Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

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. Falcone; Jose 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

doi:10.1212/WNL.0000000000002528

Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

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

Western Sydney University

Research output: Contribution to journal › Article › peer-review

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 <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

Original language	English
Pages (from-to)	1217-1226
Number of pages	10
Journal	Neurology
Volume	86
Issue number	13
DOIs	https://doi.org/10.1212/WNL.0000000000002528
Publication status	Published - 2016

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10.1212/WNL.0000000000002528

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Malik, R., Traylor, M., Pulit, S. L., Bevan, S., Hopewell, J. C., Holliday, E. G., Zhao, W., Abrantes, P., Amouyel, P., Attia, J. R., Battey, T. W. K., Berger, K., Boncoraglio, G. B., Chauhan, G., Cheng, Y.-C., Chen, W.-M., Clarke, R., Cotlarciuc, I., Debette, S., ... Dichgans, M. (2016). Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration. Neurology, 86(13), 1217-1226. https://doi.org/10.1212/WNL.0000000000002528

@article{d59fbb3dc5124901b1b0dc8e04aa0888,

title = "Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration",

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 <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.",

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

year = "2016",

doi = "10.1212/WNL.0000000000002528",

language = "English",

volume = "86",

pages = "1217--1226",

journal = "Neurology",

issn = "0028-3878",

publisher = "Wolters Kluwer Health",

number = "13",

}

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, Y-C, Chen, W-M, 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 : the METASTROKE collaboration', Neurology, vol. 86, no. 13, pp. 1217-1226. https://doi.org/10.1212/WNL.0000000000002528

TY - JOUR

T1 - Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

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

Y1 - 2016

N2 - 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 <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

AB - 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 <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

UR - https://hdl.handle.net/1959.7/uws:63811

U2 - 10.1212/WNL.0000000000002528

DO - 10.1212/WNL.0000000000002528

M3 - Article

SN - 0028-3878

VL - 86

SP - 1217

EP - 1226

JO - Neurology

JF - Neurology

IS - 13

ER -

Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

Abstract

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