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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:The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16?851 cases with state-of-the-art phenotyping data and 32?473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20?941 cases and 364?736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10?172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50?×?10-8; joint OR 1·19, 1·12-1·26, p=1·30?×?10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26?×?10-19; joint OR 1·37, 1·30-1·45, p=2·79?×?10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93?×?10-7; joint OR 1·17, 1·11-1·23, p=2·29?×?10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50?×?10-8; joint OR 1·24, 1·15-1·33, p=4·52?×?10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82?×?10-8; joint OR 1·17, 1·11-1·23, p=2·92?×?10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Dataset Information

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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