, Daniel Strbian, Yoichi Sutoh, Kozo Tanno, Steffen Tiedt, Nuria Torres-Aguila, David-Alexandre Trégouët, Stella Trompet, Anil Tuladhar, Anne Tybjærg-Hansen, Marion van Vugt, Riina Vibo, Kerri Wiggins, Daniel Woo, Huichun Xu, Qiong Yang, Mark Lathrop, Iona Millwood, Christian Gieger, Toshiharu Ninomiya, Hans Grabe, J Wouter Jukema, Ina Rissanen, Sudha Seshadri, William Longstreth, Daniel Chasman, Joanna Howson, Marguerite Irvin, Hieab Adams, Sylvia Wasssertheil-Smoller, Kaare Christensen, M. Arfan Ikram, Tatjana Rundek, Jerome Rotter, Moeen Riaz, Eleanor Simonsick, Janika Kõrv, Paulo França, Myriam Fornage, Ramin Zand, Kameshwar Prasad, Ruth Frikke-Schmidt, Frank-Erik de Leeuw, Thomas Liman, Karl Georg Haeusler, Ynte Ruigrok, Peter Heuschmann, Keum Jung, John-Anker Zwart, Teemu Niiranen, Christian Ruff, Israel Fernández-Cadenas, Robin Walters, Lili Milani, Yoichiro Kamatani, Martin Dichgans
Jazyk: angličtina
Zdroj: Research Square
Nature
DOI: 10.21203/rs.3.rs-1175817/v1
Popis: Previous genome-wide association studies (GWAS) of stroke, the second leading cause of death, have been conducted in populations of predominantly European ancestry.1,2 We undertook cross-ancestry GWAS meta-analyses of stroke and its subtypes in 110,182 stroke patients (33% non-European) and 1,503,898 control individuals of five ancestries from population- and clinic-based studies, nearly doubling the number of cases in previous stroke GWAS. We identified association signals at 89 independent loci, of which 61 were novel. Effect sizes were overall highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis using a novel machine-learning approach,3 transcriptome and proteome-wide association analyses revealed putative causal genes (e.g. SH3PXD2A and FURIN) and variants (e.g. at GRK5 and NOS3). Using a novel three-pronged approach,4 we provided genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, 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 GWAS with vascular risk factor GWAS (iPGS) showed strong prediction of ischemic stroke risk in European and, for the first time, East-Asian populations.5,6 The iPGS performed better than stroke PGS alone and better than previous best iPGS, in Europeans and East-Asians. Transferability of European-specific iPGS to East-Asians was limited. Stroke genetic risk scores were predictive of ischemic stroke independent of clinical risk factors in 52,600 clinical trial participants with cardiometabolic disease and performed considerably better than previous scores, both in Europeans and East-Asians. Altogether our results provide critical insight to inform biology, reveal potential drug targets for intervention, and provide genetic risk prediction tools across ancestries for targeted prevention.
Databáze: OpenAIRE
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