Genetic Overlap Between Diagnostic Subtypes of Ischemic Stroke

Holliday, Elizabeth G., Traylor, Matthew, Malik, Rainer, Bevan, Steve, Falcone, Guido, Hopewell, Jemma C., Cheng, Yu-Ching, Cotlarciuc, Ioana, Bis, Joshua C., Boerwinkle, Eric, Boncoraglio, Giorgio B., Clarke, Robert, Cole, John W., Fornage, Myriam, Furie, Karen L., Ikram, M. Arfan, Jannes, Jim, Kittner, Steven J., Lincz, Lisa F., Maguire, Jane M., Meschia, James F., Mosley, Thomas H., Nalls, Mike A., Oldmeadow, Christopher, Parati, Eugenio A., Psaty, Bruce M., Rothwell, Peter M., Seshadri, Sudha, Scott, Rodney J., Sharma, Pankaj, Sudlow, Cathie, Wiggins, Kerri L., Worrall, Bradford B., Rosand, Jonathan, Mitchell, Braxton D., Dichgans, Martin, Markus, Hugh S., Levi, Christopher, Attia, John and Wray, Naomi R. (2015) Genetic Overlap Between Diagnostic Subtypes of Ischemic Stroke. Stroke, 46 3: 615-615. doi:10.1161/STROKEAHA.114.007930

Author Holliday, Elizabeth G.
Traylor, Matthew
Malik, Rainer
Bevan, Steve
Falcone, Guido
Hopewell, Jemma C.
Cheng, Yu-Ching
Cotlarciuc, Ioana
Bis, Joshua C.
Boerwinkle, Eric
Boncoraglio, Giorgio B.
Clarke, Robert
Cole, John W.
Fornage, Myriam
Furie, Karen L.
Ikram, M. Arfan
Jannes, Jim
Kittner, Steven J.
Lincz, Lisa F.
Maguire, Jane M.
Meschia, James F.
Mosley, Thomas H.
Nalls, Mike A.
Oldmeadow, Christopher
Parati, Eugenio A.
Psaty, Bruce M.
Rothwell, Peter M.
Seshadri, Sudha
Scott, Rodney J.
Sharma, Pankaj
Sudlow, Cathie
Wiggins, Kerri L.
Worrall, Bradford B.
Rosand, Jonathan
Mitchell, Braxton D.
Dichgans, Martin
Markus, Hugh S.
Levi, Christopher
Attia, John
Wray, Naomi R.
Title Genetic Overlap Between Diagnostic Subtypes of Ischemic Stroke
Journal name Stroke   Check publisher's open access policy
ISSN 0039-2499
Publication date 2015-03
Year available 2015
Sub-type Article (original research)
DOI 10.1161/STROKEAHA.114.007930
Open Access Status DOI
Volume 46
Issue 3
Start page 615
End page 615
Total pages 22
Place of publication Philadelphia, PA United States
Publisher Lippincott Williams and Wilkins
Collection year 2016
Language eng
Formatted 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.
Keyword Atherosclerosis
Genetic epidemiology
Lacunar stroke
Genome wide association
Complex Traits
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
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Citation counts: TR Web of Science Citation Count  Cited 8 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 8 times in Scopus Article | Citations
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