Genetic overlap between diagnostic subtypes of ischemic stroke

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. MaguireJames 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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)615-619
Number of pages5
JournalStroke
Volume46
Issue number3
DOIs
StatePublished - Mar 1 2015

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Atherosclerosis
Arteries
Stroke
Linear Models
Meta-Analysis
Alleles
Genetic Association Studies
Opioid Receptors
Sample Size
Single Nucleotide Polymorphism
Joints
Genotype
Genome
Confidence Intervals
Phenotype
Genes

Keywords

  • Atherosclerosis
  • Genetic epidemiology
  • Lacunar stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Holliday, E. G., Traylor, M., Malik, R., Bevan, S., Falcone, G., Hopewell, J. C., ... Wray, N. R. (2015). Genetic overlap between diagnostic subtypes of ischemic stroke. Stroke, 46(3), 615-619. https://doi.org/10.1161/STROKEAHA.114.007930

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; Wray, Naomi R.

In: Stroke, Vol. 46, No. 3, 01.03.2015, p. 615-619.

Research output: Contribution to journalArticle

Holliday, EG, Traylor, M, Malik, R, Bevan, S, Falcone, G, Hopewell, JC, Cheng, YC, Cotlarciuc, I, Bis, JC, Boerwinkle, E, Boncoraglio, GB, Clarke, R, Cole, JW, Fornage, M, Furie, KL, Ikram, MA, 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 & Wray, NR 2015, 'Genetic overlap between diagnostic subtypes of ischemic stroke', Stroke, vol. 46, no. 3, pp. 615-619. https://doi.org/10.1161/STROKEAHA.114.007930
Holliday EG, Traylor M, Malik R, Bevan S, Falcone G, Hopewell JC et al. Genetic overlap between diagnostic subtypes of ischemic stroke. Stroke. 2015 Mar 1;46(3):615-619. https://doi.org/10.1161/STROKEAHA.114.007930
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. / Genetic overlap between diagnostic subtypes of ischemic stroke. In: Stroke. 2015 ; Vol. 46, No. 3. pp. 615-619.
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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.",
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T1 - Genetic overlap between diagnostic subtypes of ischemic stroke

AU - Holliday, Elizabeth G.

AU - Traylor, Matthew

AU - Malik, Rainer

AU - Bevan, Steve

AU - Falcone, Guido

AU - Hopewell, Jemma C.

AU - Cheng, Yu Ching

AU - Cotlarciuc, Ioana

AU - Bis, Joshua C.

AU - Boerwinkle, Eric

AU - Boncoraglio, Giorgio B.

AU - Clarke, Robert

AU - Cole, John W.

AU - Fornage, Myriam

AU - Furie, Karen L.

AU - Ikram, M. Arfan

AU - Jannes, Jim

AU - Kittner, Steven J.

AU - Lincz, Lisa F.

AU - Maguire, Jane M.

AU - Meschia, James F

AU - Mosley, Thomas H.

AU - Nalls, Mike A.

AU - Oldmeadow, Christopher

AU - Parati, Eugenio A.

AU - Psaty, Bruce M.

AU - Rothwell, Peter M.

AU - Seshadri, Sudha

AU - Scott, Rodney J.

AU - Sharma, Pankaj

AU - Sudlow, Cathie

AU - Wiggins, Kerri L.

AU - Worrall, Bradford B.

AU - Rosand, Jonathan

AU - Mitchell, Braxton D.

AU - Dichgans, Martin

AU - Markus, Hugh S.

AU - Levi, Christopher

AU - Attia, John

AU - Wray, Naomi R.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Genetic epidemiology

KW - Lacunar stroke

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