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. Author manuscript; available in PMC: 2010 Apr 23.
Published in final edited form as: N Engl J Med. 2009 Apr 15;360(17):1718–1728. doi: 10.1056/NEJMoa0900094

Table 2.

Most Significant Associations between Single-Nucleotide Polymorphisms (SNPs) and Stroke Phenotype.*

SNP SNP Function Minor Allele† MAF Chromosome: Position Hazard Ratio (95% CI) P Value PAR Closest Gene‡ Second Closest Gene‡ Additional SNPs at P<10−5
Name Distance Name Distance
Total stroke
rs11833579 Upstream A 0.23 12:645460 1.32 (1.20–1.44)§ 4.8×10−9 0.13 NINJ2 2.4 WNK1 87.0 3
rs12425791 Intergenic A 0.19 12:653745 1.31 (1.19–1.44)§ 1.5×10−8 0.11 NINJ2 10.7 WNK1 78.7 3
rs713536 Intergenic T 0.47 8:12943177 1.23 (1.13–1.33) 9.1×10−7 0.18 C8orf79 11.5 DLC1 42.1
rs4867131 Intergenic A 0.11 5:33047743 1.41 (1.23–1.62) 1.2×10−6 0.09 C5orf23 220.1 NPR3 224.7
rs10734548 Intronic T 0.22 11:46744149 1.23 (1.13–1.35) 4.4×10−6 0.10 CKAP5 WG F2 26.5 49
rs11609145 Intergenic G 0.20 12:3885559 1.31 (1.17–1.48) 4.9×10−6 0.12 PARP11 32.7 EFCAB4B 153.0
rs3211928 Intronic G 0.45 7:79942371 0.83 (0.77–0.90) 6.4×10−6 0.21|| CD36 WG SEMA3C 74.1 14
rs877087 Intronic T 0.45 15:31661567 1.22 (1.12–1.33) 6.5×10−6 0.17 RYR3 WG AVEN 284.1
rs7853368 Intergenic G 0.39 9:13447920 1.20 (1.11–1.29) 7.8×10−6 0.14 MPDZ 207.5 NFIB 623.9 1
rs4151467 Intronic C 0.06 13:47817924 1.44 (1.23–1.69) 8.7×10−6 0.05 RB1 WG P2RY5 65.2
rs6449093 Intergenic G 0.09 4:14638765 1.32 (1.27–1.49) 9.8×10−6 0.06 CPEB2 43.0 C1QTNF7 379.1
Ischemic stroke
rs11833579 Upstream A 0.23 12:645460 1.41 (1.27–1.56)§ 2.3×10−10 0.17 NINJ2 2.4 WNK1 87.0 3
rs12425791 Intergenic A 0.19 12:653745 1.39 (1.25–1.54)§ 2.6×10−9 0.14 NINJ2 10.7 WNK1 78.7 3
rs4867131 Intergenic A 0.11 5:33047743 1.49 (1.27–1.75) 9.9×10−7 0.10 C5orf23 220.1 NPR3 224.7
rs10837576 Intergenic A 0.29 11:41103075 0.78 (0.70–0.85) 2.1×10−6 0.27|| LRRC4C 830.8 API5 218.7
rs10794579 Downstream T 0.43 10:124676646 1.24 (1.13–1.35) 2.1×10−6 0.18 C10orf88 3.7 FAM24A 14.0 3
rs2318308 Intergenic A 0.27 14:65460852 0.75 (0.66–0.85) 3.0×10−6 0.29|| FUT8 181.1 GPHN 583.0
rs713536 Intergenic T 0.47 8:12943177 1.26 (1.14–1.38) 3.3×10−6 0.20 C8orf79 11.5 DLC1 42.0
rs17429019 Intergenic G 0.06 3:190727847 1.49 (1.26–1.76) 3.6×10−6 0.05 TP63 104.1 TPRG1 203.8 1
rs12786704 Intronic G 0.16 11:131684538 1.36 (1.19–1.55) 6.0×10−6 0.10 HNT WG OPCML 105.5
rs6820391 Intronic A 0.28 4:54255624 1.24 (1.13–1.36) 6.9×10−6 0.12 LNX1 WG FIP1L1 88.8 2
rs11615969 Intergenic C 0.09 12:75229404 1.53 (1.27–1.84) 7.4×10−6 0.09 BBS10 11.3 OSBPL8 18.6
*

P values, hazard ratios, and 95% confidence intervals (CIs) are based on a fixed-effects (inverse-variance–weighted) analysis. Each row specifically identifies only the SNP–phenotype association with the lowest P value for that locus, except for the two associations reaching genomewide significance that are both shown here. Four SNPs (rs11833579, rs12425791, rs713536, and rs4867131) were common to both total and ischemic stroke. The last column shows the number of additional SNPs at the same locus, within 250 kb of the specified SNP, that were also associated with the phenotype with a P value of less than 10−5. At the NINJ2 locus, these additional SNPs include rs728096 and rs7297967. MAF denotes minor-allele frequency, PAR population attributable risk, and WG within gene.

†

Alleles were identified on the basis of the plus strand of the National Center for Biotechnology Information (NCBI) build 36. The minor allele was also the coded allele. The MAF is based on allele frequency in the combined sample.

‡

The closest gene and second closest gene show the Human Gene Organization (HUGO) Gene Nomenclature System symbols for the two genes located closest to each SNP and the distance of the associated SNP from the 5 end (start) of the gene. Standardized gene annotations for all SNP results were derived programmatically from the University of California, Santa Cruz, Genome Browser RefSeq gene track (hg18). Distances to genes are expressed in kilobase pairs, based on NCBI build 36.

§

The hazard ratios, which were derived by combining genotyped data from the various genomewide association study platforms and from the TaqMan assay (for cohorts wherein the SNP was initially imputed), were as follows: 1.26 (95% CI, 1.16 to 1.37) for the association of rs11833579 with incident total stroke, 1.33 (95% CI, 1.21 to 1.47) with incident ischemic stroke, and 1.35 (95% CI, 1.21 to 1.50) with incident atherothrombotic stroke; for rs12425791, the corresponding hazard ratios were 1.30 (95% CI, 1.19 to 1.42), 1.33 (95% CI, 1.21 to 1.47), and 1.37 (95% CI, 1.23 to 1.54).

SNPs at this locus included intragenic SNPs within the following seven genes: CKAP5, F2, LRP4, ARFGAP2, C11orf49, DDB2, and PACSIN3. Functional annotation of all SNPs with P<1×10−6 was undertaken with the use of the FASTSNP program available online.28 We looked for SNPs that were intragenic nonsynonymous coding SNPs or intronic splice-site variants in at least moderate linkage disequilibrium (r2>0.5) with any of the significant or highly suggestive SNPs, with the use of the SNAP program (www.broad.mit.edu/mpg/snap/). We observed that rs107345486 and five other highly significant SNPs at this locus were in linkage disequilibrium with rs3816614, a nonsynonymous coding SNP within the LRP4 gene; rs10734548 was also in linkage disequilibrium with rs2070852, an intronic splice-site variant within the F2 gene.

||

Population attributable risks reported for these three SNPs were calculated with the use of the major allele as the risk allele, since the minor alleles were protective (i.e., the minor alleles had an inverse association with stroke risk).