Journal
NEUROLOGY
Volume 86, Issue 13, Pages 1217-1226Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000002528
Keywords
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Categories
Funding
- Australian National and Medical Health Research Council (NHMRC) [569257]
- Australian National Heart Foundation (NHF) [G 04S 1623]
- University of Newcastle
- Gladys M. Brawn Fellowship scheme
- Vincent Fairfax Family Foundation in Australia
- National Stroke Foundation of Australia [100071]
- Senior Fellowship from the Department of Health (UK)
- UK-India Education Research Institutive (UKIERI) from the British Council
- NIH Genes
- Environment and Health Initiative (GEI) [U01 HG004436]
- GENEVA consortium under GEI
- Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]
- Office of Research and Development, Medical Research Service
- Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs
- Johns Hopkins University Center for Inherited Disease Research (CIDR)
- NIH [HHSN268200782096C]
- GENEVA Coordinating Center [U01 HG 004446]
- Division of Adult and Community Health
- Centers for Disease Control and Prevention
- NINDS
- NIH Office of Research on Women's Health [R01 NS45012, U01 NS06920801]
- Heart Protection Study (HPS) [ISRCTN48489393]
- UK Medical Research Council (MRC)
- British Heart Foundation, Merck and Co.
- Roche Vitamins Ltd
- Merck and Co
- British Heart Foundation [FS/14/55/30806]
- NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository
- Intramural Research Program of the NIA, NIH [Z01 AG-000015-50, Z01 AG-000954-06]
- NIH-NINDS grant [R01 NS-42733, R01 NS39987]
- NINDS [U01 NS069208]
- American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]
- NIH and NHLBI's STAMPEED genomics research program [R01 HL087676]
- National Center for Research Resources
- National Center for Research resources [U54 RR020278]
- Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8, FP6 LSHM-CT2007- 037273]
- Wellcome Trust
- Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]
- MRC
- Dunhill Medical Trust
- National Institute of Health Research (NIHR)
- NIHR Biomedical Research Centre, Oxford
- Binks Trust
- Scottish Funding Council Brain Imaging Research Centre
- Division of Clinical Neurosciences
- University of Edinburgh
- Wellcome Trust Clinical Research Facility
- SINAPSE (Scottish Imaging Network-A Platform for Scientific Excellence)
- Scottish Funding Council and the Chief Scientist Office
- Vascular Dementia Research Foundation
- BHF Centre of Research Excellence in Oxford
- Wellcome Trust core award [090532/Z/09/Z]
- Department of Neurology
- University Hospital Leuven
- Fundamental Clinical Investigatorships from FWO
- Swedish Research Council [K2007-61X-20378-01-3, K2010-61X-20378-04-3]
- Swedish Heart and Lung Foundation
- Skane University Hospital, Region Skane
- Freemasons Lodge of Instruction EOS in Lund, King Gustaf V and Queen Victoria's Foundation
- Lund University
- Swedish Stroke Association
- German Federal Ministry of Education and Research [01GI9909/3]
- Institute of Epidemiology and Social Medicine University of Muenster
- German Migraine and Headache Society (DMKG)
- Almirall
- Astra Zeneca
- Berlin Chemie
- Boehringer
- Boots Health Care
- Glaxo-Smith-Kline
- Janssen Cilag
- McNeil Pharma
- MSD Sharp Dohme
- Jagiellonian University, Krakow, Poland [K/ZDS/002848]
- United States National Human Genome Research Institute (NHGRI) [U01 HG005160]
- NIHU [01 HG005157]
- investigator-initiated research [NS34447]
- United States Public Health Service
- Bethesda
- Maryland
- United States National Center for Biotechnology Information
- US National Library of Medicine
- WHI-GARNET through NHGRI GARNET [U01 HG005152]
- GARNET Coordinating Center [U01 HG005157]
- NIH Genes, Environment, and Health Initiative [GEI
- U01 HG004424]
- National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS069208]
- Johns Hopkins University [HHSN268200782096C]
- German Federal Ministry of Education and Research (BMBF)
- FP7 European Union project
- DFG as part of the CRC [1123 (B3)]
- Corona Foundation
- Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)
- Stroke Association
- [PTDC/SAU-GMG/64426/2006]
- British Heart Foundation [FS/14/55/30806] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10019] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-GMG/64426/2006] Funding Source: FCT
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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.
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