Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 near HABP2

Cheng, Y.-C. et al. (2016) Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 near HABP2. Stroke, 47(2), pp. 307-316. (doi: 10.1161/STROKEAHA.115.011328) (PMID:26732560) (PMCID:PMC4729659)

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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 21 968 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.

Item Type:Articles
Additional Information:Sources of funding: 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, Päivikki 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 projectZ01-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 ( 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-Øst. 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).
Glasgow Author(s) Enlighten ID:Walters, Professor Matthew
Authors: 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., Leys, D., Thijs, V., Metso, T. M., Tatlisumak, T., Pezzini, A., Parati, E. A., Norrving, B., Bevan, S., Rothwell, P. M., Sudlow, C., Slowik, A., Lindgren, A., Walters, M. R., Jannes, J., Shen, J., Crosslin, D., Doheny, K., Laurie, C. C., Kanse, S. M., Bis, J. C., Fornage, M., Mosley, T. H., Hopewell, J. C., Strauch, K., Müller-Nurasyid, M., Gieger, C., Waldenberger, M., Peters, A., Meisinger, C., Ikram, M. A., Longstreth, W.T., Meschia, J. F., Seshadri, S., Sharma, P., Worrall, B., Jern, C., Levi, C., Dichgans, M., Boncoraglio, G. B., Markus, H. S., Debette, S., Rolfs, A., Saleheen, D., and Mitchell, B. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Stroke
Publisher:American Heart Association
ISSN (Online):1524-4628

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