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).