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

Access to Document

10.1161/STROKEAHA.115.011328

Cite this

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

@article{2fe4843e0673465a88704dfea7412cdd,

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 = "Funding Information: The Atherosclerotic Risk in Community (ARIC): National Institutes of Health (NIH) contracts: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, U01HG004402; HHSN268200625226C, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and U01-HL096917. NIH grants: R01HL087641, R01HL59367, R01HL086694, R01HL087641, UL1RR025005, and HL093029. The Australian Stroke Genetics Collaborative (ASGC) grants: the Australian National Health and Medical Research Council (project 569257) and the Australian National Heart Foundation (grant G-04S-1623). Elizabeth Holliday supported by a fellowship (100071) from the Australian Heart Foundation and National Stroke Foundation. Bio-Repository of DNA in Stroke (BRAINS) support: the Henry Smith Charity, the UK-India Education Research Institutive from the British Council, and a Senior Fellowship from the UK Department of Health awarded to Dr Pankaj Sharma. The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study Institutional: Inserm, Lille 2 University, Institut Pasteur de Lille, and Lille University Hospital. Funding: the European Regional Development Fund (FEDER funds) and R{\'e}gion Nord-Pas de Calais in the frame of Contrat de Projets Etat-Region 2007-2013 R{\'e}gion Nord-Pas-de-Calais-Grant No 09120030, Centre National de Genotypage, Emil Aaltonen Foundation, Paavo Ilmari Ahvenainen Foundation, Helsinki University Central Hospital Research Fund, Helsinki University Medical Foundation, Pa{\"i}vikki and Sakari Sohlberg Foundation, Aarne Koskelo Foundation, Maire Taponen Foundation, Aarne and Aili Turunen Foundation, Lilly Foundation, Alfred Kordelin Foundation, Finnish Medical Foundation, Orion Farmos Research Foundation, Maud Kuistila Foundation, the Finnish Brain Foundation, Biomedicum Helsinki Foundation, Projet Hospitalier de Recherche Clinique R{\'e}gional, Fondation de France, G{\'e}nop{\^o}le de Lille, Adrinord, Basel Stroke-Funds, K{\"a}the-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences, Swiss Heart Foundation. St{\'e}phanie Debette is a recipient of a {"}Chaire d''Excellence Junior{"} grant from the Agence Nationale de la Recherche and is supported by a grant from the Fondation Leducq. V. Thijs was supported by a Fundamental Clinical Research Fellowship from FWO Flanders. The Cardiovascular Health Study (CHS) NIH contracts: HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086. NIH grants: U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01AG023629, and R01DK063491. Genotyping: the National Center for Advancing Translational Sciences, Clinical & Translational Science Institute grant UL1TR000124. The deCODE coronary artery disease/myocardial infarction Study NIH grant: R01HL089650. deCODE Genetics supported, in part, through a grant from the European Community''s Seventh Framework Programme (FP7/2007-2013), the European Network for Genetic and Genomic Epidemiology (ENGAGE) project grant agreement HEALTH-F4-2007 to 201413. The Genetics of Early-Onset Stroke (GEOS) study NIH grants: U01-HG004436, P30-DK072488, U01-NS069208, R01-NS45012, U01-NS069208, U01-HG004438, U01-HG004446, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Yu-Ching Cheng was supported by a Career Development Award from Department of Veterans Affairs. Dr Cole was supported by research grants from the Department of Veterans Affairs and the American Heart Association (15GPSPG23770000). Heart Protection Study (HPS; ISRCTN48489393): the UK Medical Research Council, British Heart Foundation (BHF), Merck & Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of vitamins). Genotyping supported by a grant to Oxford University and Centre National de G{\'e}notypage from Merck & Co. Dr Hopewell was supported by the British Heart Foundation (FS/14/55/30806). The Heart and Vascular Health Study (HVH) NIH grants R01-HL085251 and R01-HL073410. The Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) NIH grants: R01-NS42733 and R01-NS39987 and NIH intramural project Z01-AG000954. ISGS/SWISS used samples and clinical data from the NIH-National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository (http://ccr. coriell.org/ninds) and human subjects protocol numbers 2003-081 and 2004-147. Controls for ISGS/SWISS obtained from the Baltimore Longitudinal Study of Aging with support from the NIA Intramural Research Program (Z01-AG000015-50, human subjects protocol number 2003-078). The MILANO study supported by Annual Research Funding of the Italian Ministry of Health (grants: RC-2007/LR6, RC-2008/LR6; RC-2009/LR8; RC-2010/LR8). The Sahlgrenska Academy Study of Ischemic Stroke (SAHLSIS) the Swedish Research Council, the Swedish state, and the Swedish Heart and Lung Foundation. Sandip Kanse acknowledges funding from Behring Roentgen Stiftung, Deutscheforschungsgemeinschaft and Helse S{\o}r-∅st. Stroke in Young Fabry Patients (SIFAP) NIH grant: U01-HG004436. Control subjects for SIFAP provided by the KORA (Cooperative Health Research in the Region of Augsburg [Germany]) study (see below, WTCCC2-Munich). Risk Assessment of Cerebrovascular Events Study (RACE). Grants: to the University of Cambridge from the Wellcome Trust, British Heart Foundation, UK Medical Research Council, Pfizer, Novartis, and Merck and NIH Grant U01-HG004436. The Rotterdam study Institutional: The Netherlands Organization of Scientific Research (175.010.2005.011), the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research Netherlands Consortium for Healthy Ageing (050-060-810), Nederlandse Hartstichting (2009B102), the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission, and the Municipality of Rotterdam to the Rotterdam Study. The Wellcome Trust Case-Control Consortium 2 (WTCCC2): WTCCC2-UK: the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z and WT084724MA), The Stroke Association, the Medical Research Council (grants WT095219MA and G1001799), Dunhill Medical Trust, National Institute of Health Research (NIHR), the NIHR Biomedical Research Centre, the Binks Trust, the Scottish Funding Council and the Chief Scientist Office. P.M. Rothwell has a Wellcome Trust Senior Investigator Award and an NIHR Senior Investigator Award, and C. Sudlow has a Wellcome Trust clinician scientist award. WTCCC2-Munich: Grants: the German Federal Ministry of Education and Research in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes-AT-target (261123) to M. Dichgans and from the Vascular Dementia Research Foundation. The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen-German Research Center for Environmental Health. Additional KORA support was from the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universit{\"a}t, as part of LMUinnovativ. WTCCC Immunochip: supported by the WTCCC2. Lund Stroke Register: the Swedish Research Council, The Swedish Heart-Lung Foundation, Region Sk{\aa}ne, the Freemasons Lodge of Instruction EOS in Lund, King Gustaf V, and Queen Victoria''s Foundation, Lund University, the Swedish Stroke Association, Region Sk{\aa}ne Competence Centre (RSKC Malm{\"o}), and Labmedicin Sk{\aa}ne, University and Regional Laboratories Region Sk{\aa}ne, Sweden. Investigator support: Stroke Association Project Grant TSA-2013/01 (Matthew Traylor), the National Research Leading Center, Jagiellonian University, Krakow, Poland (Agnieszka Slowik), and NIHR Senior Investigator award (Hugh Markus). 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",

}

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.

N1 - Funding Information: The Atherosclerotic Risk in Community (ARIC): National Institutes of Health (NIH) contracts: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, U01HG004402; HHSN268200625226C, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and U01-HL096917. NIH grants: R01HL087641, R01HL59367, R01HL086694, R01HL087641, UL1RR025005, and HL093029. The Australian Stroke Genetics Collaborative (ASGC) grants: the Australian National Health and Medical Research Council (project 569257) and the Australian National Heart Foundation (grant G-04S-1623). Elizabeth Holliday supported by a fellowship (100071) from the Australian Heart Foundation and National Stroke Foundation. Bio-Repository of DNA in Stroke (BRAINS) support: the Henry Smith Charity, the UK-India Education Research Institutive from the British Council, and a Senior Fellowship from the UK Department of Health awarded to Dr Pankaj Sharma. The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study Institutional: Inserm, Lille 2 University, Institut Pasteur de Lille, and Lille University Hospital. Funding: the European Regional Development Fund (FEDER funds) and Région Nord-Pas de Calais in the frame of Contrat de Projets Etat-Region 2007-2013 Région Nord-Pas-de-Calais-Grant No 09120030, Centre National de Genotypage, Emil Aaltonen Foundation, Paavo Ilmari Ahvenainen Foundation, Helsinki University Central Hospital Research Fund, Helsinki University Medical Foundation, Païvikki and Sakari Sohlberg Foundation, Aarne Koskelo Foundation, Maire Taponen Foundation, Aarne and Aili Turunen Foundation, Lilly Foundation, Alfred Kordelin Foundation, Finnish Medical Foundation, Orion Farmos Research Foundation, Maud Kuistila Foundation, the Finnish Brain Foundation, Biomedicum Helsinki Foundation, Projet Hospitalier de Recherche Clinique Régional, Fondation de France, Génopôle de Lille, Adrinord, Basel Stroke-Funds, Käthe-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences, Swiss Heart Foundation. Stéphanie Debette is a recipient of a "Chaire d''Excellence Junior" grant from the Agence Nationale de la Recherche and is supported by a grant from the Fondation Leducq. V. Thijs was supported by a Fundamental Clinical Research Fellowship from FWO Flanders. The Cardiovascular Health Study (CHS) NIH contracts: HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086. NIH grants: U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01AG023629, and R01DK063491. Genotyping: the National Center for Advancing Translational Sciences, Clinical & Translational Science Institute grant UL1TR000124. The deCODE coronary artery disease/myocardial infarction Study NIH grant: R01HL089650. deCODE Genetics supported, in part, through a grant from the European Community''s Seventh Framework Programme (FP7/2007-2013), the European Network for Genetic and Genomic Epidemiology (ENGAGE) project grant agreement HEALTH-F4-2007 to 201413. The Genetics of Early-Onset Stroke (GEOS) study NIH grants: U01-HG004436, P30-DK072488, U01-NS069208, R01-NS45012, U01-NS069208, U01-HG004438, U01-HG004446, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Yu-Ching Cheng was supported by a Career Development Award from Department of Veterans Affairs. Dr Cole was supported by research grants from the Department of Veterans Affairs and the American Heart Association (15GPSPG23770000). Heart Protection Study (HPS; ISRCTN48489393): the UK Medical Research Council, British Heart Foundation (BHF), Merck & Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of vitamins). Genotyping supported by a grant to Oxford University and Centre National de Génotypage from Merck & Co. Dr Hopewell was supported by the British Heart Foundation (FS/14/55/30806). The Heart and Vascular Health Study (HVH) NIH grants R01-HL085251 and R01-HL073410. The Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) NIH grants: R01-NS42733 and R01-NS39987 and NIH intramural project Z01-AG000954. ISGS/SWISS used samples and clinical data from the NIH-National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository (http://ccr. coriell.org/ninds) and human subjects protocol numbers 2003-081 and 2004-147. Controls for ISGS/SWISS obtained from the Baltimore Longitudinal Study of Aging with support from the NIA Intramural Research Program (Z01-AG000015-50, human subjects protocol number 2003-078). The MILANO study supported by Annual Research Funding of the Italian Ministry of Health (grants: RC-2007/LR6, RC-2008/LR6; RC-2009/LR8; RC-2010/LR8). The Sahlgrenska Academy Study of Ischemic Stroke (SAHLSIS) the Swedish Research Council, the Swedish state, and the Swedish Heart and Lung Foundation. Sandip Kanse acknowledges funding from Behring Roentgen Stiftung, Deutscheforschungsgemeinschaft and Helse Sør-∅st. Stroke in Young Fabry Patients (SIFAP) NIH grant: U01-HG004436. Control subjects for SIFAP provided by the KORA (Cooperative Health Research in the Region of Augsburg [Germany]) study (see below, WTCCC2-Munich). Risk Assessment of Cerebrovascular Events Study (RACE). Grants: to the University of Cambridge from the Wellcome Trust, British Heart Foundation, UK Medical Research Council, Pfizer, Novartis, and Merck and NIH Grant U01-HG004436. The Rotterdam study Institutional: The Netherlands Organization of Scientific Research (175.010.2005.011), the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research Netherlands Consortium for Healthy Ageing (050-060-810), Nederlandse Hartstichting (2009B102), the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission, and the Municipality of Rotterdam to the Rotterdam Study. The Wellcome Trust Case-Control Consortium 2 (WTCCC2): WTCCC2-UK: the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z and WT084724MA), The Stroke Association, the Medical Research Council (grants WT095219MA and G1001799), Dunhill Medical Trust, National Institute of Health Research (NIHR), the NIHR Biomedical Research Centre, the Binks Trust, the Scottish Funding Council and the Chief Scientist Office. P.M. Rothwell has a Wellcome Trust Senior Investigator Award and an NIHR Senior Investigator Award, and C. Sudlow has a Wellcome Trust clinician scientist award. WTCCC2-Munich: Grants: the German Federal Ministry of Education and Research in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes-AT-target (261123) to M. Dichgans and from the Vascular Dementia Research Foundation. The KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health. Additional KORA support was from the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. WTCCC Immunochip: supported by the WTCCC2. Lund Stroke Register: the Swedish Research Council, The Swedish Heart-Lung Foundation, Region Skåne, the Freemasons Lodge of Instruction EOS in Lund, King Gustaf V, and Queen Victoria''s Foundation, Lund University, the Swedish Stroke Association, Region Skåne Competence Centre (RSKC Malmö), and Labmedicin Skåne, University and Regional Laboratories Region Skåne, Sweden. Investigator support: Stroke Association Project Grant TSA-2013/01 (Matthew Traylor), the National Research Leading Center, Jagiellonian University, Krakow, Poland (Agnieszka Slowik), and NIHR Senior Investigator award (Hugh Markus). Publisher Copyright: © 2016 American Heart Association, Inc.

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

UR - http://www.scopus.com/inward/record.url?scp=84969389433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969389433&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.115.011328

DO - 10.1161/STROKEAHA.115.011328

M3 - Article

C2 - 26732560

AN - SCOPUS:84969389433

SN - 0039-2499

VL - 47

SP - 307

EP - 316

JO - Stroke

JF - Stroke

IS - 2

ER -

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

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