Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

Yu Ching Cheng; Tara M. Stanne; Anne Katrin Giese; Weang Kee Ho; Matthew Traylor; Philippe Amouyel; Elizabeth G. Holliday; Rainer Malik; Huichun Xu; Steven J. Kittner; John W. Cole; Jeffrey R. O'Connell; John Danesh; Asif Rasheed; Wei Zhao; Stefan Engelter; Caspar Grond-Ginsbach; Yoichiro Kamatani; Mark Lathrop; Didier Leys; Vincent Thijs; Tiina M. Metso; Turgut Tatlisumak; Alessandro Pezzini; Eugenio A. Parati; Bo Norrving; Steve Bevan; Peter M. Rothwell; Cathie Sudlow; Agnieszka Slowik; Arne Lindgren; Matthew R. Walters; Jim Jannes; Jess Shen; David Crosslin; Kimberly Doheny; Cathy C. Laurie; Sandip M. Kanse; Joshua C. Bis; Myriam Fornage; Thomas H. Mosley; Jemma C. Hopewell; Konstantin Strauch; Martina Müller-Nurasyid; Christian Gieger; Melanie Waldenberger; Annette Peters; Christine Meisinger; M. Arfan Ikram; W. T. Longstreth; James F. Meschia; Sudha Seshadri; Pankaj Sharma; Bradford Worrall; Christina Jern; Christopher Levi; Martin Dichgans; Giorgio B. Boncoraglio; Hugh S. Markus; Stephanie Debette; Arndt Rolfs; Danish Saleheen; Braxton D. Mitchell

doi:10.1161/STROKEAHA.115.011328

Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

Yu Ching Cheng, Tara M. Stanne, Anne Katrin Giese, Weang Kee Ho, Matthew Traylor, Philippe Amouyel, Elizabeth G. Holliday, Rainer Malik, Huichun Xu, Steven J. Kittner, John W. Cole, Jeffrey R. O'Connell, John Danesh, Asif Rasheed, Wei Zhao, Stefan Engelter, Caspar Grond-Ginsbach, Yoichiro Kamatani, Mark Lathrop, Didier LeysVincent Thijs, Tiina M. Metso, Turgut Tatlisumak, Alessandro Pezzini, Eugenio A. Parati, Bo Norrving, Steve Bevan, Peter M. Rothwell, Cathie Sudlow, Agnieszka Slowik, Arne Lindgren, Matthew R. Walters, Jim Jannes, Jess Shen, David Crosslin, Kimberly Doheny, Cathy C. Laurie, Sandip M. Kanse, Joshua C. Bis, Myriam Fornage, Thomas H. Mosley, Jemma C. Hopewell, Konstantin Strauch, Martina Müller-Nurasyid, Christian Gieger, Melanie Waldenberger, Annette Peters, Christine Meisinger, M. Arfan Ikram, W. T. Longstreth, James F. Meschia, Sudha Seshadri, Pankaj Sharma, Bradford Worrall, Christina Jern, Christopher Levi, Martin Dichgans, Giorgio B. Boncoraglio, Hugh S. Markus, Stephanie Debette, Arndt Rolfs, Danish Saleheen, Braxton D. Mitchell

Neurology

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

32 Scopus citations

Abstract

Background and Purpose - Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early-versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset < 60 years. Methods. The discovery stage of our genome-wide association studies included 4505 cases and 21968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10^-6 and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results.One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10^-9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII.activating protease levels, a product of HABP2. Conclusions.HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

Original language	English (US)
Pages (from-to)	307-316
Number of pages	10
Journal	Stroke
Volume	47
Issue number	2
DOIs	https://doi.org/10.1161/STROKEAHA.115.011328
State	Published - Feb 1 2016

Keywords

Factor VII
Genetics
Genome-wide analysis
Ischemic stroke
Stroke

ASJC Scopus subject areas

Clinical Neurology
Cardiology and Cardiovascular Medicine
Advanced and Specialized Nursing

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10.1161/STROKEAHA.115.011328

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Cheng, Y. C., Stanne, T. M., Giese, A. K., Ho, W. K., Traylor, M., Amouyel, P., Holliday, E. G., Malik, R., Xu, H., Kittner, S. J., Cole, J. W., O'Connell, J. R., Danesh, J., Rasheed, A., Zhao, W., Engelter, S., Grond-Ginsbach, C., Kamatani, Y., Lathrop, M., ... Mitchell, B. D. (2016). Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. Stroke, 47(2), 307-316. https://doi.org/10.1161/STROKEAHA.115.011328

Cheng, YC, Stanne, TM, Giese, AK, Ho, WK, Traylor, M, Amouyel, P, Holliday, EG, Malik, R, Xu, H, Kittner, SJ, Cole, JW, O'Connell, JR, Danesh, J, Rasheed, A, Zhao, W, Engelter, S, Grond-Ginsbach, C, Kamatani, Y, Lathrop, M, Leys, D, Thijs, V, Metso, TM, Tatlisumak, T, Pezzini, A, Parati, EA, Norrving, B, Bevan, S, Rothwell, PM, Sudlow, C, Slowik, A, Lindgren, A, Walters, MR, Jannes, J, Shen, J, Crosslin, D, Doheny, K, Laurie, CC, Kanse, SM, Bis, JC, Fornage, M, Mosley, TH, Hopewell, JC, Strauch, K, Müller-Nurasyid, M, Gieger, C, Waldenberger, M, Peters, A, Meisinger, C, Ikram, MA, Longstreth, WT, Meschia, JF, Seshadri, S, Sharma, P, Worrall, B, Jern, C, Levi, C, Dichgans, M, Boncoraglio, GB, Markus, HS, Debette, S, Rolfs, A, Saleheen, D & Mitchell, BD 2016, 'Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2', Stroke, vol. 47, no. 2, pp. 307-316. https://doi.org/10.1161/STROKEAHA.115.011328

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title = "Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2",

abstract = "Background and Purpose - Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early-versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset < 60 years. Methods. The discovery stage of our genome-wide association studies included 4505 cases and 21968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10-6 and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results.One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10-9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII.activating protease levels, a product of HABP2. Conclusions.HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.",

keywords = "Factor VII, Genetics, Genome-wide analysis, Ischemic stroke, Stroke",

author = "Cheng, {Yu Ching} and Stanne, {Tara M.} and Giese, {Anne Katrin} and Ho, {Weang Kee} and Matthew Traylor and Philippe Amouyel and Holliday, {Elizabeth G.} and Rainer Malik and Huichun Xu and Kittner, {Steven J.} and Cole, {John W.} and O'Connell, {Jeffrey R.} and John Danesh and Asif Rasheed and Wei Zhao and Stefan Engelter and Caspar Grond-Ginsbach and Yoichiro Kamatani and Mark Lathrop and Didier Leys and Vincent Thijs and Metso, {Tiina M.} and Turgut Tatlisumak and Alessandro Pezzini and Parati, {Eugenio A.} and Bo Norrving and Steve Bevan and Rothwell, {Peter M.} and Cathie Sudlow and Agnieszka Slowik and Arne Lindgren and Walters, {Matthew R.} and Jim Jannes and Jess Shen and David Crosslin and Kimberly Doheny and Laurie, {Cathy C.} and Kanse, {Sandip M.} and Bis, {Joshua C.} and Myriam Fornage and Mosley, {Thomas H.} and Hopewell, {Jemma C.} and Konstantin Strauch and Martina M{\"u}ller-Nurasyid and Christian Gieger and Melanie Waldenberger and Annette Peters and Christine Meisinger and Ikram, {M. Arfan} and Longstreth, {W. T.} and Meschia, {James F.} and Sudha Seshadri and Pankaj Sharma and Bradford Worrall and Christina Jern and Christopher Levi and Martin Dichgans and Boncoraglio, {Giorgio B.} and Markus, {Hugh S.} and Stephanie Debette and Arndt Rolfs and Danish Saleheen and Mitchell, {Braxton D.}",

note = "Publisher Copyright: {\textcopyright} 2016 American Heart Association, Inc.",

year = "2016",

month = feb,

day = "1",

doi = "10.1161/STROKEAHA.115.011328",

language = "English (US)",

volume = "47",

pages = "307--316",

journal = "Stroke",

issn = "0039-2499",

publisher = "Lippincott Williams and Wilkins",

number = "2",

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TY - JOUR

T1 - Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

AU - Cheng, Yu Ching

AU - Stanne, Tara M.

AU - Giese, Anne Katrin

AU - Ho, Weang Kee

AU - Traylor, Matthew

AU - Amouyel, Philippe

AU - Holliday, Elizabeth G.

AU - Malik, Rainer

AU - Xu, Huichun

AU - Kittner, Steven J.

AU - Cole, John W.

AU - O'Connell, Jeffrey R.

AU - Danesh, John

AU - Rasheed, Asif

AU - Zhao, Wei

AU - Engelter, Stefan

AU - Grond-Ginsbach, Caspar

AU - Kamatani, Yoichiro

AU - Lathrop, Mark

AU - Leys, Didier

AU - Thijs, Vincent

AU - Metso, Tiina M.

AU - Tatlisumak, Turgut

AU - Pezzini, Alessandro

AU - Parati, Eugenio A.

AU - Norrving, Bo

AU - Bevan, Steve

AU - Rothwell, Peter M.

AU - Sudlow, Cathie

AU - Slowik, Agnieszka

AU - Lindgren, Arne

AU - Walters, Matthew R.

AU - Jannes, Jim

AU - Shen, Jess

AU - Crosslin, David

AU - Doheny, Kimberly

AU - Laurie, Cathy C.

AU - Kanse, Sandip M.

AU - Bis, Joshua C.

AU - Fornage, Myriam

AU - Mosley, Thomas H.

AU - Hopewell, Jemma C.

AU - Strauch, Konstantin

AU - Müller-Nurasyid, Martina

AU - Gieger, Christian

AU - Waldenberger, Melanie

AU - Peters, Annette

AU - Meisinger, Christine

AU - Ikram, M. Arfan

AU - Longstreth, W. T.

AU - Meschia, James F.

AU - Seshadri, Sudha

AU - Sharma, Pankaj

AU - Worrall, Bradford

AU - Jern, Christina

AU - Levi, Christopher

AU - Dichgans, Martin

AU - Boncoraglio, Giorgio B.

AU - Markus, Hugh S.

AU - Debette, Stephanie

AU - Rolfs, Arndt

AU - Saleheen, Danish

AU - Mitchell, Braxton D.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Background and Purpose - Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early-versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset < 60 years. Methods. The discovery stage of our genome-wide association studies included 4505 cases and 21968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10-6 and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results.One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10-9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII.activating protease levels, a product of HABP2. Conclusions.HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

AB - Background and Purpose - Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early-versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset < 60 years. Methods. The discovery stage of our genome-wide association studies included 4505 cases and 21968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10-6 and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results.One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10-9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII.activating protease levels, a product of HABP2. Conclusions.HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

KW - Factor VII

KW - Genetics

KW - Genome-wide analysis

KW - Ischemic stroke

KW - Stroke

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DO - 10.1161/STROKEAHA.115.011328

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SN - 0039-2499

VL - 47

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JO - Stroke

JF - Stroke

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Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

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