NDLI: Genetic overlap between diagnostic subtypes of ischemic stroke.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Worrall, Bradford B. Furie, Karen L. Psaty, Bruce M. Wray, Naomi R. Hopewell, Jemma C. Falcone, Guido Holliday, Elizabeth G. Mitchell, Braxton D. Boerwinkle, Eric Mosley, Thomas H. Levi, Christopher Cotlarciuc, Ioana Scott, Rodney J. Attia, John Fornage, Myriam Wiggins, Kerri L. Oldmeadow, Christopher Bevan, Steve Sudlow, Cathie Cole, John W. Maguire, Jane M. Rothwell, Peter M. Sharma, Pankaj Rosand, Jonathan Bis, Joshua C. Parati, Eugenio A. Kittner, Steven J. Nalls, Mike A. Lincz, Lisa F. Ikram, M. Arfan Seshadri, Sudha Meschia, James F. Dichgans, Martin Malik, Rainer Cheng, Yu-Ching Jannes, Jim Clarke, Robert Traylor, Matthew Boncoraglio, Giorgio B. Markus, Hugh S.
Organization	Australian Stroke Genetics Collaborative
Description	Author Affiliation: Holliday EG ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Traylor M ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Malik R ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Bevan S ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Falcone G ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Hopewell JC ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Cheng YC ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Cotlarciuc I ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Bis JC ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Boerwinkle E ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Boncoraglio GB ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Clarke R ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Cole JW ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Fornage M ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Furie KL ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Ikram MA ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Jannes J ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Kittner SJ ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Lincz LF ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Maguire JM ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Meschia JF ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Mosley TH ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Nalls MA ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Oldmeadow C ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Parati EA ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Psaty BM ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Rothwell PM ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Seshadri S ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Scott RJ ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Sharma P ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Sudlow C ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Wiggins KL ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Worrall BB ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Rosand J ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Mitchell BD ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Dichgans M ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Markus HS ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Levi C ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Attia J ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia); Wray NR ( From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia)
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.
ISSN	00392499
e-ISSN	15244628
DOI	10.1161/STROKEAHA.114.007930
Journal	Stroke
Issue Number	3
Volume Number	46
Language	English
Publisher	Lippincott Williams & Wilkins (on behalf of the American Heart Association)
Publisher Date	2015-03-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Atherosclerosis Genetics Cerebral Small Vessel Diseases Embolism Stroke Alleles Diagnosis Cohort Studies Data Interpretation, Statistical Genome-wide Association Study Genotype Ischemia Linear Models Meta-analysis As Topic Phenotype Polymorphism, Single Nucleotide Research Support, Non-u.s. Gov't Discipline Cardiology
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine Neuroscience Advanced and Specialized Nursing Neurology (clinical)

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