Study Report

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Basic Info

Reference	Van Den Bogaert, A., 2006 (a) PMID: 17015812
Citation	Van Den Bogaert, A., K. Sleegers, et al. (2006). "Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population." Arch Gen Psychiatry 63(10): 1103-1110.
Disease Type	Bipolar Disorder & Major Depressive Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	135 patients with UP disorder, 182 patients with BP disorder and 364 controls
SNP/Region/Marker Size	38 SNPs
Predominant Ethnicity	Caucasian
Population	Swedish
Gender	87 women, 48 men with unipolar disorder; 96 women, 86 men with bipolar disorder; 202 women, 162 men controls
Age Group	adults : mean age=61.6 (SD=13.4) years of unipolar disorder, mean age=55.8 (SD=14.25) years of bipolar disorder, mean age=58.0 (SD=13.0) years of controls

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	The mean (SD) age at disease onset for patientswith UP disorder was 37.8 (16.7) years and for patients with BP disorder, 27.8 (11.5) years. The following disease characteristics were gathered for both patient groups: age at disease onset, first-episode symptoms (depression, hypomania/ mania), heredity for affective disorders, and presence of phaserelated psychotic symptoms, suicide attempts, melancholia, and atypical features, and mean follow-up age.
Technique	genotyping was performed by pyrosequencing on a PSQ HS96 pyrosequencer
Statistical Method	Allelic SNP and haplotype associations were calculated using 5000 permutations with Whap. Haplotype frequencies for marker combinations in the patient-control samples were estimated using the program Haplotyper. The level of significance for all statistical tests was defined as P<0.05.
Result Summary	Significant allelic association was identified in our UP disorder association sample for an htSNP located in the 5' promoter region (rs11178997;P=.001). Haplotype analysis supported this significant result by the presence of a protective factor on hapblock 2 (Pspecific=.002). In the BP disorder association sample, single-marker association identified a significant htSNP in the upstream regulatory region (rs4131348; P=.004). Moreover, haplotype analysis in the BP disorder sample showed that the same htSNPs from hapblock 2 associated with UP disorder were also significantly associated with BP disorder (Pspecific=.002). Haplotype-based analysis of TPH2 in patients with UP and BP disorder and controls from northern Swedish descent provides preliminary evidence for protective association in both disorders and thus supports a central role for TPH2 in the pathogenesis of affective disorders.

Genetic factors reported by this study for BD

SNPs reported by this study for BD (count: 7)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs1487275	TPH2	A/C	genotypic P-value = 0.83, allelic P-value = 0.82		Negative
rs11178997	TPH2	A/T	genotypic P-value = 0.18, allelic P-value = 0.16		Negative
rs10748185	TPH2	A/G	genotypic P-value = 0.049, allelic P-value = 0.05		Positive
rs4474484	TPH2	A/G	genotypic P-value = 0.43, allelic P-value = 0.42		Negative
rs4131348	TBC1D15 TPH2	C/T	genotypic P-value = 0.004, allelic P-value = 0.004	In the sample of patients with BP disorder and controls, sig...... In the sample of patients with BP disorder and controls, significant association was observed because of a decrease of the C allele of rs4131348 in the patients with BP disorder, from 21.9% to 14.6% (P=.004). More...	Positive
rs2129575	TPH2	G/T	genotypic P-value = 0.18, allelic P-value = 0.17		Negative
rs1843809	TPH2	G/T	genotypic P-value = 0.25, allelic P-value = 0.23		Negative

Haplotypes reported by this study for BD (count: 7)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs4131348' target=_blank>rs4131348 - rs4131348' target=_blank>rs4131348	C-T	TPH2	global P-value = 0.004	A protective BP disorder association was also observed for h...... A protective BP disorder association was also observed for hapblock 1 because of a decrease of 7.3% of the C allele of rs4131348. More...	Positive
rs11178997 - rs10748185 - rs2129575 - rs1843809	T-A-G-T	TPH2	global P-value = 0.02, P-value = 0.09	We also observed differences in haplotype distribution betwe...... We also observed differences in haplotype distribution between patients with BP disorder and control individuals in hapblock 2 (Pglobal=.02). This significant finding is the result of a decrease in the frequency of haplotype TGTT, from 25% in control individuals to 15% in patients with BP disorder (Pspecific=.002). More...	Negative
rs11178997 - rs10748185 - rs2129575 - rs1843809	T-G-T-T	TPH2	global P-value = 0.02, P-value = 0.002	We also observed differences in haplotype distribution betwe...... We also observed differences in haplotype distribution between patients with BP disorder and control individuals in hapblock 2 (Pglobal=.02). This significant finding is the result of a decrease in the frequency of haplotype TGTT, from 25% in control individuals to 15% in patients with BP disorder (Pspecific=.002). More...	Positive
rs11178997 - rs10748185 - rs2129575 - rs1843809	A-G-T-T	TPH2	global P-value = 0.02, P-value = 0.17	We also observed differences in haplotype distribution betwe...... We also observed differences in haplotype distribution between patients with BP disorder and control individuals in hapblock 2 (Pglobal=.02). This significant finding is the result of a decrease in the frequency of haplotype TGTT, from 25% in control individuals to 15% in patients with BP disorder (Pspecific=.002). More...	Negative
rs1487275 - rs4474484	A-G, C-A, A-A	TPH2	global P-value = 0.42	For hapblock 3, no significant association was identified wi...... For hapblock 3, no significant association was identified with BP disorder. More...	Negative
rs11178997 - rs10748185 - rs2129575 - rs1843809	T-G-G-T	TPH2	global P-value = 0.02, P-value = 0.74	We also observed differences in haplotype distribution betwe...... We also observed differences in haplotype distribution between patients with BP disorder and control individuals in hapblock 2 (Pglobal=.02). This significant finding is the result of a decrease in the frequency of haplotype TGTT, from 25% in control individuals to 15% in patients with BP disorder (Pspecific=.002). More...	Negative
rs11178997 - rs10748185 - rs2129575 - rs1843809	T-G-G-G	TPH2	global P-value = 0.02, P-value = 0.41	We also observed differences in haplotype distribution betwe...... We also observed differences in haplotype distribution between patients with BP disorder and control individuals in hapblock 2 (Pglobal=.02). This significant finding is the result of a decrease in the frequency of haplotype TGTT, from 25% in control individuals to 15% in patients with BP disorder (Pspecific=.002). More...	Negative

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

Gene	Statistical Values/Author Comments	Result Category
TPH2	Haplotype-based analysis of TPH2 in patients with UP and BP disorder and controls from northern Swed...... Haplotype-based analysis of TPH2 in patients with UP and BP disorder and controls from northern Swedish descent provides preliminary evidence for protective association in both disorders and thus supports a central role for TPH2 in the pathogenesis of affective disorders. More...	Positive

Genetic factors reported by this study for SZ and/or MDD

SNPs reported by this study for SZ/MDD

Disease	SNP	Related Gene(s)	Statistical Values	Description	Result Category
MDD	rs1843809	TPH2	genotypic P-value = 0.81, allelic P-value = 0.78		Negative
MDD	rs2129575	TPH2	genotypic P-value = 0.43, allelic P-value = 0.43		Negative
MDD	rs11178997	TPH2	genotypic P-value = 0.001, allelic P-value = 0.001	In the sample of patients with UP disorder and controls, significant association was observed for the A allele of rs11178997.	Positive
MDD	rs1487275	TPH2	genotypic P-value = 0.57, allelic P-value = 0.53		Negative
MDD	rs4131348	TBC1D15 TPH2	genotypic P-value = 0.54, allelic P-value = 0.54		Negative
MDD	rs4474484	TPH2	genotypic P-value = 0.38, allelic P-value = 0.35		Negative
MDD	rs10748185	TPH2	genotypic P-value = 0.48, allelic P-value = 0.48		Negative

Haplotypes reported by this study for SZ/MDD

Disease	Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Description	Result Category
MDD	rs4131348' target=_blank>rs4131348 - rs4131348' target=_blank>rs4131348	C-T	TPH2	global P-value = 0.54	No associations were observed between haplotypes in hapblocks 1 or 3 and UP disorder	Negative
MDD	rs11178997 - rs10748185 - rs2129575 - rs1843809	T-A-G-T	TPH2	global P-value = 0.04, P-value = 0.67	We identified a significant difference in haplotype distribution between patients with UP disorder and control individuals for hapblock 2 (Pglobal=.04), which is the result of a specific decrease in the frequency of haplotype AGTT, from 5% in control individuals to 0.4% in patients with UP disorder.	Negative
MDD	rs11178997 - rs10748185 - rs2129575 - rs1843809	T-G-T-T	TPH2	global P-value = 0.04, P-value = 0.94	We identified a significant difference in haplotype distribution between patients with UP disorder and control individuals for hapblock 2 (Pglobal=.04), which is the result of a specific decrease in the frequency of haplotype AGTT, from 5% in control individuals to 0.4% in patients with UP disorder.	Negative
MDD	rs11178997 - rs10748185 - rs2129575 - rs1843809	A-G-T-T	TPH2	global P-value = 0.04, P-value = 0.002	We identified a significant difference in haplotype distribution between patients with UP disorder and control individuals for hapblock 2 (Pglobal=.04), which is the result of a specific decrease in the frequency of haplotype AGTT, from 5% in control individuals to 0.4% in patients with UP disorder.	Positive
MDD	rs1487275 - rs4474484	A-G, C-A, A-A	TPH2	global P-value = 0.64	No associations were observed between haplotypes in hapblocks 1 or 3 and UP disorder	Negative
MDD	rs11178997 - rs10748185 - rs2129575 - rs1843809	T-G-G-T	TPH2	global P-value = 0.04, P-value = 0.60	We identified a significant difference in haplotype distribution between patients with UP disorder and control individuals for hapblock 2 (Pglobal=.04), which is the result of a specific decrease in the frequency of haplotype AGTT, from 5% in control individuals to 0.4% in patients with UP disorder.	Negative
MDD	rs11178997 - rs10748185 - rs2129575 - rs1843809	T-G-G-G	TPH2	global P-value = 0.04, P-value = 0.67	We identified a significant difference in haplotype distribution between patients with UP disorder and control individuals for hapblock 2 (Pglobal=.04), which is the result of a specific decrease in the frequency of haplotype AGTT, from 5% in control individuals to 0.4% in patients with UP disorder.	Negative

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
MDD	TPH2	Haplotype-based analysis of TPH2 in patients with UP and BP disorder and controls from northern Swedish descent provides preliminary evidence for protective association in both disorders and thus supports a central role for TPH2 in the pathogenesis of affective disorders.	Positive