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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Study Report

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Basic Info

Reference	Cichon, S., 2008 PMID: 17905754
Citation	Cichon, S., I. Winge, et al. (2008). "Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder." Hum Mol Genet 17(1): 87-97.
Disease Type	Bipolar I Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	The sample comprised 636 BPAD patients and 1070 population-based controls of German descen.
SNP/Region/Marker Size	15 SNPs
Predominant Ethnicity	Caucasian
Population	Germany and Russia
Gender	47% male and 53% female for the German cases; 51.5% female and 48.5% male for the German control sample. 44.1% male and 55.9% female for the Russian cases; 54.3% female and 45.7% male for the Russian control sample.
Age Group	adults : The German patients: mean age=43.7 (SD=13.1) years; the German controls: mean age=48.4 (SD=15.5) years. The Russian patients: mean age of oneset=26.8 (SD=11.3) years; the Russian controls: mean age=38.1 (SD=15.4) years.

Detail Info

Sample Diagnosis	DSM-IV
Replication Size	Replication sample from Russia, consisting of 247 BPAD patients and 230 controls
Technique	genotyping
Statistical Method	Hardy-Weinberg equilibrium and intermarker LD as expressed by r² and D' was calculated and visualized using the HAPLOVIEW v.3.32 software. LD measures for all 15 markers tested in all three control populations. Patient-control single-marker association analysis was performed using the program FAMHAP (30). For comparison, all calculations were also performed using the UNPHASED software package version 3.0.6. In addition, the non-synonymous SNP (rs17110563) was analysed using Fisher's exact test. The results were almost identical to the results obtained with the Cochrane-Armitage trend test used in FAMHAP. ANOVA and pairwise t-tests were used to compare the properties of the mutant forms of TPH2 with the WT enzyme.
Result Summary	SNPs located in a haplotype block covering the 50 region of the gene as well as a rare, non-synonymous SNP, resulting in a Pro206Ser substitution, showed significant association with bipolar disorder. The odds ratio for the minor allele in the pooled sample was 1.5 (95% CI 1.2-1.9) for rs11178997 (in the 50-associated haplotype block) and 4.8 (95% CI 1.6-14.8) for rs17110563 encoding the Pro206Ser substitution. Examination of the functional effects of TPH2 Pro206Ser provided evidence for a reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism in BD.

SNPs reported by this study for BD (count: 15)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs1843809	TPH2	T/G	G	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.26 in the Russian BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in Combined German/Russian sample.		Positive
rs4760820	TPH2	C/G	G	Cochrane-Armitage trend test P-value = 0.3 in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.49 in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.48 in Combined German/Russian sample.		Positive
rs17110563	TPH2	C/T	T	Cochrane-Armitage trend test P-value = 0.0066 , OR (95% CI)=5.1 (1.4-18.8) in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.21 , OR (95% CI)=3.7 (0.4-33.5) in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.0024 , OR (95% CI)=4.8 (1.6-14.8) in Combined German/Russian sample.	In the German sample, SNP rs17110563 also showed association...... In the German sample, SNP rs17110563 also showed association: nine out of 636 BPAD patients were heterozygous for Pro206Ser, compared with only three out of 1070 controls. More...	Positive
rs17722134	TPH2	A/G	G	Cochrane-Armitage trend test P-value = 0.09 in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.0633 in the Russian BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in Combined German/Russian sample.		Positive
rs1487275	TPH2	T/G	G	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in the Russian BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in Combined German/Russian sample.		Negative
rs17110477	TPH2	T/A	A	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in the Russian BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in Combined German/Russian sample.		Negative
rs1386486	TPH2	C/T	T	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in the Russian BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in Combined German/Russian sample.		Negative
rs1386497	TPH2	A/C	C	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.29 in the Russian BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in Combined German/Russian sample.		Positive
rs11615016	TPH2	A/G	G	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in the Russian BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in Combined German/Russian sample.		Negative
rs11834097	TPH2	C/T	T	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.22 in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.39 in Combined German/Russian sample.		Positive
rs11178998	TPH2	A/G	G	Cochrane-Armitage trend test P-value = 0.0051 , OR (95% CI)=1.5 (1.1-1.9) in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.0852 , OR (95% CI)=1.6 (0.94-2.6) in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.00098 , OR (95% CI)=1.5 (1.2-1.9) in Combined German/Russian sample.	In the German sample, the minor alleles of SNPs rs11178997, ...... In the German sample, the minor alleles of SNPs rs11178997, rs11178998 and rs7954758 were significantly over-represented in BPAD patients when compared with controls. In the Russian replication sample, the three SNPs in the 5' region showed a non-significant trend. More...	Positive
rs11178999	TPH2	G/A	A	Cochrane-Armitage trend test P-value > .0.5 in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.34 in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.29 in Combined German/Russian sample.		Positive
rs10748185	TPH2	A/G	G	Cochrane-Armitage trend test P-value = 0.4 in the German BPAD sample. Cochrane-Armitage trend test P-value > .0.5 in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.33 in Combined German/Russian sample.		Positive
rs11178997	TPH2	T/A	A	Cochrane-Armitage trend test P-value = 0.0047 , OR (95% CI)=1.5 (1.1-1.9) in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.0668 , OR (95% CI)=1.6 (0.96-2.6) in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.00073 , OR (95% CI)=1.5 (1.2-1.9) in Combined German/Russian sample.	In the German sample, the minor alleles of SNPs rs11178997, ...... In the German sample, the minor alleles of SNPs rs11178997, rs11178998 and rs7954758 were significantly over-represented in BPAD patients when compared with controls. In the Russian replication sample, the three SNPs in the 5' region showed a non-significant trend. More...	Positive
rs7954758	TPH2	A/G	G	Cochrane-Armitage trend test P-value = 0.0039 , OR (95% CI)=1.5 (1.1-1.9) in the German BPAD sample. Cochrane-Armitage trend test P-value = 0.0668 , OR (95% CI)=1.6 (0.96-2.6) in the Russian BPAD sample. Cochrane-Armitage trend test P-value = 0.0006 , OR (95% CI)=1.5 (1.2-1.9) in Combined German/Russian sample.	In the German sample, the minor alleles of SNPs rs11178997, ...... In the German sample, the minor alleles of SNPs rs11178997, rs11178998 and rs7954758 were significantly over-represented in BPAD patients when compared with controls. In the Russian replication sample, the three SNPs in the 5' region showed a non-signific. More...	Positive

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