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Nature · 2022

Stroke genetics informs drug discovery and risk prediction across ancestries.

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

Аннотация

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.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты