Identification of additional risk loci for stroke and small vessel disease
Autor: | Matthew Traylor, Vilmundur Gudnason, Kerri L. Wiggins, Christophe Tzourio, Reinhold E. Schmidt, Hugo J. Aparicio, Tamara B. Harris, Audrey Y. Chu, Oscar R. Benavente, Anton J. M. de Craen, Nancy L. Pedersen, Lars Lannfelt, Didier Leys, Erkki Vartiainen, Myriam Fornage, Marileen L.P. Portegies, Nicholas L. Smith, Daniel Woo, Martin Dichgans, John W. Cole, Christina Jern, Christopher R Levi, Kenneth Rice, André G. Uitterlinden, Rebecca F. Gottesman, M. Arfan Ikram, Ralph L. Sacco, Cornelia M. van Duijn, Samuli Ripatti, Anita L. DeStefano, Donna K. Arnett, Curtis R. French, Tobias Kurth, Tomi Pastinen, Raji P. Grewal, Susan R. Heckbert, Jordi Jimenez-Conde, Jemma C. Hopewell, Cecilia M. Lindgren, Azadeh Reyahi, Michèle M. Sale, Marcello Ricardo Paulista Markus, Albert Hofman, Seung Hoan Choi, Peter J. Koudstaal, Veikko Salomaa, Robert Clarke, Arne Lindgren, B. Gwen Windham, Farid Radmanesh, Peter M. Rothwell, Carsten Oliver Schmidt, Xueqiu Jian, David S. Knopman, Yongmei Liu, Joan Montaner, Jean-François Dartigues, Paul M. Ridker, Julie A. Johnson, Stefan Gustafsson, Jerome I. Rotter, Manja Kloss, Tatjana Rundek, David J. Stott, Ganesh Chauhan, Ordan J. Lehmann, Ali Moussavi Nik, Marcel den Hoed, Alessandro Pezzini, Jin-Moo Lee, Hans J. Grabe, Sylvia Wassertheil-Smoller, Anders Hamsten, Thomas H. Mosley, Muralidharan Sargurupremraj, Lenore J. Launer, Kathryn M. Rexrode, Quenna Wong, Jonathan Rosand, David A. Bennett, Philip L. De Jager, James F. Meschia, Alexa S. Beiser, J. Wouter Jukema, Traci M. Bartz, Mike A. Nalls, Cathie Sudlow, Erik Ingelsson, Yoichiro Kamatani, Ulf Schminke, Joris Deelen, Stéphanie Debette, Andrew P. Morris, Aki S. Havulinna, Sudha Seshadri, Bradford B. Worrall, Stephen S. Rich, Lars Lindgren, Hieab H.H. Adams, Ani Manichaikul, Jean-Sébastien Vidal, Bruce M. Psaty, Julie E. Buring, Jean Dallongeville, Oscar L. Lopez, Corey R. Arnold, Olle Melander, Olafur Kjartansson, Alexander Teumer, Sarah J. Childs, William T. Longstreth, Charles C. White, Stefan T. Engelter, Daniel I. Chasman, Norrina B. Allen, Rainer Malik, Vincent Thijs, Stella Trompet, Joshua C. Bis, Ian Ford, Peter Carlsson, Céline Bellenguez, Sara L. Pulit, Pankaj Sharma, Patrik K. E. Magnusson, Flora Xue, Giorgio B. Boncoraglio, Mark Lathrop, Melissa E. Garcia, Andrew D. Johnson, Steve Bevan, Albert V. Smith, Claudia L. Satizabal, Agnieszka Slowik, Michael Griswold, Claudine Berr, Hugh S. Markus |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
Adult
Male 0301 basic medicine Adolescent Population Genome-wide association study Biology Bioinformatics Article Brain ischemia Mice Young Adult 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being medicine Animals Humans Child education Allele frequency Stroke Aged Aged 80 and over education.field_of_study Cerebral infarction Forkhead Transcription Factors Odds ratio Middle Aged 16. Peace & justice medicine.disease R1 3. Good health Minor allele frequency 030104 developmental biology Genetic Loci Cerebral Small Vessel Diseases Child Preschool Female Neurology (clinical) 030217 neurology & neurosurgery Genome-Wide Association Study |
Zdroj: | Sudlow, C 2016, ' Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies ', Lancet Neurology . https://doi.org/10.1016/S1474-4422(16)00102-2 |
ISSN: | 1474-4465 1474-4422 |
Popis: | Background 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. Methods 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−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−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. Findings 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. Interpretation 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. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq. |
Databáze: | OpenAIRE |
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