Dataset Information

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

ABSTRACT: Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n?=?18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

SUBMITTER: Malik R

PROVIDER: S-EPMC5968830 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Malik Rainer R Chauhan Ganesh G Traylor Matthew M Sargurupremraj Muralidharan M Okada Yukinori Y Mishra Aniket A Rutten-Jacobs Loes L Giese Anne-Katrin AK van der Laan Sander W SW Gretarsdottir Solveig S Anderson Christopher D CD Chong Michael M Adams Hieab H H HHH Ago Tetsuro T Almgren Peter P Amouyel Philippe P Ay Hakan H Bartz Traci M TM Benavente Oscar R OR Bevan Steve S Boncoraglio Giorgio B GB Brown Robert D RD Butterworth Adam S AS Carrera Caty C Carty Cara L CL Chasman Daniel I DI Chen Wei-Min WM Cole John W JW Correa Adolfo A Cotlarciuc Ioana I Cruchaga Carlos C Danesh John J de Bakker Paul I W PIW DeStefano Anita L AL den Hoed Marcel M Duan Qing Q Engelter Stefan T ST Falcone Guido J GJ Gottesman Rebecca F RF Grewal Raji P RP Gudnason Vilmundur V Gustafsson Stefan S Haessler Jeffrey J Harris Tamara B TB Hassan Ahamad A Havulinna Aki S AS Heckbert Susan R SR Holliday Elizabeth G EG Howard George G Hsu Fang-Chi FC Hyacinth Hyacinth I HI Ikram M Arfan MA Ingelsson Erik E Irvin Marguerite R MR Jian Xueqiu X Jiménez-Conde Jordi J Johnson Julie A JA Jukema J Wouter JW Kanai Masahiro M Keene Keith L KL Kissela Brett M BM Kleindorfer Dawn O DO Kooperberg Charles C Kubo Michiaki M Lange Leslie A LA Langefeld Carl D CD Langenberg Claudia C Launer Lenore J LJ Lee Jin-Moo JM Lemmens Robin R Leys Didier D Lewis Cathryn M CM Lin Wei-Yu WY Lindgren Arne G AG Lorentzen Erik E Magnusson Patrik K PK Maguire Jane J Manichaikul Ani A McArdle Patrick F PF Meschia James F JF Mitchell Braxton D BD Mosley Thomas H TH Nalls Michael A MA Ninomiya Toshiharu T O'Donnell Martin J MJ Psaty Bruce M BM Pulit Sara L SL Rannikmäe Kristiina K Reiner Alexander P AP Rexrode Kathryn M KM Rice Kenneth K Rich Stephen S SS Ridker Paul M PM Rost Natalia S NS Rothwell Peter M PM Rotter Jerome I JI Rundek Tatjana T Sacco Ralph L RL Sakaue Saori S Sale Michele M MM Salomaa Veikko V Sapkota Bishwa R BR Schmidt Reinhold R Schmidt Carsten O CO Schminke Ulf U Sharma Pankaj P Slowik Agnieszka A Sudlow Cathie L M CLM Tanislav Christian C Tatlisumak Turgut T Taylor Kent D KD Thijs Vincent N S VNS Thorleifsson Gudmar G Thorsteinsdottir Unnur U Tiedt Steffen S Trompet Stella S Tzourio Christophe C van Duijn Cornelia M CM Walters Matthew M Wareham Nicholas J NJ Wassertheil-Smoller Sylvia S Wilson James G JG Wiggins Kerri L KL Yang Qiong Q Yusuf Salim S Bis Joshua C JC Pastinen Tomi T Ruusalepp Arno A Schadt Eric E EE Koplev Simon S Björkegren Johan L M JLM Codoni Veronica V Civelek Mete M Smith Nicholas L NL Trégouët David A DA Christophersen Ingrid E IE Roselli Carolina C Lubitz Steven A SA Ellinor Patrick T PT Tai E Shyong ES Kooner Jaspal S JS Kato Norihiro N He Jiang J van der Harst Pim P Elliott Paul P Chambers John C JC Takeuchi Fumihiko F Johnson Andrew D AD Sanghera Dharambir K DK Melander Olle O Jern Christina C Strbian Daniel D Fernandez-Cadenas Israel I Longstreth W T WT Rolfs Arndt A Hata Jun J Woo Daniel D Rosand Jonathan J Pare Guillaume G Hopewell Jemma C JC Saleheen Danish D Stefansson Kari K Worrall Bradford B BB Kittner Steven J SJ Seshadri Sudha S Fornage Myriam M Markus Hugh S HS Howson Joanna M M JMM Kamatani Yoichiro Y Debette Stephanie S Dichgans Martin M

Nature genetics 20180312 4

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-dise ...[more]

PMID: 29531354

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Project description:BackgroundCalcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS.MethodsWe performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study.ResultsWe identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis.ConclusionsWe performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

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Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Publications

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

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