Study Report

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Basic Info

Reference	Kuo, P. H., 2014 PMID: 24444492
Citation	Kuo, P. H., et al. (2014). "Identification of novel loci for bipolar I disorder in a multi-stage genome-wide association study." Prog Neuropsychopharmacol Biol Psychiatry 51C: 58-64.
Disease Type	Bipolar I Disorder
Study Design	case-control
Study Type	Genome-wide association study
Sample Size	200 BPD-1 patients and 200 controls
SNP/Region/Marker Size	970,342 SNPs
Predominant Ethnicity	Mongloid
Population	Taiwanese
Age Group	adults : index probands aged between 18 and 70 years;

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	Patients who had a diagnosis of schizophrenia, schizoaffective disorder, or substance-inducedmood disorderwere excluded. Only participants whose parents and grandparents were all Han Chinese were selected for genotyping and genetic analysis.
Replication Size	240 patients and 240 controls for fine-mapping in the second stage, and 351 cases and 341 controls for replication in the third stage.
Technique	Pooling based GWA testing was used. Whole-genome genotyping was performed using the Illumina Human Omni1-Quad array with 970,342 SNPs. The recorded output variables for each analyzed SNP on the BeadChip were analyzed with the Beadstudio software.
Statistical Method	For the pooling based GWA testing, we previously developed a novel rank-based method to identify top-ranked associated markers. At the individual genotyping stage, differences in allelic or genotypic frequencies between patients and controls were examined by logistic regression models for the additive, dominant and recessive genetic models using PLINK version 1.07. The odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in regression models. The Benjamini and Hochberg multiple comparison procedure was applied to control for the false discovery rate (FDR) in analyses. Additionally, a gene-based test was employed to analyze the associations between the 8 candidate genes and BPD-I in PLINK with independent markers (default setting with pairwise r2 less than 0.5) selected in a gene region. The empirical P-values of regression models for single marker and gene-based tests were obtained by 100,000 permutations.
Result Summary	Among the top-ranked markers from the discovery stage, eight genes and 15 individual SNPs were evaluated in the fine-mapping stage. At this stage, rs7619173, which is not in a gene coding region, showed the most significant association (P=2.0E-05) with BPD-I. Four genes had empirical P-values b 0.05, including KCNH7 (P = 0.0047), MYST4 (P = 0.0047), NRXN3 (P = 0.0095), and SEMA3D (P = 0.037). For markers genotyped in replication samples, rs7619173 exhibited a significant association (Pcombined=2.0E-04) after multiple testing correction, while markers rs11001178 (MYST4) and rs2217887 (NRXN3) showed weak associations (Pcombined= 0.02) with BPD-I.

SNPs reported by this study for BD (count: 22)

SNP	Related Gene(s)	Statistical Values	Author Comments	Result Category
rs9485899		P-value=0.00085,Â OR=1.6, 95%CI=1.2-2.0 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs11946541		P-value=0.00971,Â OR=0.7, 95%CI=0.5-0.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs9569968		P-value=0.00785,Â OR=1.4, 95%CI=1.1-1.8 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs4326265		P-value=0.00651,Â OR=1.5, 95%CI=1.1-2.0 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs2220984		P-value=0.00725,Â OR=0.7, 95%CI=0.5-0.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs216515		P-value=0.01275,Â OR=0.7, 95%CI=0.6-0.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs7281895		P-value=0.00294,Â OR=1.5, 95%CI=1.1-1.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs7237766		P-value=0.01604,Â OR=1.4, 95%CI=1.1-1.8 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs1435013	KCNH7	P-value=0.02044,Â OR=0.7, 95%CI=0.6-0.95 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs1222938	DCC	P-value=0.04746,Â OR=0.8, 95%CI=0.6-0.99 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs16931793	KAT6B	P-value=0.01045,Â OR=0.6, 95%CI=0.4-0.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs11001178	KAT6B	P-value=0.00075,Â OR=0.6, 95%CI=0.5-0.8 for the second stage, combined P-value=0.02 for the replication stage.	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs7917746	KAT6B	P-value=0.03282,Â OR=0.7, 95%CI=0.6-0.98 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs7909358	KAT6B	P-value=0.02090,Â OR=0.7, 95%CI=0.5-0.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs13322211	ROBO2	P-value=0.01172,Â OR=1.6, 95%CI=1.1-2.3 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs2217887	NRXN3	P-value=0.00233,Â OR=1.7, 95%CI=1.2-2.3 for the second stage, combined P-value=0.02 for the replication stage.	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs10260011	SEMA3D	P-value=0.01226,Â OR=1.4, 95%CI=1.1-1.8 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs6736615	KCNH7	P-value=0.00960,Â OR=1.4, 95%CI=1.1-1.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs7619173	SOX2-OT	P-value=0.00002,Â OR=0.5, 95%CI=0.4-0.7 for the second stage, combined P-value=2E-04 for the replication stage.	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs7651261	SOX2-OT	P-value=0.00018,Â OR=0.6, 95%CI=0.2-0.8 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs9850867		P-value=0.01631,Â OR=0.7, 95%CI=0.6-0.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive
rs6814785		P-value=0.00142,Â OR=0.7, 95%CI=0.5-0.9 for the second stage	The marker is identified to be associated with bipolar disor...... The marker is identified to be associated with bipolar disorder in the fine-mapping stage with P-value less than 0.05. More...	Positive

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

Gene	Statistical Values/Author Comments	Result Category
SEMA3D	Gene-based P-value (allelic model) =0.0419, P-value (additive model) =0.0368. SEMA3D, with a P-value of less than 0.05 (P= 0.037). SEMA3D, with a P-value of less than 0.05 (P= 0.037).	Positive
ROBO2	Gene-based P-value (allelic model) =0.1065, P-value (additive model) =0.0878. ROBO2 stood out for their potential biological plausibility to be associated with bipolar illness. ROBO2 stood out for their potential biological plausibility to be associated with bipolar illness.	Negative
FAM19A2	No significant association was observed. No significant association was observed.	Negative
DAB1	No significant association was observed. No significant association was observed.	Negative
KCNH7	Gene-based P-value (allelic model) =0.0573, P-value (additive model) =0.0047. KCNH7, a gene associated with voltage-gated potassium channels (P= 0.0047) KCNH7, a gene associated with voltage-gated potassium channels (P= 0.0047)	Positive
DCC	Gene-based P-value (allelic model) = 0.4426, P-value (additive model) =0.4147. DCC stood out for their potential biological plausibility to be associated with bipolar illness. DCC stood out for their potential biological plausibility to be associated with bipolar illness.	Negative
NRXN3	Gene-based P-value (allelic model) =0.0071, P-value (additive model) =0.0095. NRXN3, which encodes receptors or ligands that regulate neuronal positioning, axon guidance, cell mi...... NRXN3, which encodes receptors or ligands that regulate neuronal positioning, axon guidance, cell migration and adhesion (P= 0.0095) More...	Positive
KAT6B	Gene-based P-value (allelic model) =0.0078, P-value (additive model) =0.0047. MYST4, which encodes histone acetyltransferase (P = 0.0047) MYST4, which encodes histone acetyltransferase (P = 0.0047)	Positive