Low-frequency and common genetic variation in ischemic stroke

Rainer Malik, Matthew Traylor, Sara L. Pulit, Steve Bevan, Jemma C. Hopewell, Elizabeth G. Holliday, Wei Zhao, Patricia Abrantes, Philippe Amouyel, John R. Attia, Thomas W K Battey, Klaus Berger, Giorgio B. Boncoraglio, Ganesh Chauhan, Yu Ching Cheng, Wei Min Chen, Robert Clarke, Ioana Cotlarciuc, Stephanie Debette, Guido J. FalconeJose M. Ferro, Dale M. Gamble, Andreea Ilinca, Steven J. Kittner, Christina E. Kourkoulis, Robin Lemmens, Christopher R. Levi, Peter Lichtner, Arne Lindgren, Jingmin Liu, James F. Meschia, Braxton D. Mitchell, Sofia A. Oliveira, Joana Pera, Alex P. Reiner, Peter M. Rothwell, Pankaj Sharma, Agnieszka Slowik, Cathie L M Sudlow, Turgut Tatlisumak, Vincent Thijs, Astrid M. Vicente, Daniel Woo, Sudha Seshadri, Danish Saleheen, Jonathan Rosand, Hugh S. Markus, Bradford B. Worrall, Martin Dichgans

Research output: Contribution to journalArticle

Abstract

Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p <1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency

Original languageEnglish
Pages (from-to)1217-1226
Number of pages10
JournalNeurology
Volume86
Issue number13
DOIs
Publication statusPublished - Mar 29 2016

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Stroke
Gene Frequency
Genome
Genome-Wide Association Study
Meta-Analysis

ASJC Scopus subject areas

  • Clinical Neurology

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Malik, R., Traylor, M., Pulit, S. L., Bevan, S., Hopewell, J. C., Holliday, E. G., ... Dichgans, M. (2016). Low-frequency and common genetic variation in ischemic stroke. Neurology, 86(13), 1217-1226. https://doi.org/10.1212/WNL.0000000000002528

Low-frequency and common genetic variation in ischemic stroke. / Malik, Rainer; Traylor, Matthew; Pulit, Sara L.; Bevan, Steve; Hopewell, Jemma C.; Holliday, Elizabeth G.; Zhao, Wei; Abrantes, Patricia; Amouyel, Philippe; Attia, John R.; Battey, Thomas W K; Berger, Klaus; Boncoraglio, Giorgio B.; Chauhan, Ganesh; Cheng, Yu Ching; Chen, Wei Min; Clarke, Robert; Cotlarciuc, Ioana; Debette, Stephanie; Falcone, Guido J.; Ferro, Jose M.; Gamble, Dale M.; Ilinca, Andreea; Kittner, Steven J.; Kourkoulis, Christina E.; Lemmens, Robin; Levi, Christopher R.; Lichtner, Peter; Lindgren, Arne; Liu, Jingmin; Meschia, James F.; Mitchell, Braxton D.; Oliveira, Sofia A.; Pera, Joana; Reiner, Alex P.; Rothwell, Peter M.; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L M; Tatlisumak, Turgut; Thijs, Vincent; Vicente, Astrid M.; Woo, Daniel; Seshadri, Sudha; Saleheen, Danish; Rosand, Jonathan; Markus, Hugh S.; Worrall, Bradford B.; Dichgans, Martin.

In: Neurology, Vol. 86, No. 13, 29.03.2016, p. 1217-1226.

Research output: Contribution to journalArticle

Malik, R, Traylor, M, Pulit, SL, Bevan, S, Hopewell, JC, Holliday, EG, Zhao, W, Abrantes, P, Amouyel, P, Attia, JR, Battey, TWK, Berger, K, Boncoraglio, GB, Chauhan, G, Cheng, YC, Chen, WM, Clarke, R, Cotlarciuc, I, Debette, S, Falcone, GJ, Ferro, JM, Gamble, DM, Ilinca, A, Kittner, SJ, Kourkoulis, CE, Lemmens, R, Levi, CR, Lichtner, P, Lindgren, A, Liu, J, Meschia, JF, Mitchell, BD, Oliveira, SA, Pera, J, Reiner, AP, Rothwell, PM, Sharma, P, Slowik, A, Sudlow, CLM, Tatlisumak, T, Thijs, V, Vicente, AM, Woo, D, Seshadri, S, Saleheen, D, Rosand, J, Markus, HS, Worrall, BB & Dichgans, M 2016, 'Low-frequency and common genetic variation in ischemic stroke', Neurology, vol. 86, no. 13, pp. 1217-1226. https://doi.org/10.1212/WNL.0000000000002528
Malik R, Traylor M, Pulit SL, Bevan S, Hopewell JC, Holliday EG et al. Low-frequency and common genetic variation in ischemic stroke. Neurology. 2016 Mar 29;86(13):1217-1226. https://doi.org/10.1212/WNL.0000000000002528
Malik, Rainer ; Traylor, Matthew ; Pulit, Sara L. ; Bevan, Steve ; Hopewell, Jemma C. ; Holliday, Elizabeth G. ; Zhao, Wei ; Abrantes, Patricia ; Amouyel, Philippe ; Attia, John R. ; Battey, Thomas W K ; Berger, Klaus ; Boncoraglio, Giorgio B. ; Chauhan, Ganesh ; Cheng, Yu Ching ; Chen, Wei Min ; Clarke, Robert ; Cotlarciuc, Ioana ; Debette, Stephanie ; Falcone, Guido J. ; Ferro, Jose M. ; Gamble, Dale M. ; Ilinca, Andreea ; Kittner, Steven J. ; Kourkoulis, Christina E. ; Lemmens, Robin ; Levi, Christopher R. ; Lichtner, Peter ; Lindgren, Arne ; Liu, Jingmin ; Meschia, James F. ; Mitchell, Braxton D. ; Oliveira, Sofia A. ; Pera, Joana ; Reiner, Alex P. ; Rothwell, Peter M. ; Sharma, Pankaj ; Slowik, Agnieszka ; Sudlow, Cathie L M ; Tatlisumak, Turgut ; Thijs, Vincent ; Vicente, Astrid M. ; Woo, Daniel ; Seshadri, Sudha ; Saleheen, Danish ; Rosand, Jonathan ; Markus, Hugh S. ; Worrall, Bradford B. ; Dichgans, Martin. / Low-frequency and common genetic variation in ischemic stroke. In: Neurology. 2016 ; Vol. 86, No. 13. pp. 1217-1226.
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abstract = "Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p <1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency",
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AU - Malik, Rainer

AU - Traylor, Matthew

AU - Pulit, Sara L.

AU - Bevan, Steve

AU - Hopewell, Jemma C.

AU - Holliday, Elizabeth G.

AU - Zhao, Wei

AU - Abrantes, Patricia

AU - Amouyel, Philippe

AU - Attia, John R.

AU - Battey, Thomas W K

AU - Berger, Klaus

AU - Boncoraglio, Giorgio B.

AU - Chauhan, Ganesh

AU - Cheng, Yu Ching

AU - Chen, Wei Min

AU - Clarke, Robert

AU - Cotlarciuc, Ioana

AU - Debette, Stephanie

AU - Falcone, Guido J.

AU - Ferro, Jose M.

AU - Gamble, Dale M.

AU - Ilinca, Andreea

AU - Kittner, Steven J.

AU - Kourkoulis, Christina E.

AU - Lemmens, Robin

AU - Levi, Christopher R.

AU - Lichtner, Peter

AU - Lindgren, Arne

AU - Liu, Jingmin

AU - Meschia, James F.

AU - Mitchell, Braxton D.

AU - Oliveira, Sofia A.

AU - Pera, Joana

AU - Reiner, Alex P.

AU - Rothwell, Peter M.

AU - Sharma, Pankaj

AU - Slowik, Agnieszka

AU - Sudlow, Cathie L M

AU - Tatlisumak, Turgut

AU - Thijs, Vincent

AU - Vicente, Astrid M.

AU - Woo, Daniel

AU - Seshadri, Sudha

AU - Saleheen, Danish

AU - Rosand, Jonathan

AU - Markus, Hugh S.

AU - Worrall, Bradford B.

AU - Dichgans, Martin

PY - 2016/3/29

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