Year: 2015
Type: article
Study design: Observational Study
Abstract: BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene. CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
Source: Stroke
Authors: Elizabeth G. Holliday, Matthew Traylor, Rainer Malik, Steve Bevan, Guido Falcone, Jemma C. Hopewell, Yu-Ching Cheng, Ioana Cotlarciuc, Joshua C. Bis, Eric Boerwinkle, Giorgio B. Boncoraglio, Robert Clarke, John W. Cole, Myriam Fornage, Karen L. Furie, M. Arfan Ikram, Jim Jannes, Steven J. Kittner, Lisa F. Lincz, Jane M. Maguire, James F. Meschia, Thomas H. Mosley, Mike A. Nalls, Christopher Oldmeadow, Eugenio A. Parati, Bruce M. Psaty, Peter M. Rothwell, Sudha Seshadri, Rodney J. Scott, Pankaj Sharma, Cathie Sudlow, Kerri L. Wiggins, Bradford B. Worrall, Jonathan Rosand, Braxton D. Mitchell, Martin Dichgans, Hugh S. Markus, Christopher Levi, John Attia, Naomi R. Wray
Institutions: University of Cambridge, Hunter Medical Research Institute, Institut für Schlaganfall- und Demenzforschung, University of Newcastle Australia, Harvard University, Imperial College London, Fondazione IRCCS Istituto Neurologico Carlo Besta, Rhode Island Hospital, Mayo Clinic in Florida, Group Health Cooperative
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Wellcome Trust, National Institute for Health and Care Research, British Heart Foundation, National Institutes of Health, National Institute on Aging, National Human Genome Research Institute, National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke
Awards: UC Davis Alzheimer's Disease Core Center, NIHR Senior Investigator Award, Pharmacogenomic, genetic and trial-based studies of lipid-modifying therapies and vascular risk, Improving prevention of stroke by better understanding of existing risk factors and treatments., Pharmacogenomic studies in VISP: results & implications for clinical trial design, G573982542, Cerebrovascular Atherosclerosis: Genes & Gene Expression, G7249074514, AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE, Epidemiology of Dementia in the Framingham Study, The NINDS International Stroke Genetics Consortium Study, Precursors of Stroke Incidence and Prognosis
OpenAlex ID: W2016777899