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Brief Report   |    
Genetic Association Analysis of Serotonin System Genes in Bipolar Affective Disorder
John B. Vincent, Ph.D.; Mario Masellis, M.Sc.; Jacob Lawrence, M.B., B.S., M.R.C.Psych.; Victor Choi, B.Sc.; Hugh M.D. Gurling, M.D., M.Phil., F.R.C.Psych.; Sagar V. Parikh, M.D.; James L. Kennedy, M.D.
Am J Psychiatry 1999;156:136-138.
Abstract

OBJECTIVE: This study examined the putative role of serotonin genes in the etiology of bipolar affective disorder. METHOD: Genetic association analysis was performed for individuals with bipolar affective disorder and unaffected subjects closely matched in age, sex, and ethnic background (N=103 in each group). The allele and genotype frequencies of polymorphisms at the genes for serotonin receptors HTR1A, HTR1Dα, HTR1Dβ, HTR2A, HTR2C, HTR7, tryptophan hydroxylase (TPH), and the serotonin transporter (hSERT) were compared in the two groups of subjects. RESULTS: Statistically significant positive associations were found for HTR2A and hSERT polymorphisms. However, results from an independent replication group of over 100 patients with bipolar affective disorder and their matched comparison subjects failed to confirm these associations. CONCLUSIONS: These results suggest that the serotonin genes studied are not associated with bipolar affective disorder, although transmission disequilibrium studies are required in order to confirm this conclusion.

Abstract Teaser
Figures in this Article

The role of the serotonin system in affective disorders has been the subject of extensive research R15601CHEDHFDD. In particular, many antidepressant drugs used for treating the depressive phase of bipolar affective disorder target the serotonin system R15601CHEDCHGB. Evidence from twin, adoption, and family studies suggests that a strong genetic factor is implicated in bipolar affective disorder R15601CHEBIDAC. A number of studies of candidate genes have also implicated serotonin genes in bipolar affective disorder, most notably HTR2A R15601CHEDBHJJ, HTR2C R15601CHEDAJFG, the serotonin transporter (hSERT) R15601CHEDEGCB, and tryptophan hydroxylase (TPH) R15601CHEDIDDF. In an attempt to replicate these prior studies and to provide a comprehensive assessment of the genetic involvement of the serotonin system in bipolar affective disorder, we conducted association studies of 10 polymorphisms in eight candidate genes from the serotonin system (HTR1A, HTR1Dα, HTR1Dβ, HTR2A, HTR2C, HTR7, hSERT, and TPH).

Individuals with bipolar affective disorder were recruited from the Bipolar Clinic at The Clarke Institute of Psychiatry, Toronto. They met the Research Diagnostic Criteria for bipolar affective disorder as determined by interview with the Schedule for Affective Disorders and Schizophrenia—Lifetime Version R15601CHEDDGIH. All of the bipolar subjects (N=103) were classified as having bipolar affective disorder, type I. The comparison subjects were recruited from staff members at Case Western Reserve University, Cleveland, and the local community around The Clarke Institute and had no history of major psychiatric illness. They were closely matched pairwise to the unrelated bipolar subjects in age (± 5 years), sex, and detailed ethnic background, including preimmigration roots. The mean ages of the affected subjects and the comparison group were similar (mean=39.16 years, SD=10.83, and mean=38.07 years, SD=10.41, respectively; t=0.73, df=204, p=0.46, two-tailed test). In both groups 57% (N=59) of the subjects were female and 43% (N=44) were male; 95% were Caucasian, 3% Oriental, and 2% Native Canadian. All individuals in the comparison group were above the median age at onset for bipolar affective disorder (18 years for males, 20 years for females) R15601CHECDGBB and thus had largely passed through the age of risk for developing the disorder.

In order to corroborate or refute any positive findings in the group with bipolar affective disorder, candidate genes demonstrating positive associations were examined in an independent replication sample of 109 individuals with bipolar affective disorder, type I (diagnosed with use of the same criteria that were used for the original study group) and a paired comparison group matched in sex and ethnicity (all patients and comparison subjects were Irish, Scottish, Welsh, or English with United Kingdom or Irish ancestry). Local ethical committee approval and written consent from each subject were obtained.

Blood was drawn and DNA was extracted. The genotype data were analyzed with chi-square tests (SPSS 7.0, Chicago). Linkage disequilibrium was assessed by a maximum likelihood method.

The polymorphisms genotyped in the patient and comparison groups and the results of the analysis are shown in T1. Polymerase chain reaction genotyping was performed as specified in the references in the table. Patient and comparison group genotypes were in Hardy-Weinberg equilibrium for all of the polymorphisms. The frequency of the C102 allele for the HTR2A MspI polymorphism was significantly elevated among the affected individuals. Also, a significant decrease in the frequency of heterozygotes was observed for the hSERT insertion/deletion polymorphism in the affected group. For the hSERT variable number of tandem repeats (VNTR) polymorphism, an increase in frequency of the 12/12 homozygotes was observed in the affected group.

These results become nonsignificant once multiple testing has been taken into consideration. Furthermore, within the replication sample, both hSERT polymorphisms and the HTR2A MspI polymorphism were not significantly different in the affected group and the comparison group. Strong linkage disequilibrium was observed between the hSERT VNTR and insertion/deletion polymorphisms (χ2=25.21, df=2, p<0.001). Linkage disequilibrium between the HTR2A MspI and BbvI polymorphisms was weak and not statistically significant. Under both dominant and recessive models, no haplotype associations with bipolar affective disorder were observed for the HTR2A and hSERT polymorphisms.

Overall, these results do not support a role for serotonin system genes in bipolar affective disorder, and they contradict several recent publications that have suggested positive associations with affective disorders R15601CHEDBHJJR15601CHEDIDDF. No conclusions can be drawn concerning HTR1A and HTR7, because the polymorphisms used were too infrequent, and thus the sample power was too low. However, since extensive screening for mutations within the coding region and promoters of these genes has been performed, and only very rare mutations have been found R15601CHEDJACD, R15601CHEBGGDC, it seems unlikely that mutations at these genes play a major role in bipolar affective disorder. A number of other important genes in the serotonin system, such as HTR4 and HTR5, have not yet been studied for genetic involvement in bipolar affective disorder owing to the lack of availability of suitable polymorphisms.

Our study differs from previous studies in that the comparison group was carefully matched pairwise in age, sex, and ethnicity, in order to diminish effects of population stratification. We also used an independent replication sample, which failed to corroborate the findings in the initial sample. With the use of a family-based comparison group versus ill individuals, as in a transmission disequilibrium test, the problem of population stratification is eliminated. In order to more fully investigate the genetic involvement of serotonin genes in bipolar affective disorder, we propose a transmission disequilibrium test study in a minimum of 200 individuals with bipolar affective disorder and both parents to analyze whether specific alleles at these genes are transmitted more frequently from parents to affected individuals (subjects for such a study are currently being collected).

Presented in part at Human Genome Mapping (HGM ’97), Toronto, March 6–8, 1997Received March 13, 1998; revision received June 11, 1998; accepted Aug. 4, 1998. From the Neurogenetics Section and the Bipolar Clinic, The Clarke Institute of Psychiatry, University of Toronto; and the Molecular Psychiatry Laboratory, Windeyer Institute of Medical Sciences, Department of Psychiatry and Behavioural Sciences, University College London Medical School, London. Address reprint requests to Dr. Kennedy, Neurogenetics Section, R-30, The Clarke Institute of Psychiatry, 250 College St., Toronto, ON M5T 1R8, Canada; kennedyj@cs.clarke-inst.on.ca (e-mail). Supported by a Medical Research Council (Canada)/Schizophrenia Society of Canada Research Fellowship to Dr. Vincent. Collection of the U.K. sample was enabled by a research lectureship to Dr. Lawrence from the Priory Hospital, Roehampton, London. The authors thank Wendy Hiscox for assistance in collecting the Canadian patient sample.

 
Meltzer H: Serotonergic dysfunction in depression. Br J Psychiatry Suppl  1989; 8:25–31
[PubMed]
 
Lucas JJ, Hen R: New players in the 5-HT receptor field: genes and knockouts. Trends Pharmacol Sci  1995; 16:246–252
[PubMed]
[CrossRef]
 
Gershon ES, Martinez M, Goldin LR, Gejman PV: Genetic mapping of common diseases: the challenges of manic-depressive illness and schizophrenia. Trends Genet  1990; 6:282–287
[PubMed]
[CrossRef]
 
Gutierrez B, Arranz M, Fananas L, Valles V, Guillamat R, van Os J, Collier D: 5HT2A receptor gene and bipolar affective disorder (letter). Lancet  1995; 346:969
[PubMed]
[CrossRef]
 
Gutierrez B, Fananas L, Arranz M, Valles V, Guillamat R, van Os J, Collier D: Allelic association analysis of the 5HT2C receptor gene in bipolar affective disorder. Neurosci Lett  1996; 212:65–67
[PubMed]
[CrossRef]
 
Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwin GM, Smith CAD: Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet  1996; 347:731–733
[PubMed]
[CrossRef]
 
Bellivier F, Leboyer M, Courtet P, Buresi C, Beaufils B, Samolyk D, Allilaire JF, Feingold J, Mallet J, Malafosse A: Association between the tryptophan hydroxylase gene and manic-depressive illness. Arch Gen Psychiatry  1998; 55:33–37
[PubMed]
[CrossRef]
 
Spitzer RL, Endicott J: Schedule for Affective Disorders and Schizophrenia—Lifetime Version (SADS-L). New York, New York State Psychiatric Institute, Biometrics Research, 1978
 
Burke KC, Burke JD, Regier DA, Rae DS: Age at onset of selected mental disorders in five community populations. Arch Gen Psychiatry  1990; 47:511–518
[PubMed]
 
Bolos AM, Goldman D, Dean M: Dinucleotide repeat and alu repeat polymorphisms at the 5HT1A (HTR1A) receptor gene. Psychiatr Genet  1993; 3:235–240
[CrossRef]
 
Erdmann J, Shimron-Abarbanell D, Rietschel M, Albus M, Maier W, Korner J, Bondy B, Chen K, Shih JC, Knapp M, Propping P, Nothen MM: Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet  1996; 97:614–619
[PubMed]
[CrossRef]
 
Erdmann J, Nothen MM, Shimron-Abarbanell D, Rietschel M, Albus M, Borrmann M, Maier W, Franzek E, Korner J, Weigelt B, Fimmers R, Propping P: The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder. Molecular Psychiatry  1996; 1:392–397
[PubMed]
 
Warren JT Jr, Peacock ML, Fink JK: A RsaI polymorphism in the human serotonin receptor gene (HTR1A); detection by DGGE and RFLP analysis. Hum Mol Genet  1992; 1:778
 
Erdmann J, Shimron-Abarbanell D, Cichon S, Albus M, Maier W, Lichtermann D, Minges J, Reuner U, Franzek E, Ertl MA, Hebebrand J, Remschmidt H, Lehmkuhl H, Lehmkuhl G, Poustka F, Schmidt M, Fimmers R, Korner J, Rietschel M, Propping P, Nothen M: Systematic screening for mutations in the promoter and the coding region of the 5HT1A gene. Am J Med Genet Neuropsychiatr Genet  1995; 60:393–399
[CrossRef]
 
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References

Meltzer H: Serotonergic dysfunction in depression. Br J Psychiatry Suppl  1989; 8:25–31
[PubMed]
 
Lucas JJ, Hen R: New players in the 5-HT receptor field: genes and knockouts. Trends Pharmacol Sci  1995; 16:246–252
[PubMed]
[CrossRef]
 
Gershon ES, Martinez M, Goldin LR, Gejman PV: Genetic mapping of common diseases: the challenges of manic-depressive illness and schizophrenia. Trends Genet  1990; 6:282–287
[PubMed]
[CrossRef]
 
Gutierrez B, Arranz M, Fananas L, Valles V, Guillamat R, van Os J, Collier D: 5HT2A receptor gene and bipolar affective disorder (letter). Lancet  1995; 346:969
[PubMed]
[CrossRef]
 
Gutierrez B, Fananas L, Arranz M, Valles V, Guillamat R, van Os J, Collier D: Allelic association analysis of the 5HT2C receptor gene in bipolar affective disorder. Neurosci Lett  1996; 212:65–67
[PubMed]
[CrossRef]
 
Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwin GM, Smith CAD: Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet  1996; 347:731–733
[PubMed]
[CrossRef]
 
Bellivier F, Leboyer M, Courtet P, Buresi C, Beaufils B, Samolyk D, Allilaire JF, Feingold J, Mallet J, Malafosse A: Association between the tryptophan hydroxylase gene and manic-depressive illness. Arch Gen Psychiatry  1998; 55:33–37
[PubMed]
[CrossRef]
 
Spitzer RL, Endicott J: Schedule for Affective Disorders and Schizophrenia—Lifetime Version (SADS-L). New York, New York State Psychiatric Institute, Biometrics Research, 1978
 
Burke KC, Burke JD, Regier DA, Rae DS: Age at onset of selected mental disorders in five community populations. Arch Gen Psychiatry  1990; 47:511–518
[PubMed]
 
Bolos AM, Goldman D, Dean M: Dinucleotide repeat and alu repeat polymorphisms at the 5HT1A (HTR1A) receptor gene. Psychiatr Genet  1993; 3:235–240
[CrossRef]
 
Erdmann J, Shimron-Abarbanell D, Rietschel M, Albus M, Maier W, Korner J, Bondy B, Chen K, Shih JC, Knapp M, Propping P, Nothen MM: Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet  1996; 97:614–619
[PubMed]
[CrossRef]
 
Erdmann J, Nothen MM, Shimron-Abarbanell D, Rietschel M, Albus M, Borrmann M, Maier W, Franzek E, Korner J, Weigelt B, Fimmers R, Propping P: The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder. Molecular Psychiatry  1996; 1:392–397
[PubMed]
 
Warren JT Jr, Peacock ML, Fink JK: A RsaI polymorphism in the human serotonin receptor gene (HTR1A); detection by DGGE and RFLP analysis. Hum Mol Genet  1992; 1:778
 
Erdmann J, Shimron-Abarbanell D, Cichon S, Albus M, Maier W, Lichtermann D, Minges J, Reuner U, Franzek E, Ertl MA, Hebebrand J, Remschmidt H, Lehmkuhl H, Lehmkuhl G, Poustka F, Schmidt M, Fimmers R, Korner J, Rietschel M, Propping P, Nothen M: Systematic screening for mutations in the promoter and the coding region of the 5HT1A gene. Am J Med Genet Neuropsychiatr Genet  1995; 60:393–399
[CrossRef]
 
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