Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study

Pulit, Sara L. and McArdle, Patrick F. and Wong, Quenna and Malik, Rainer and Gwinn, Katrina and Achterberg, Sefanja and Algra, Ale and Amouyel, Philippe and Anderson, Christopher D. and Arnett, Donna K. and Arsava, Ethem Murat and Attia, John and Ay, Hakan and Bartz, Traci M. and Battey, Thomas and Benavente, Oscar R. and Bevan, Steve and Biffi, Alessandro and Bis, Joshua C. and Blanton, Susan H. and Boncoraglio, Giorgio B. and Brown, Robert D. and Burgess, Annette I. and Carrera, Caty and Chapman Smith, Sherita N. and Chasman, Daniel I. and Chauhan, Ganesh and Chen, Wei-Min and Cheng, Yu-Ching and Chong, Michael and Cloonan, Lisa K. and Cole, John W. and Cotlarciuc, Ioana and Cruchaga, Carlos and Cuadrado-Godia, Elisa and Dave, Tushar and Dawson, Jesse and Debette, Stéphanie and Delavaran, Hossein and Dell, Cameron A. and Dichgans, Martin and Doheny, Kimberly F. and Dong, Chuanhui and Duggan, David J. and Engström, Gunnar and Evans, Michele K. and Pallejà, Xavier Estivill and Faul, Jessica D. and Fernández-Cadenas, Israel and Fornage, Myriam and Frossard, Philippe M. and Furie, Karen and Gamble, Dale M. and Gieger, Christian and Giese, Anne-Katrin and Giralt-Steinhauer, Eva and González, Hector M. and Goris, An and Gretarsdottir, Solveig and Grewal, Raji P. and Grittner, Ulrike and Gustafsson, Stefan and Han, Buhm and Hankey, Graeme J. and Heitsch, Laura and Higgins, Peter and Hochberg, Marc C. and Holliday, Elizabeth and Hopewell, Jemma C. and Horenstein, Richard B. and Howard, George and Ikram, M. Arfan and Ilinca, Andreea and Ingelsson, Erik and Irvin, Marguerite R. and Jackson, Rebecca D. and Jern, Christina and Conde, Jordi Jiménez and Johnson, Julie A. and Jood, Katarina and Kahn, Muhammad S. and Kaplan, Robert and Kappelle, L Jaap and Kardia, Sharon L. R. and Keene, Keith L. and Kissela, Brett M. and Kleindorfer, Dawn O. and Koblar, Simon and Labovitz, Daniel and Launer, Lenore J. and Laurie, Cathy C. and Laurie, Cecelia A. and Lee, Cue Hyunkyu and Lee, Jin-Moo and Lehm, Manuel and Lemmens, Robin and Levi, Christopher and Leys, Didier and Lindgren, Arne and Longstreth, W. T. and Maguire, Jane and Manichaikul, Ani and Markus, Hugh S. and McClure, Leslie A. and McDonough, Caitrin W. and Meisinger, Christa and Melander, Olle and Meschia, James F. and Mola-Caminal, Marina and Montaner, Joan and Mosley, Thomas H. and Müller-Nurasyid, Martina and Nalls, Mike A. and O'Connell, Jeffrey R. and O'Donnell, Martin and Ois, ángel and Papanicolaou, George J. and Paré, Guillaume and Peddareddygari, Leema Reddy and Pedersén, Annie and Pera, Joanna and Peters, Annette and Poole, Deborah and Psaty, Bruce M. and Rabionet, Raquel and Raffeld, Miriam R. and Rannikmäe, Kristiina and Rasheed, Asif and Redfors, Petra and Reiner, Alex P. and Rexrode, Kathryn and Ribasés, Marta and Rich, Stephen S. and Robberecht, Wim and Rodriguez-Campello, Ana and Rolfs, Arndt and Roquer, Jaume and Rose, Lynda M. and Rosenbaum, Daniel and Rost, Natalia S. and Rothwell, Peter M. and Rundek, Tatjana and Ryan, Kathleen A. and Sacco, Ralph L. and Sale, Michèle M. and Saleheen, Danish and Salomaa, Veikko and Sánchez-Mora, Cristina and Schmidt, Carsten Oliver and Schmidt, Helena and Schmidt, Reinhold and Schürks, Markus and Scott, Rodney and Segal, Helen C. and Seiler, Stephan and Seshadri, Sudha and Sharma, Pankaj and Shuldiner, Alan R. and Silver, Brian and Slowik, Agnieszka and Smith, Jennifer A. and Söderholm, Martin and Soriano, Carolina and Sparks, Mary J. and Stanne, Tara and Stefansson, Kari and Stine, O. Colin and Strauch, Konstantin and Sturm, Jonathan and Sudlow, Cathie L. M. and Tajuddin, Salman M. and Talbert, Robert L. and Tatlisumak, Turgut and Thijs, Vincent and Thorleifsson, Gudmar and Thorsteindottir, Unnur and Tiedt, Steffen and Traylor, Matthew and Trompet, Stella and Valant, Valerie and Waldenberger, Melanie and Walters, Matthew and Wang, Liyong and Wassertheil-Smoller, Sylvia and Weir, David R. and Wiggins, Kerri L. and Williams, Stephen R. and Wloch-Kopec, Dorota and Woo, Daniel and Woodfield, Rebecca and Wu, Ona and Xu, Huichun and Zonderman, Alan B. and Worrall, Bradford B. and de Bakker, Paul I. W. and Kittner, Steven J. and Mitchell, Braxton D. and Rosand, Jonathan and Mitchell, Braxton D. and Ay, Hakan and Gwinn, Katrina and Kittner, Steven J. and Lindgren, Arne and Meschia, James F. and Pulit, Sara L. and Sudlow, Cathie L. M. and Thijs, Vincent and Woo, Daniel and Worrall, Bradford B. Worrall and Arnett, Donna K. Arnett and Benavente, Oscar and Cole, John W. and Dichgans, Martin and Grewal, Raji P. and Jern, Christina and Conde, Jordi Jiménez and Johnson, Julie A. and Kittner, Steven J. and Lee, Jin-Moo and Levi, Christopher and Lindgren, Arne and Markus, Hugh S. and Melander, Olle and Meschia, James F. and Rexrode, Kathryn and Rosand, Jonathan and Rothwell, Peter M. and Rundek, Tatjana and Sacco, Ralph L. and Schmidt, Reinhold and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L. M. and Thijs, Vincent and Wasssertheil-Smoller, Sylvia and Woo, Daniel and Worrall, Bradford B. (2016) Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. The Lancet Neurology, 15 (2). pp. 174-184. ISSN 1474-4422

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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.

Keywords:stroke, NotOAChecked
Subjects:C Biological Sciences > C400 Genetics
C Biological Sciences > C420 Human Genetics
C Biological Sciences > C440 Molecular Genetics
C Biological Sciences > C431 Medical Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:27842
Deposited On:18 Jul 2017 14:47

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