Association between Serotonin-Related Polymorphisms in 5HT2A, TPH1, TPH2 Genes and Bipolar Disorder in Korean Population

다국어 초록 (Multilingual Abstract)

Objective: The aim of the present study was to examine the association between serotoninrelated gene polymorphisms and bipolar disorder in the Korean population. In addition, we sought to explore the relationship between the clinical characteristics of bipolar patients and serotonin-related gene polymorphisms.
Methods: Inpatients with bipolar disorder (n=103) and control subjects (n=86) were genotyped for 5HT2A 1438A/G, tryptophan hydroxylase 1 (TPH1) 218 A/C, and TPH2 703G/T. We divided patients with bipolar disorder into two groups according to the presence of psychotic symptoms. The severity of their symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).
Results: There were no significant differences in the genotype distributions or allelic frequencies in the three serotonergic polymorphisms between patients with bipolar disorder and normal controls. There were significant differences in genotype distributions and allele frequencies of the 5-HT2A -1438A/G polymorphism between the psychotic mania group and the non-psychotic mania group (genotype: χ2=7.50, p=0.024; allele: χ2=5.92, p=0.015). However,after Bonferroni correction this signifact difference disappeared. We did not find significant differences in the genotype distributions or allelic frequencies in the TPH1 218 A/C and TPH2 703G/T polymorphisms between the psychotic mania group and non-psychotic mania group.
Conclusion: We failed to found the statistically significant association between three polymorphisms and bipolar disorder. However, there was a trend towards association between 5-HT2A -1438A/G polymorphism and psychotic symptom in bipolar disorder. Future research should seek to clarify this association.

참고문헌 (Reference)

1 오승용, "한국인 양극성 장애와 5-HT2A Receptor Gene Promoter-1438A/G Polymorphism과의 연관성 연구" 대한신경정신의학회 40 (40): 81-86, 2001

2 De Luca V, "Tryptophan hydroxylase 2 gene expression and promoter polymorphisms in bipolar disorder and schizophrenia" 183 : 378-382, 2005

3 Chen C, "The tryptophan hydroxylase gene influences risk for bipolar disorder but not major depressive disorder: results of meta-analyses" 10 : 816-821, 2008

4 McGuffin P, "The heritability of bipolar affective disorder and the genetic relationship to unipolar depression" 60 : 497-502, 2003

5 Bech P, "The BRPS: psychometric developments" 24 : 118-121, 1988

6 Parsons MJ, "The -1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity" 56 : 406-410, 2004

7 Yoon HK, "TPH2 -703G/T SNP may have important effect on susceptibility to suicidal behavior in major depression" 33 : 403-409, 2009

8 Walther DJ, "Synthesis of serotonin by a second tryptophan hydroxylase isoform" 299 : 76-, 2003

9 First M, "Structured clinical Interview for DSM-IV Axis I Disorder-Patient Edition (SCID-I/NP, version 2.0)" Biometrics Research Department, New York State Psychiatric Institute 1998

10 Stahl SM, "Stahl’s essential psychopharmacology-neuroscientific basis and practical application. 3rd edition" Cambridge University Press 484-, 2008

11 Zhang HY, "Serotonin2A receptor gene polymorphism in mood disorders" 41 : 768-773, 1997

12 Stahl SM, "Sahl’s essential psychopharmacology, neuroscientific basis and practical applications. 3rd edition" Cambridge U.P 359-361, 2008

13 Patel PD, "Robust and tissue-specific expression of TPH2 versus TPH 1 in rat raphe and pineal gland" 55 : 428-433, 2004

14 Myers RL, "Polymorphisms in the regulatory region of the human serotonin 5-HT2A receptor gene (HTR2A) influence gene expression" 61 : 167-173, 2007

15 Lai TJ, "Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan" 6 : 14-, 2005

16 Lopez VA, "Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts" 61 : 181-186, 2007

17 Lalovic A, "Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior" 114 : 533-540, 2002

18 Merikangas KR, "Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication" 64 : 543-552, 2007

19 Etain B, "Lack of association between 5-HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample" 129B : 29-33, 2004

20 Grigoroiu-Serbanescu M, "Investigation of the tryptophan hydroxylase 2 gene in bipolar I disorder in the Romanian population" 18 : 240-247, 2008

21 Gouzoulis-Mayfrank E, "Inhibition of return in the human 5HT2A agonist and NMDA antagonist model of psychosis" 31 : 431-441, 2006

22 Jequier E, "Further studies on tryptophan hydroxylase in rat brainstem and beef pineal" 18 : 1071-1081, 1969

23 Glenthoj BY, "Frontal dopamine D(2/3) receptor binding in drugnaive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender" 60 : 621-629, 2006

24 Arranz MJ, "Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine" 3 : 61-66, 1998

25 APA (American Psychological Association), "Diagnostic and statistical manual of mental disorders, 4th edition" American Psychiatric Press 1994

26 Lin YM, "Association of functional polymorphisms of the human tryptophan hydroxylase 2 gene with risk for bipolar disorder in Han Chinese" 64 : 1015-1024, 2007

27 Bellivier F, "Association between the tryptophan hydroxylase gene and manic- depressive illness" 55 : 33-37, 1998

28 Yoon HK, "Association between serotonin-related gene polymorphisms and suicidal behavior in depressive patients" 32 : 1293-1297, 2008

29 Manuck SB, "Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene" 45 : 603-614, 1999

30 Walther DJ, "A unique central tryptophan hydroxylase isoform" 66 : 1673-1680, 2003

31 Nielsen DA, "A tryptophan hydroxylase gene marker for suicidality and alcoholism" 55 : 593-602, 1998

32 Young RC, "A rating scale for mania: reliability, validity and sensitivity" 133 : 429-435, 1978

33 Spurlock G, "A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter" 3 : 42-49, 1998

34 Ohara K, "5-HT2A receptor gene promoter polymorphism-1438G/A and mood disorders" 9 : 1139-1141, 1998

35 Chee IS, "5-HT2A receptor gene promoter polymorphism -1438A/G and bipolar disorder" 11 : 111-114, 2001