Genomewide association studies of stroke

Abstract

Background: The genes underlying the risk of stroke in the general population remain undetermined.

Methods: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

Results: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

Conclusions: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Figure 1. Results of Tests for the Association between Stroke and Each SNP Measured in the Genomewide Association Study

P values (based on the fixed-effects model) are shown in signal-intensity (Manhattan) plots relative to their genomic position for total stroke (Panel A) and ischemic stroke (Panel B). Within each chromosome, the results are plotted left to right from the p-terminal end. The top horizontal line indicates the chosen threshold for genomewide significance, P = 5×10⁻⁸; the middle line indicates the threshold for P = 10⁻⁵; and the bottom line indicates the threshold for P = 10⁻⁴.

Figure 2. Forest Plots Showing Associations between Single-Nucleotide Polymorphisms and Total, Ischemic, and Atherothrombotic Strokes

The associations between rs11833579 and total stroke (Panel A), ischemic stroke (Panel C), and atherothrombotic stroke (Panel E) and between rs12425791 and total stroke (Panel B), ischemic stroke (Panel D), and atherothrombotic stroke (Panel F) are based on directly genotyped data. Individual studies (blue boxes) are plotted against the individual effect sizes (hazard ratios). The red diamonds indicate the overall hazard ratios. The size of the blue box is inversely proportional to the variance. Horizontal lines indicate 95% confidence intervals. The dashed vertical line in each panel shows the value for no effect (hazard ratio = 1.0). ARIC denotes Atherosclerosis Risk in Communities study, CHS Cardiovascular Health Study, FHS Framingham Heart Study, and RS Rotterdam Study.

Figure 3. Associations in the Region Centered on rs11833579 and Containing NINJ2

All single-nucleotide polymorphisms are plotted with their P values (on combined analysis) against their genomic position. P values for total stroke and ischemic stroke are shown. The light blue line represents the estimated recombination rates. Blue arrows indicate gene annotations.