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

Tuesday,2014-04-01 13:31 America/Los_Angeles — poolea2
TitleMultilocus 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, Ikram, AM, 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/Institutional AuthorsWellcome Trust Case Control Consortium 2,
JournalStroke
Volume45
Issue2
Pagination394-402
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<p><b>BACKGROUND AND PURPOSE: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>
DOI10.1161/STROKEAHA.113.002938
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
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
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R01 NS045012 / NS / NINDS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
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U01 HG004446 / HG / NHGRI NIH HHS / United States
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095626 / / Wellcome Trust / United Kingdom
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R01 HL080295 / HL / NHLBI NIH HHS / United States
085475/B/08/Z / / Wellcome Trust / United Kingdom
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HHSN268201100007C / / PHS HHS / United States
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Z01 AG007380-03 / / Intramural NIH HHS / United States
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OSRP2/1006 / / The Dunhill Medical Trust / United Kingdom
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HHSN268201100006C / / PHS HHS / United States
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085475/Z/08/Z / / Wellcome Trust / United Kingdom
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N01HC85081 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States

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