Study Report

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Basic Info

Reference	Lin, Y. M., 2007 PMID: 17768266
Citation	Lin, Y. M., S. C. Chao, et al. (2007). "Association of functional polymorphisms of the human tryptophan hydroxylase 2 gene with risk for bipolar disorder in Han Chinese." Arch Gen Psychiatry 64(9): 1015-1024.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	105 patients with bipolar I disorder and 106 controls
SNP/Region/Marker Size	6 SNPs
Predominant Ethnicity	Mongloid
Population	Chinese
Gender	not mentioned
Age Group	not mentioned

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	Patients were recruited through direct clinical interviews conducted by the treating clinician according the procedure described in the DSM-IV diagnoses of lifetime major depressive disorder and BPI. Additional information required to reach a diagnosis was also collected from all clinical and hospital records where available. Only one patient was found to have co-morbid psychiatric condition with alcohol abuse. Although about 10% of the patients have medical problems like hypertension or diabetes, the diseases are common in general population as well.
Technique	direct sequencing, genotyping using TaqMan and RNA Isolation and Real-Time Q-RT-PCR
Statistical Method	Differences in genotype and allele distributions between patients and controls were analyzed using a chi-square test implemented in computer software (SNPAlyze version 4.1; Japan). Odds ratio and power estimation were estimated using SAS and Power Analysis and Sample Size (PASS) 2005 software respectively. In addition to the chi-square test, the SNPAlyze software was used for additional value of Akaike's information criterion (AIC) to evaluate the relationship between individual SNPs and diseases. Both construction of haplotypes that was based on the expectation maximization (EM) algorism and the permutation test for case-control study were performed using SNPAlyze. Additional odds ratios for haplotype and disease association were calculated using the SAS (SAS Institute) program. Gene-gene interaction was plotted using odds ratios calculated from of association analysis between specific haplotype-allele combinations and disease.
Result Summary	Significant haplotype association of TPH2 polymorphisms and BPD was identified (P<0.001). In addition, allelic alteration of polymorphisms in the promoter region and exon 2 of TPH2 caused noteworthy functional losses in promoter and enzyme activities, respectively, indicating the potential susceptibility loci for BPD. They found that the odds ratio changed from 3.73 of the TAG haplotype to 4.81 or 1.68, depending on the combined effect of both TPH genotypes. These data suggested an interaction between the 2 TPH genes to confer a risk for BPD. This study supports the involvement of TPH2 in the etiology of BPD, and the functional singlenucleotide polymorphisms identified herein might be the susceptibility loci for BPD. Although the interaction between the 2 TPH genes merits further investigation, their findings suggest that the interactive effect should be considered in future studies of serotonin-related disorders.

SNPs reported by this study for BD (count: 5)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs11179003	TPH2	C/T	chi-square P-value = 0.71	this SNP was not associated with the disease this SNP was not associated with the disease	Negative
rs11178998	TPH2	A/G	chi-square P-value = 0.40	this SNP was not associated with the disease this SNP was not associated with the disease	Negative
rs11178997	TPH2	T/A	chi-square P-value = 0.72	this SNP was not associated with the disease this SNP was not associated with the disease	Negative
rs4570625	TPH2	T/G	chi-square P-value = 0.45	this SNP was not associated with the disease this SNP was not associated with the disease	Negative
rs17110747	TPH2	G/A	chi-square P-value = 0.07	this SNP was not associated with the disease this SNP was not associated with the disease	Negative

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

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
TPH1_-346G - rs4570625 - rs11178997 - rs11178998	G, T-A-G	TPH1 TPH2	P-value < 0.001, OR (95% CI)=4.81 (2.62-8.83)	Of those with the TPH2 TAG haplotype, the risk was 4.81 time...... Of those with the TPH2 TAG haplotype, the risk was 4.81 times greater for individuals who also had the TPH1-346G allele More...	Positive
rs4570625 - rs11178997 - rs11178998	Others	TPH2	P-value = 0.21, OR (95% CI)=0.43 (0.11-1.68); Total and global P values were < 0.001		Negative
rs4570625 - rs11178997 - rs11178998	T-A-A	TPH2	P-value < 0.001, OR (95% CI)=0.19 (0.08-0.46); Total and global P values were < 0.001	significant differences in distribution between groups were ...... significant differences in distribution between groups were detected for haplotype TAA, even after a Bonferroni correction; the TAA haplotype was with significant protective effects More...	Positive
TPH1_G-346T - rs4570625 - rs11178997 - rs11178998	G/T, non T-A-G	TPH1 TPH2	P-value = 0.32, OR (95% CI)=0.84 (0.59-1.19)		Negative
rs4570625 - rs11178997 - rs11178998	G-T-G	TPH2	P-value < 0.001; Total and global P values were < 0.001	significant differences in distribution between groups were ...... significant differences in distribution between groups were detected for haplotype GTG, even after a Bonferroni correction More...	Positive
rs4570625 - rs11178997 - rs11178998	T-T-A	TPH2	P-value = 0.54, OR (95% CI)=0.89 (0.60-1.30); Total and global P values were < 0.001	TTA haplotype was equally distributed between patients and c...... TTA haplotype was equally distributed between patients and controls More...	Negative
rs4570625 - rs11178997 - rs11178998	G-T-A	TPH2	P-value = 0.01, OR (95% CI)=1.7 (1.11-2.59); Total and global P values were < 0.001		Positive
TPH1_-346T - rs4570625 - rs11178997 - rs11178998	T, T-A-G	TPH1 TPH2	P-value = 0.22, OR (95% CI)=1.68 (0.72-3.89)	The risk for BPD was only 1.68 times greater if the individu...... The risk for BPD was only 1.68 times greater if the individual carrying the TPH2 risk haplotype had a TPH1-347T allele, and the difference between the 2 subgroups was not significant More...	Negative
rs4570625 - rs11178997 - rs11178998	T-A-G	TPH2	P-value < 0.001, OR (95% CI)=3.73 (1.89-7.36); Total and global P values were < 0.001	significant differences in distribution between groups were ...... significant differences in distribution between groups were detected for haplotype TAG, even after a Bonferroni correction; the TAG haplotype was associated with noteworthy risk More...	Positive
TPH1_G-346T - rs4570625 - rs11178997 - rs11178998	G/T, T-A-G	TPH1 TPH2	P-value = 0.08, OR (95% CI)=2.40 (0.90-6.35)		Negative

Other variants reported by this study for BD (count: 1)

Variant Name	Related Gene	Type	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
TPH2 C2755A	TPH2	point mutation	C/A		chi-square P-value = 0.03	A significant difference in allele distribution between pati...... A significant difference in allele distribution between patients and controls was obtained for SNP C2755A, but not significant after Bonferroni correction More...	Positive

Genes reported by this study for BD (count: 2)

Gene	Statistical Values/Author Comments	Result Category
TPH2	A significant difference in allele distribution was obtained for SNP C2755A; the effect of TPH2 on ...... A significant difference in allele distribution was obtained for SNP C2755A; the effect of TPH2 on BPD etiology can be influenced by the presence of TPH1. More...	Positive
TPH1	The effect of TPH2 on BPD etiology can be influenced by the presence of TPH1. The effect of TPH2 on BPD etiology can be influenced by the presence of TPH1.	Positive

Gene-gene interactions reported by this study for BD (count: 1)

Gene Group	Markers	Statistical Values	Author Comments	Result Category
TPH1 TPH2	TPH1_-346G - rs4570625 - rs11178997 - rs11178998	Haplotype cross these two genes were tested. P-value < 0.001, OR (95% CI) = 4.81 (2.62-8.83)	Of those with the TPH2 TAG haplotype, the risk was 4.81 time...... Of those with the TPH2 TAG haplotype, the risk was 4.81 times greater for individuals who also had the TPH1-346G allele More...	Positive