Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Chauhan, Ganesh and Arnold, Corey R. and Chu, Audrey Y. and Fornage, Myriam and Reyahi, Azadeh and Bis, Joshua C. and Havulinna, Aki S. and Sargurupremraj, Muralidharan and Smith, Albert Vernon and Adams, Hieab H. H. and Choi, Seung Hoan and Pulit, Sara L. and Trompet, Stella and Garcia, Melissa E. and Manichaikul, Ani and Teumer, Alexander and Gustafsson, Stefan and Bartz, Traci M. and Bellenguez, Céline and Vidal, Jean Sebastien and Jian, Xueqiu and Kjartansson, Olafur and Wiggins, Kerri L. and Satizabal, Claudia L. and Xue, Flora and Ripatti, Samuli and Liu, Yongmei and Deelen, Joris and den Hoed, Marcel and Bevan, Steve and Hopewell, Jemma C. and Malik, Rainer and Heckbert, Susan R. and Rice, Kenneth and Smith, Nicholas L. and Levi, Christopher and Sharma, Pankaj and Sudlow, Cathie LM and Nik, Ali Moussavi and Cole, John W. and Schmidt, Reinhold and Meschia, James and Thijs, Vincent and Lindgren, Arne and Melander, Olle and Grewal, Raji P. and Sacco, Ralph L. and Rundek, Tatjana and Rothwell, Peter M. and Arnett, Donna K. and Jern, Christina and Johnson, Julie A. and Benavente, Oscar R. and Wassertheil-Smoller, Sylvia and Lee, Jin-Moo and Wong, Quenna and Aparicio, Hugo J. and Engelter, Stefan T. and Kloss, Manja and Leys, Didier and Pezzini, Alessandro and Buring, Julie E. and Ridker, Paul M. and Berr, Claudine and Dartigues, Jean-François and Hamsten, Anders and Magnusson, Patrik K. and Traylor, Matthew and Pedersen, Nancy L. and Lannfelt, Lars and Lindgren, Lars and Lindgren, Cecilia M. and Morris, Andrew P. and Jimenez-Conde, Jordi and Montaner, Joan and Radmanesh, Farid and Slowik, Agnieszka and Woo, Daniel and Hofman, Albert and Koudstaal, Peter J. and Portegies, Marileen L. P. and Uitterlinden, André G. and de Craen, Anton J. M. and Ford, Ian and Jukema, J. Wouter and Stott, David J. and Allen, Norrina B. and Sale, Michele M. and Johnson, Andrew D. and Bennett, David A. and De Jager, Philip L. and White, Charles C. and Grabe, Hans Jörgen and Markus, Marcello Ricardo Paulista and Schminke, Ulf and Boncoraglio, Giorgio B. and Clarke, Robert and Kamatani, Yoichiro and Dallongeville, Jean and Lopez, Oscar L. and Rotter, Jerome I. and Nalls, Michael A. and Gottesman, Rebecca F. and Griswold, Michael E. and Knopman, David S. and Windham, B. Gwen and Beiser, Alexa and Markus, Hugh S. and Vartiainen, Erkki and French, Curtis R. and Dichgans, Martin and Pastinen, Tomi and Lathrop, Mark and Gudnason, Vilmundur and Kurth, Tobias and Psaty, Bruce M. and Harris, Tamara B. and Rich, Stephen S. and deStefano, Anita L. and Schmidt, Carsten Oliver and Worrall, Bradford B. and Rosand, Jonathan and Salomaa, Veikko and Mosley, Thomas H. and Ingelsson, Erik and van Duijn, Cornelia M. and Tzourio, Christophe and Rexrode, Kathryn M. and Lehmann, Ordan J. and Launer, Lenore J. and Ikram, M. Arfan and Carlsson, Peter and Chasman, Daniel I. and Childs, Sarah J. and Longstreth, William T. and Seshadri, Sudha and Debette, Stéphanie (2016) Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. The Lancet Neurology, 15 (7). pp. 695-707. ISSN 1474-4422

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Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies.

For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants.

We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage.

We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms.

Additional Information:The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN) and the International Stroke Genetics Consortium (ISGC)
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
ID Code:27847
Deposited On:18 Jul 2017 18:07

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