TY - JOUR T1 - Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. JF - Stroke Y1 - 2014 A1 - Malik, Rainer A1 - Bevan, Steve A1 - Nalls, Michael A A1 - Holliday, Elizabeth G A1 - Devan, William J A1 - Cheng, Yu-Ching A1 - Ibrahim-Verbaas, Carla A A1 - Verhaaren, Benjamin F J A1 - Bis, Joshua C A1 - Joon, Aron Y A1 - de Stefano, Anita L A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Ikram, M Arfan A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Sharma, Pankaj A1 - Mitchell, Braxton D A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Levi, Christopher A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Dichgans, Martin KW - Adult KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Blood Pressure KW - Brain Ischemia KW - Case-Control Studies KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Multilocus Sequence Typing KW - Polymorphism, Single Nucleotide KW - Population KW - Prospective Studies KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Stroke AB -

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.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract ER -