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

Rainer Malik, Steve Bevan, Michael A. Nalls, Elizabeth G. Holliday, William J. Devan, Yu Ching Cheng, Carla A. Ibrahim-Verbaas, Benjamin F.J. Verhaaren, Joshua C. Bis, Aron Y. Joon, Anita L. De Stefano, Myriam Fornage, Bruce M. Psaty, M. Arfan Ikram, Lenore J. Launer, Cornelia M. Van Duijn, Pankaj Sharma, Braxton D. Mitchell, Jonathan Rosand, James F. MeschiaChristopher Levi, Peter M. Rothwell, Cathie Sudlow, Hugh S. Markus, Sudha Seshadri, Martin Dichgans

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)394-402
Number of pages9
Issue number2
StatePublished - Feb 2014


  • Genetic
  • Genetics
  • Polymorphism
  • Risk assessment
  • Risk factors

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing


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