Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.
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.
['Malik|Rainer|R|', 'Bevan|Steve|S|', 'Nalls|Michael A|MA|', 'Holliday|Elizabeth G|EG|', 'Devan|William J|WJ|', 'Cheng|Yu-Ching|YC|', 'Ibrahim-Verbaas|Carla A|CA|', 'Verhaaren|Benjamin F J|BF|', 'Bis|Joshua C|JC|', 'Joon|Aron Y|AY|', 'de Stefano|Anita L|AL|', 'Fornage|Myriam|M|', 'Psaty|Bruce M|BM|', 'Ikram|M Arfan|MA|', 'Launer|Lenore J|LJ|', 'van Duijn|Cornelia M|CM|', 'Sharma|Pankaj|P|', 'Mitchell|Braxton D|BD|', 'Rosand|Jonathan|J|', 'Meschia|James F|JF|', 'Levi|Christopher|C|', 'Rothwell|Peter M|PM|', 'Sudlow|Cathie|C|', 'Markus|Hugh S|HS|', 'Seshadri|Sudha|S|', 'Dichgans|Martin|M|', '|||']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D001281:Atrial Fibrillation D001794:Blood Pressure D002545:Brain Ischemia D016022:Case-Control Studies D015331:Cohort Studies D003324:Coronary Artery Disease D005260:Female D020022:Genetic Predisposition to Disease D014644:Genetic Variation D055106:Genome-Wide Association Study D006801:Humans D006973:Hypertension D008297:Male D008875:Middle Aged D058885:Multilocus Sequence Typing D020641:Polymorphism, Single Nucleotide D011153:Population D011446:Prospective Studies D015203:Reproducibility of Results D018570:Risk Assessment D012307:Risk Factors D012737:Sex Factors D020521:Stroke
genetics risk factors polymorphism, genetic risk assessment