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Basic Info

Reference	Scott, L. J.,2009 PMID: 19416921
Citation	Scott, L. J., P. Muglia, et al. (2009). Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry. Proc Natl Acad Sci U S A 106(18): 7501-7506.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Genome-wide association study
Sample Size	(i) 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee.(ii)1,868 BP cases and an expanded reference set of 12,831 individuals from the Wellcome Trust Case Control Consortium (WTCCC).
SNP/Region/Marker Size	NIMH/Pritzker:541,327 SNPs;GSK: 521,990 SNPs;WTCCC:397,653 SNPs
Predominant Ethnicity	Caucasian
Population	NIMH/Pritzker,GSK and WTCCC collection
Gender	females proportion:62.8% in cases and 50.3% in controls in NIMH/Pritzker samples,in cases(64.2% in complete sample,64.9% in reduced sample) and 58.6% in controls in GSK samples,63% in cases and 51% in controls in WTCCC samples
Age Group	Adults : Mean age(SD)(year):42.2 (12.6) in cases and 42.2 (13.4) in controls in NIMH/Pritzker samples,in cases(47.1 (12.2) in complete sample,46.8 (12.3) in reduced sample) and 39.5 (16.3) in controls in GSK samples,40-49 in cases in WTCCC samples

Detail Info

Sample Diagnosis	DSM
Sample Status	To test for SNP-BP association in additional well-characterized samples, we analyzed data for 2.3million genotyped and imputed SNPs on 3,700 individuals in 2 sample sets: (i) 1,177 bipolar I (BP I) cases and 772 controls from the National Institutes of Mental Health Genetic Initiative Repository and the Prechter Repository [National Institute of Mental Health (NIMH)/Pritzker], and (ii) 899 BP cases and 904 controls from London and Dundee, U.K., and Toronto, Canada whose collection was sponsored by GlaxoSmith-Kline Research and Development (GSK). We analyzed the NIMH/Pritzker and GSK GWAS samples separately and performed a 2-study meta-analysis. We then imputed and analyzed the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium (WTCCC) (4) for 1,868 BP cases and an expanded reference set of 12,831 individuals. The expanded reference set comprised a blood donor sample and 6 non-BP disease case groups. After removing from the GSK London sample 261 cases that overlapped with theWTCCC sample, we performed a 3-study meta-analysis of 3,683 cases and 14,507 extended reference set individuals.
Technique	Affymetrix & Illumina
Statistical Method	GWA Analysis.We analyzed the observed allele counts or imputed allele dosages, using logistic regression assuming an additive genetic model, with genotype-based PCs and study site (GSK only) as covariates, and then repeated the analysis without PCs. Meta-Analysis of GWA Samples. We performed a fixed effects meta-analysis, using the OR and 95% confidence intervals to combine the association evidence from the study-specific GWA analyses.Evidence for heterogeneity between ORs was assessed using Cochrans's Q-statistic and I².
Result Summary	The strongest association P value for this 2-study meta-analysis was 2.4 x 10(-6). We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P approximately 10(-7): 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 x 10(-7)) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.

SNPs reported by this study for BD (count: 23)

SNP	Related Gene(s)	Allele Change	Statistical Values	Result Category
rs1042779	ITIH1	A/G	NIMH/Pritzker: OR (95% CI)=1.2(1.04-1.38), P-value = 0.015; GSK(reduced sample): OR (95% CI)=1.31(1.11-1.54), P-value = 0.0012; WTCCC: OR (95% CI)=1.16(1.07-1.25), P-value = 0.00012; 3-study meta-analysis: OR (95% CI)=1.19(1.11-1.27), P-value = 0.00000018; Heterogeneity: I²%=0, P-value = 0.4	Trend
rs11711888	PTPRG	A/G	NIMH/Pritzker: OR (95% CI)=3.31(1.84-5.96), P-value = 0.000067; GSK(complete sample): OR (95% CI)=2.2(1.24-3.91), P-value = 0.0071; 2-study meta-analysis: OR (95% CI)=2.69(1.77-4.08), P-value = 0.0000035; Heterogeneity: I²%=0, P-value = 0.33	Trend
rs10246960		T/C	NIMH/Pritzker: OR (95% CI)=1.41(1.16-1.71), P-value = 0.00061; GSK(complete sample): OR (95% CI)=1.33(1.1-1.61), P-value = 0.0034; 2-study meta-analysis: OR (95% CI)=1.37(1.19-1.57), P-value = 0.0000096; Heterogeneity: I²%=0, P-value = 0.68	Trend
rs1035050		T/C	NIMH/Pritzker: OR (95% CI)=1.16(1.01-1.34), P-value = 0.038; GSK(reduced sample): OR (95% CI)=1.12(0.96-1.31), P-value = 0.13; WTCCC: OR (95% CI)=1.19(1.09-1.29), P-value = 0.000069; 3-study meta-analysis: OR (95% CI)=1.17(1.09-1.25), P-value = 0.000009; Heterogeneity: I²%=0, P-value = 0.84	Trend
rs13409348	CTNNA2	G/C	NIMH/Pritzker: OR (95% CI)=1.12(0.95-1.32), P-value = 0.18; GSK(reduced sample): OR (95% CI)=1.2(1.00-1.43), P-value = 0.045; WTCCC: OR (95% CI)=1.22(1.12-1.33), P-value = 0.0000071; 3-study meta-analysis: OR (95% CI)=1.2(1.11-1.29), P-value = 0.0000027; Heterogeneity: I²%=0, P-value = 0.67	Trend
rs17169582		G/A	NIMH/Pritzker: OR (95% CI)=1.21(0.94-1.55), P-value = 0.14; GSK(reduced sample): OR (95% CI)=1.11(0.86-1.43), P-value = 0.42; WTCCC: OR (95% CI)=1.3(1.16-1.46), P-value = 0.0000075; 3-study meta-analysis: OR (95% CI)=1.26(1.14-1.39), P-value = 0.0000098; Heterogeneity: I²%=0, P-value = 0.5	Trend
rs12568099		T/C	NIMH/Pritzker: OR (95% CI)=1.48(0.90-2.42), P-value = 0.12; GSK(reduced sample): OR (95% CI)=2.17(1.26-3.77), P-value = 0.0054; WTCCC: OR (95% CI)=1.49(1.20-1.85), P-value = 0.00031; 3-study meta-analysis: OR (95% CI)=1.56(1.28-1.9), P-value = 0.0000098; Heterogeneity: I²%=0, P-value = 0.44	Trend
rs12998006		T/C	NIMH/Pritzker: OR (95% CI)=1.27(1.07-1.5), P-value = 0.0061; GSK(complete sample): OR (95% CI)=1.42(1.21-1.66), P-value = 0.000013; 2-study meta-analysis: OR (95% CI)=1.35(1.2-1.51), P-value = 0.00000076; Heterogeneity: I²%=0, P-value = 0.33	Trend
rs2242663	CTSF ACTN3	T/C	NIMH/Pritzker: OR (95% CI)=1.29(1.09-1.53), P-value = 0.0028; GSK(reduced sample): OR (95% CI)=1.32(1.10-1.59), P-value = 0.0024; WTCCC: OR (95% CI)=1.15(1.05-1.25), P-value = 0.0015; 3-study meta-analysis: OR (95% CI)=1.2(1.11-1.29), P-value = 0.0000013; Heterogeneity: I²%=33, P-value = 0.23	Trend
rs2537859		T/C	NIMH/Pritzker: OR (95% CI)=1.05(0.91-1.20), P-value = 0.53; GSK(reduced sample): OR (95% CI)=1.41(1.21-1.65), P-value = 0.000011; WTCCC: OR (95% CI)=1.14(1.06-1.23), P-value = 0.00071; 3-study meta-analysis: OR (95% CI)=1.16(1.09-1.24), P-value = 0.0000042; Heterogeneity: I²%=76, P-value = 0.014	Trend
rs17418283	MCTP1	C/T	NIMH/Pritzker: OR (95% CI)=1.09(0.93-1.28), P-value = 0.31; GSK(reduced sample): OR (95% CI)=1.19(1.01-1.41), P-value = 0.038; WTCCC: OR (95% CI)=1.25(1.15-1.36), P-value = 0.000000097; 3-study meta-analysis: OR (95% CI)=1.21(1.13-1.3), P-value = 0.00000013; Heterogeneity: I²%=15, P-value = 0.31	Trend
rs17498325		G/A	NIMH/Pritzker: OR (95% CI)=1.42(1.09-1.87), P-value = 0.01; GSK(complete sample): OR (95% CI)=1.46(1.2-1.79), P-value = 0.00021; 2-study meta-analysis: OR (95% CI)=1.45(1.23-1.71), P-value = 0.0000091; Heterogeneity: I²%=0, P-value = 0.88	Trend
rs6494849	RNU6-745P	A/C	NIMH/Pritzker: OR (95% CI)=1.24(1.00-1.54), P-value = 0.049; GSK(reduced sample): OR (95% CI)=1.11(0.88-1.38), P-value = 0.38; WTCCC: OR (95% CI)=1.26(1.14-1.40), P-value = 0.00001; 3-study meta-analysis: OR (95% CI)=1.23(1.13-1.35), P-value = 0.0000065; Heterogeneity: I²%=0, P-value = 0.57	Trend
rs472913	NFIX	C/G	NIMH/Pritzker: OR (95% CI)=1.12(0.97-1.29), P-value = 0.11; GSK(reduced sample): OR (95% CI)=1.17(1.00-1.36), P-value = 0.051; WTCCC: OR (95% CI)=1.20?(1.11-1.28), P-value = 0.00000063; 3-study meta-analysis: OR (95% CI)=1.18(1.11-1.25), P-value = 0.0000002; Heterogeneity: I²%=0, P-value = 0.72	Trend
rs2905072	GFI1B	A/G	NIMH/Pritzker: OR (95% CI)=1.43(1.20-1.70), P-value = 0.000058; GSK(reduced sample): OR (95% CI)=1.14(0.95-1.38), P-value = 0.16; WTCCC: OR (95% CI)=1.16(1.05-1.28), P-value = 0.0043; 3-study meta-analysis: OR (95% CI)=1.21(1.11-1.32), P-value = 0.0000064; Heterogeneity: I²%=56, P-value = 0.1	Trend
rs2813164		G/A	NIMH/Pritzker: OR (95% CI)=1.39(1.19-1.62), P-value = 0.000021; GSK(complete sample): OR (95% CI)=1.24(1.07-1.44), P-value = 0.0048; 2-study meta-analysis: OR (95% CI)=1.31(1.18-1.46), P-value = 0.00000083; Heterogeneity: I²%=9, P-value = 0.3	Trend
rs7250872	REXO1 ATP8B3	T/C	NIMH/Pritzker: OR (95% CI)=1.18(1.01-1.37), P-value = 0.035; GSK(reduced sample): OR (95% CI)=1.33(1.14-1.56), P-value = 0.00043; WTCCC: OR (95% CI)=1.18(1.06-1.30), P-value = 0.0024; 3-study meta-analysis: OR (95% CI)=1.21(1.12-1.31), P-value = 0.0000017; Heterogeneity: I²%=0, P-value = 0.41	Trend
rs6990255		T/C	NIMH/Pritzker: OR (95% CI)=1.41(1.00-2.00), P-value = 0.048; GSK(reduced sample): OR (95% CI)=1.28(0.91-1.81), P-value = 0.16; WTCCC: OR (95% CI)=1.33?(1.16-1.51), P-value = 0.000057; 3-study meta-analysis: OR (95% CI)=1.33(1.18-1.51), P-value = 0.0000058; Heterogeneity: I²%=0, P-value = 0.92	Trend
rs6901299	TRDN	G/A	NIMH/Pritzker: OR (95% CI)=1.05(0.86-1.27), P-value = 0.66; GSK(reduced sample): OR (95% CI)=1.18(0.95-1.46), P-value = 0.12; WTCCC: OR (95% CI)=1.26(1.15-1.39), P-value = 0.000002; 3-study meta-analysis: OR (95% CI)=1.21(1.11-1.31), P-value = 0.0000097; Heterogeneity: I²%=35, P-value = 0.21	Trend
rs6733011	KIAA1211L	G/A	NIMH/Pritzker: OR (95% CI)=1.11(0.95-1.29), P-value = 0.19; GSK(reduced sample): OR (95% CI)=1.13(0.96-1.32), P-value = 0.14; WTCCC: OR (95% CI)=1.2(1.11-1.29), P-value = 0.0000019; 3-study meta-analysis: OR (95% CI)=1.17(1.1-1.25), P-value = 0.0000026; Heterogeneity: I²%=0, P-value = 0.59	Trend
rs7867133	GDA	A/G	NIMH/Pritzker: OR (95% CI)=1.23(1.04-1.44), P-value = 0.013; GSK(complete sample): OR (95% CI)=1.39(1.19-1.63), P-value = 0.000033; 2-study meta-analysis: OR (95% CI)=1.31(1.17-1.47), P-value = 0.0000039; Heterogeneity: I²%=20, P-value = 0.26	Trend
rs7593459		T/A	NIMH/Pritzker: OR (95% CI)=1.27(1.09-1.48), P-value = 0.0019; GSK(complete sample): OR (95% CI)=1.31(1.14-1.51), P-value = 0.00014; 2-study meta-analysis: OR (95% CI)=1.29(1.16-1.44), P-value = 0.0000016; Heterogeneity: I²%=0, P-value = 0.76	Trend
rs7427021		G/A	NIMH/Pritzker: OR (95% CI)=1.05(0.91-1.23), P-value = 0.49; GSK(reduced sample): OR (95% CI)=1.25(1.06-1.47), P-value = 0.0089; WTCCC: OR (95% CI)=1.17(1.09-1.26), P-value = 0.000015; 3-study meta-analysis: OR (95% CI)=1.16(1.09-1.24), P-value = 0.0000049; Heterogeneity: I²%=14, P-value = 0.31	Trend