Study Report

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Basic Info

Reference	Sklar, P., 2008 PMID: 18317468
Citation	Sklar, P., J. W. Smoller, et al. (2008). "Whole-genome association study of bipolar disorder." Mol Psychiatry 13(6): 558-569.
Disease Type	Bipolar I Disorder
Study Design	case-control
Study Type	Genome-wide association study
Sample Size	1461 patients with bipolar (BP) 1 disorder, 2008 controls
SNP/Region/Marker Size	372,193 SNPs; 304 SNPs for replication
Predominant Ethnicity	Caucasian
Population	European
Age Group	adults : over 18 years of age

Detail Info

Sample Diagnosis	DSM-IV
Replication Size	family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls)
Technique	Genotyping was performed using the Affymetrix GeneChip Human Mapping 500K Array Set. Genotyping of replication SNPs were performed in the NIMH and Edinburgh samples by Sequenom MassArray.
Statistical Method	We performed all data analysis and quality control (QC) using the PLINK software package. The primary analysis was of single SNPs using the Cochran-Mantel-Haenszel test to assess allelic association with disease conditional on the strata as defined by the stratification analysis. For each SNP, we also calculated standard, allelic association tests not conditioned on strata, based on a X² test for independence. We used additional haplotype-based analyses to validate and refine the signals of the most associated SNPs (labeled 'reference SNPs' here). First, we used local haplotype information to probabilistically reconstruct missing genotypes for each reference SNP, to further ensure that the associations were not due to biased genotyping failure (labeled the pSNP test). Second, we scanned the local region for haplotypes (not including the reference SNP) which we call 'proxies,' that were in linkage disequilibrium (LD) with the reference SNP (r² > 0.2). All proxy haplotypes of up to four SNPs out of up to six SNPs on either side and within 250 kb of the reference SNP are then tested for association with disease (the pHAP test). We analyzed the combined NIMH-GI and Edinburgh replication samples using the DFAM test implemented in PLINK.
Result Summary	Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

SNPs reported by this study for BD (count: 20)

SNP	Related Gene(s)	Allele Change	Statistical Values	Result Category
rs16931058	C9orf91	A/G	CMH (Cochran-Mantel-Haenszel) P-value = 3.57E-06, allelic P-value = 2.34E-06, OR=1.76, pSNP test P-value = 2.34E-06, pHAP test P-value = 9.11E-06, r²=0.88	Trend
rs1444067	CDH7	T/G	CMH (Cochran-Mantel-Haenszel) P-value = 1.83E-05, allelic P-value = 3.41E-05, OR=1.23, pSNP test P-value = 7.26E-05, pHAP test P-value = 5.56E-06, r²=0.61	Trend
rs1341139	RNF219	C/A	CMH (Cochran-Mantel-Haenszel) P-value = 7.23E-06, allelic P-value = 3.16E-05, OR=0.56, pSNP test P-value = 2.15E-05, pHAP test P-value = 1.59E-04, r²=0.45	Negative
rs12970791	CDH7	A/C	CMH (Cochran-Mantel-Haenszel) P-value = 2.73E-05, allelic P-value = 5.30E-05, OR=1.22, pSNP test P-value = 5.55E-05, pHAP test P-value = 1.22E-05, r²=0.65	Trend
rs11050038	FAR2	C/T	CMH (Cochran-Mantel-Haenszel) P-value = 1.47E-05, allelic P-value = 2.18E-05, OR=0.77, pSNP test P-value = 2.18E-05, pHAP test P-value = 2.60E-05, r²=0.98	Negative
rs11049998	FAR2	G/A	CMH (Cochran-Mantel-Haenszel) P-value = 3.33E-05, allelic P-value = 3.93E-05, OR=0.77, pSNP test P-value = 2.95E-05, pHAP test P-value = 2.05E-04, r²=0.78	Negative
rs10982292	ATP6V1G1	A/G	CMH (Cochran-Mantel-Haenszel) P-value = 3.32E-05, allelic P-value = 2.86E-05, OR=1.82, pSNP test P-value = 2.52E-05, pHAP test P-value = 6.81E-06, r²=0.77	Trend
rs10491113	TMEM132E	A/G	CMH (Cochran-Mantel-Haenszel) P-value = 2.69E-05, allelic P-value = 9.90E-06, OR=0.74, pSNP test P-value = 1.03E-05, pHAP test P-value = 7.36E-02, r²=0.21	Trend
rs4939921	MYO5B	G/A	CMH (Cochran-Mantel-Haenszel) P-value = 1.66E-07, allelic P-value = 5.02E-07, OR=1.51, pSNP test P-value = 5.09E-07, pHAP test P-value = 2.04E-08, r²=0.42	Trend
rs5963419	OTC	C/T	CMH (Cochran-Mantel-Haenszel) P-value = 3.44E-05, allelic P-value = 3.53E-05, OR=1.27, pSNP test P-value = 4.22E-05, pHAP test P-value = 4.71E-05, r²=0.99	Negative
rs729969	EGFR	T/C	CMH (Cochran-Mantel-Haenszel) P-value = 3.30E-05, allelic P-value = 9.29E-06, OR=1.36, pSNP test P-value = 8.67E-06, pHAP test P-value = 8.36E-08, r²=0.68	Trend
rs9817739	RFTN1	T/C	CMH (Cochran-Mantel-Haenszel) P-value = 3.47E-05, allelic P-value = 7.26E-05, OR=0.79, pSNP test P-value = 7.30E-05, pHAP test P-value = 7.24E-03, r²=0.28	Negative
rs1705236	TSPAN8	T/A	CMH (Cochran-Mantel-Haenszel) P-value = 6.11E-07, allelic P-value = 1.47E-06, OR=0.58, pSNP test P-value = 1.46E-06, pHAP test P-value = 7.57E-07, r²=0.87	Trend
rs17172438	EGFR	C/T	CMH (Cochran-Mantel-Haenszel) P-value = 3.26E-05, allelic P-value = 1.26E-05, OR=1.32, pSNP test P-value = 1.58E-05, pHAP test P-value = 9.28E-07, r²=0.69	Trend
rs2274598	C9orf91	C/T	CMH (Cochran-Mantel-Haenszel) P-value = 1.68E-05, allelic P-value = 1.28E-05, OR=1.87, pSNP test P-value = 2.30E-05, pHAP test P-value = 7.04E-06, r²=0.83	Trend
rs2658046	CDH7	G/A	CMH (Cochran-Mantel-Haenszel) P-value = 2.09E-05, allelic P-value = 4.31E-05, OR=1.22, pSNP test P-value = 5.34E-05, pHAP test P-value = 2.31E-05, r²=0.94	Negative
rs2850699	CDH7	C/A	CMH (Cochran-Mantel-Haenszel) P-value = 2.78E-05, allelic P-value = 6.02E-05, OR=1.22, pSNP test P-value = 6.02E-05, pHAP test P-value = 4.40E-05, r²=0.95	Negative
rs2850700	CDH7	T/C	CMH (Cochran-Mantel-Haenszel) P-value = 1.93E-05, allelic P-value = 4.36E-05, OR=1.22, pSNP test P-value = 6.02E-05, pHAP test P-value = 2.50E-05, r²=0.98	Negative
rs2900591	C9orf91	T/C	CMH (Cochran-Mantel-Haenszel) P-value = 2.06E-05, allelic P-value = 2.68E-05, OR=1.71, pSNP test P-value = 8.05E-06, pHAP test P-value = 6.66E-06, r²=0.55	Trend
rs4455070	CDH7	T/A	CMH (Cochran-Mantel-Haenszel) P-value = 3.26E-05, allelic P-value = 5.60E-05, OR=1.22, pSNP test P-value = 4.10E-05, pHAP test P-value = 1.34E-05, r²=0.64	Negative

Genes reported by this study for BD (count: 8)

Gene	Statistical Values/Author Comments	Result Category
TSPAN8	Our strongest single SNP results are found in myosin5B (TSPAN8; P-value = 6.11E-07). Haplotype anal...... Our strongest single SNP results are found in myosin5B (TSPAN8; P-value = 6.11E-07). Haplotype analysis further supported single SNP results highlighting TSPAN8 (P-value = 7.57E-07) More...	Trend
RNF219	No significant association of this gene was observed in BD. No significant association of this gene was observed in BD.	Negative
EGFR	Haplotype analysis further supported single SNP results highlighting EGFR (P-value = 8.36E-08) Haplotype analysis further supported single SNP results highlighting EGFR (P-value = 8.36E-08)	Trend
TMEM132E	Suggestive association of this gene was found. Suggestive association of this gene was found.	Trend
CDH7	Suggestive association of this gene was found. Suggestive association of this gene was found.	Trend
FAR2	No significant association of this gene was observed in BD. No significant association of this gene was observed in BD.	Negative
MYO5B	Our strongest single SNP results are found in myosin5B (MYO5B; P-value = 1.66E-07). Haplotype analy...... Our strongest single SNP results are found in myosin5B (MYO5B; P-value = 1.66E-07). Haplotype analysis further supported single SNP results highlighting MYO5B (P value=2.04E-08) More...	Trend
ATP6V1G1	Suggestive association of this gene was found. Suggestive association of this gene was found.	Trend