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Stroke DOI:10.1161/STROKEAHA.113.002938

Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.

Publication TypeJournal Article
Year of Publication2014
AuthorsMalik, R, Bevan, S, Nalls, MA, Holliday, EG, Devan, WJ, Cheng, Y-C, Ibrahim-Verbaas, CA, Verhaaren, BFJ, Bis, JC, Joon, AY, de Stefano, AL, Fornage, M, Psaty, BM, M Ikram, A, Launer, LJ, van Duijn, CM, Sharma, P, Mitchell, BD, Rosand, J, Meschia, JF, Levi, C, Rothwell, PM, Sudlow, C, Markus, HS, Seshadri, S, Dichgans, M
Corporate AuthorsWellcome Trust Case Control Consortium 2
JournalStroke
Volume45
Issue2
Pages394-402
Date Published2014 Feb
ISSN1524-4628
KeywordsAdult, Aged, Aged, 80 and over, Atrial Fibrillation, Blood Pressure, Brain Ischemia, Case-Control Studies, Cohort Studies, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Multilocus Sequence Typing, Polymorphism, Single Nucleotide, Population, Prospective Studies, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Stroke
Abstract

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

URLhttp://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=24436234
DOI10.1161/STROKEAHA.113.002938
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract

Alternate JournalStroke
PubMed ID24436234
PubMed Central IDPMC4006951
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
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