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

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.

Keywords: genetics; polymorphism, genetic; risk assessment; risk factors.

Figure 1

Distribution of genetic risk score (GRS) in patients with ischemic stroke and controls in the merged derivation sample (WTCCC2-UK and WTCCC2-Munich). Shown are weighted GRSs (wGRSs) for atrial fibrillation, coronary artery disease, diastolic blood pressure, hypertension, and systolic blood pressure. Bottom right, The combined GRS (cGRS). Red line represents the distribution of the risk score in cases; and black line, the distribution of the risk score in controls. Note that the wGRS for AF is constituted by variants from 2 risk loci, which explains the bimodal distribution.

Figure 2

Odds ratios for risk categories defined using the combined genetic risk score. A, Clinic-based derivation sample. B, Merged clinic-based derivation and replication sample. The primary (left) y axis displays the percentage of cases and controls in each quintile, the secondary (right) y axis displays the odds ratio (OR) associated with each quintile where the middle (third) quintile serves as a reference.

Figure 3

Receiver operating characteristic curves for models predicting a diagnosis of ischemic stroke in the derivation sample (A) and in the merged clinic-based derivation and replication sample (B). The reduced model of only covariates is shown in green, the full model including the combined genetic risk score (cGRS) in purple. The blue line represents the cGRS without covariates. The black dashed diagonal line represents a random prediction.