BDgene

Core Gene from Gene Prioritization Pathways from PBA (Pathway-based Analysis) Enriched Pathways for Core Genes Enriched Pathways for Cross-disorder Genes

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Basic Info

Reference	Zhou, X.,2009 PMID: 19401786
Citation	Zhou, X., W. Tang, et al. (2009). Transcription factor SP4 is a susceptibility gene for bipolar disorder. PLoS One 4(4): e5196.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	UCSD and NIMH bipolar collections:1872 individuals from 427 Caucasian families;Chinese trio families with schizophrenia:308 individuals from 325 trio families .
SNP/Region/Marker Size	10 SNPs
Predominant Ethnicity	Caucasian and Mongloid
Population	UCSD collections,NIMH collections and Chinese
Gender	Chinese bipolar cases and control sample:bipolar patients (male: 284, female: 222) and controls (male: 287, female: 220);Chinese trio families with schizophrenia:145 female and 163 male probands
Age Group	Adults : Mean age(SD)(year):Chinese bipolar cases and control sample:37.8(11.4) in cases and 36.4(8.7) in controls;Chinese trio families with schizophrenia:24.0(6.6)

Detail Info

Sample Diagnosis	DSM
Sample Status	(1)UCSD and NIMH families with bipolar disorder:The total sample for analysis included 1872 individuals from 427 Caucasian families, approximately half of which consisted of both parents and one affected offspring with the remaining consisting of both parents and two or more affected offspring. The average family consisted of 4.4 individuals in 2 generations. The families chosen for this study derived from several sources. The National Institute of Mental Health Genetics Initiative for Bipolar Disorder waves 1-4 pedigree collections were collected as part of a consortium and ascertained through a bipolar I proband, and assessed using the Diagnostic Interview for Genetic Studies (DIGS). Families were also drawn from the University California San Diego consortium including collection sites at UCSD, University of British Columbia, and University of Cincinnati. These families were ascertained through a bipolar I or bipolar II proband and selected for the presence of at least two other mood disordered family members.(2)Chinese bipolar cases and control sample:All the subjects were of Han origin from Anhui province. Among the 506 bipolar patients diagnosed using DSM-IV, 419 (82.8%) patients were type I Bipolar. Final diagnosis was made with two independent psychiatrists on the basis of interview and medical records. All participating subjects provided written informed consent according to procedures approved by the Ethic Committee of Bio-X Center, Shanghai Jiao Tong University.(3)Chinese trio families with schizophrenia:A total of 325 trio families were collected from several different sites with 126 families from Shanghai, 71 families from Shanxi province, 86 families from Jilin province, and 42 families from Changchun. All subjects were Han Chinese in origin. There were 145 female and 163 male probands with an average age of 24.0(SD=6.6). Clinical diagnoses were made according to DSM-IV,and ascertained by an independent clinician. All the subjects provided written informed consent according to procedures approved by the Ethic Committee of Bio-X Center, Shanghai Jiao Tong University.
Replication Size	Chinese bipolar cases and control sample:506 unrelated bipolar patients and 507 unrelated controls
Technique	genotyping
Statistical Method	(1)In the Caucasian sample, Haploview v.4.0 was used to perform the parenTDT test using single SNPs and haplotypes.Permutations tests were performed to correct for multiple comparisons.UNPHASED was used for genotypic association analyses.(2)Haploview v.4.0 was used to calculate allele frequencies,Hardy-Weinberg Equilibrium (HWE), and p value of both single SNPs and haplotypes in Chinese BP case control samples.(3)The family-based association analyses of the single SNPs and haplotypes in the Chinese schizophrenia trio families were performed using the TDTPHASE module implemented in the UNPHASED program. An E-M algorithm was used to estimate missing genotypes and excessively rare haplotypes were removed from the analyses.
Result Summary	Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029), and two of them (rs12673091, rs3735440) were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012) also displayed a significant association. The SNP7 (rs12673091) was therefore significantly associated in all three samples, and shared the same susceptibility allele (A) across all three samples. On the other hand, we found a gene dosage effect for mouse Sp4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in Sp4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support Sp4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of Sp4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these psychiatric disorders.

SNPs reported by this study for BD (count: 10)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs40245	SP4	T/A		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is A, MAF=0.38, P-value = 0.273; Chinese Case-Controls for Bipolar Disorder: Risk allele is A, MAF=0.06, P-value = 0.009	Significant association was observed in Chinese Case-Control...... Significant association was observed in Chinese Case-Controls for Bipolar Disorder. More...	Positive
rs3735440	SP4	T/C		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is C, MAF=0.34, P-value = 0.019; Chinese Case-Controls for Bipolar Disorder: Risk allele is C, MAF=0.08, P-value = 0.029	Significant association was observed in Caucasian Families f...... Significant association was observed in Caucasian Families for Bipolar Disorder and Chinese Case-Controls for Bipolar Disorder . More...	Positive
rs2282888	SP4	A/G		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is G, MAF=0.39, P-value = 0.07; Chinese Case-Controls for Bipolar Disorder: Risk allele is G, MAF=0.09, P-value = 0.067	No significant association was observed No significant association was observed	Negative
rs12673091	SP4	A/G		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is A, MAF=0.28, P-value = 0.0005; Chinese Case-Controls for Bipolar Disorder: Risk allele is A, MAF=0.13, P-value = 0.002	Significant association was observed in Caucasian Families f...... Significant association was observed in Caucasian Families for Bipolar Disorder and Chinese Case-Controls for Bipolar Disorder . More...	Positive
rs12668354	SP4	A/C		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is C, MAF=0.33, P-value = 0.022; Chinese Case-Controls for Bipolar Disorder: Risk allele is C, MAF=0.09, P-value = 0.163	Significant association was observed in Caucasian Families f...... Significant association was observed in Caucasian Families for Bipolar Disorder. More...	Positive
rs11974306	SP4	A/T		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is T, MAF=0.5, P-value = 0.018	Significant association was observed in Caucasian Families f...... Significant association was observed in Caucasian Families for Bipolar Disorder. More...	Positive
rs10276352	SP4	A/G		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is G, MAF=0.44P-value = 0.102; Chinese Case-Controls for Bipolar Disorder: Risk allele is G, MAF=0.28, P-value = 0.095	No significant association was observed. No significant association was observed.	Negative
rs10261327	SP4	C/T		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is C, MAF=0.46P-value = 0.379; Chinese Case-Controls for Bipolar Disorder: Risk allele is C, MAF=0.49P-value = 0.953	No significant association was observed No significant association was observed	Negative
rs10245440	SP4	C/A		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is A, MAF=0.24, P-value = 0.647; Chinese Case-Controls for Bipolar Disorder: Risk allele is C, MAF=0.46, P-value = 0.187	No significant association was observed No significant association was observed	Negative
rs1018954	SP4	T/A		Allelic association: Caucasian Families for Bipolar Disorder: TDT: Risk allele is A, MAF=0.42, P-value = 0.592; Chinese Case-Controls for Bipolar Disorder: Risk allele is A, MAF=0.04, P-value = 0.001	Significant association was observed in Chinese Case-Control...... Significant association was observed in Chinese Case-Controls for Bipolar Disorder. More...	Positive

Haplotypes reported by this study for BD (count: 10)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs12668354 - rs12673091 - rs1018954 - rs3735440 - rs11974306	A-A-A-T-A	SP4	Haplotypic association:Global P-value = 0.004, Individual P-value = 0.684	Significant association was found in global P-value. Significant association was found in global P-value.	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440 - rs11974306	A-A-A-C-T	SP4	Haplotypic association:Global P-value = 0.004, Individual P-value = 0.585	Significant association was found in global P-value. Significant association was found in global P-value.	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440 - rs11974306	A-G-A-T-A	SP4	Haplotypic association:Global P-value = 0.004, Individual P-value = 0.232	Significant association was found in global P-value. Significant association was found in global P-value.	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440 - rs11974306	A-A-A-T-T	SP4	Haplotypic association:Global P-value = 0.004, Individual P-value = 0.511	Significant association was found in global P-value. Significant association was found in global P-value.	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440 - rs11974306	A-G-T-T-T	SP4	Haplotypic association:Global P-value = 0.004, Individual P-value = 0.907	Significant association was found in global P-value. Significant association was found in global P-value.	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440 - rs11974306	A-G-T-T-A	SP4	Haplotypic association:Global P-value = 0.004, Individual P-value = 0.0004	Significant association was found in global P-value and indi...... Significant association was found in global P-value and individual P-value. More...	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440 - rs11974306	C-A-T-C-T	SP4	Haplotypic association:Global P-value = 0.004, Individual P-value = 0.019	Significant association was found in global P-value and indi...... Significant association was found in global P-value and individual P-value. More...	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440	A-A-A-T	SP4	Haplotypic association:Individual P-value = 0.03	Significant association was found in individual P-value. Significant association was found in individual P-value.	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440	C-A-T-C	SP4	Haplotypic association:Individual P-value = 0.027	Significant association was found in individual P-value. Significant association was found in individual P-value.	Positive
rs12668354 - rs12673091 - rs1018954 - rs3735440	A-G-T-T	SP4	Haplotypic association:Individual P-value = 0.04	Significant association was found in individual P-value. Significant association was found in individual P-value.	Positive

Genes reported by this study for BD (count: 1)