Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease
Year: 2015
Type: article
Study design: Observational Study
Abstract: OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
Source: Neurology
Authors: Kristiina Rannikmäe, Gail Davies, Pippa A. Thomson, Steve Bevan, William J. Devan, Guido J. Falcone, Matthew Traylor, Christopher D. Anderson, Thomas W.K. Battey, Farid Radmanesh, Ranjan Deka, Jessica G. Woo, Lisa J. Martin, Jordi Jimenez-Conde, Magdy Selim, Devin L. Brown, Scott L. Silliman, Chelsea S. Kidwell, Joan Montaner, Carl D. Langefeld, Agnieszka Slowik, Björn M. Hansen, Arne G. Lindgren, James F. Meschia, Myriam Fornage, Joshua C. Bis, Stéphanie Debette, Mohammad A. Ikram, Will T. Longstreth, Reinhold Schmidt, Cathy R. Zhang, Qiong Yang, Pankaj Sharma, Steven J. Kittner, Braxton D. Mitchell, Elizabeth G. Holliday, Christopher R. Levi, John Attia, Peter M. Rothwell, Deborah L. Poole, Giorgio B. Boncoraglio, Bruce M. Psaty, Rainer Malik, Natalia Rost, Bradford B. Worrall, Martin Dichgans, Tom Van Agtmael, Daniel Woo, Hugh S. Markus, Sudha Seshadri, Jonathan Rosand, Cathie L.M. Sudlow
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Veterans Affairs, Massachusetts General Hospital, Wake Forest University, Cincinnati Children's Hospital Medical Center, School of Medicine, Boston University, University of Washington, University of Cincinnati, Uniwersytet Jagielloński Collegium Medicum, Wellcome Trust, University of Texas Health Science Center at Houston, Broad Institute, National Institute for Health and Care Research, Kidney Research UK, University of Oxford, University of Glasgow, Hunter Medical Research Institute, Institut National de la Santé et de la Recherche Médicale, Lunds Universitet, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Karl-Franzens-Universität Graz, Medizinische Universität Graz, Skånes universitetssjukhus, Centre for Cognitive Ageing and Cognitive Epidemiology, College of Medicine, University of Cincinnati, School of Public Health, University of Texas Health Science Center at Houston, Medical Research Council, Biotechnology and Biological Sciences Research Council, Royal Holloway, University of London, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke
OpenAlex ID: W2170165089