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Genetic overlap between diagnostic subtypes of ischemic stroke.

TitleGenetic overlap between diagnostic subtypes of ischemic stroke.
Publication TypeJournal Article
Year of Publication2015
AuthorsHolliday EG, Traylor M, Malik R, Bevan S, Falcone G, Hopewell JC, Cheng Y-C, Cotlarciuc I, Bis JC, Boerwinkle E, Boncoraglio GB, Clarke R, Cole JW, Fornage M, Furie KL, M Ikram A, Jannes J, Kittner SJ, Lincz LF, Maguire JM, Meschia JF, Mosley TH, Nalls MA, Oldmeadow C, Parati EA, Psaty BM, Rothwell PM, Seshadri S, Scott RJ, Sharma P, Sudlow C, Wiggins KL, Worrall BB, Rosand J, Mitchell BD, Dichgans M, Markus HS, Levi C, Attia J
Secondary AuthorsWray NR
Corporate AuthorsAustralian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2, International Stroke Genetics Consortium
JournalStroke
Volume46
Issue3
Pagination615-9
Date Published2015 Mar
ISSN1524-4628
KeywordsAlleles, Atherosclerosis, Cerebral Small Vessel Diseases, Cohort Studies, Data Interpretation, Statistical, Embolism, Genome-Wide Association Study, Genotype, Humans, Ischemia, Linear Models, Meta-Analysis as Topic, Phenotype, Polymorphism, Single Nucleotide, Stroke
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.

DOI10.1161/STROKEAHA.114.007930
Alternate JournalStroke
PubMed ID25613305
PubMed Central IDPMC4342266
Grant ListU01 HG005160 / HG / NHGRI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
095626 / WT_ / Wellcome Trust / United Kingdom
L30 DC006823 / DC / NIDCD NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
FS/14/55/30806 / BHF_ / British Heart Foundation / United Kingdom
OSRP2/1006 / DMT_ / The Dunhill Medical Trust / United Kingdom
P30 AG010129 / AG / NIA NIH HHS / United States
K08 NS045802 / NS / NINDS NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States