Abstract
Impaired brain serotonin neurotransmission is a potential component of the diathesis of major depression. Tryptophan hydroxylase-2 (TPH2), is the rate limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and a cause of impaired serotonin transmission. Here, we identify a novel TPH2 short isoform with truncated catalytic domain expressed in human brainstem, prefrontal cortex, hippocampus and amygdala. An exploratory study of 166 Caucasian subjects revealed association with major depression or suicide of a novel single nucleotide polymorphism (SNP) g.22879A>G located in exon 6 of this short isoform. This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Milak MS, Parsey RV, Keilp J, Oquendo MA, Malone KM, Mann JJ . Neuroanatomic correlates of psychopathologic components of major depressive disorder. Arch Gen Psychiatry 2005; 62: 397–408.
Stockmeier CA . Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 2003; 37: 357–373.
Mann J, Arango V . Abnormalities of Brain Structure and Function in Mood Disorder. Oxford University Press: San Francisco, 2003.
Sullivan PF, Neale MC, Kendler KS . Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.
Statham DJ, Heath AC, Madden PA, Bucholz KK, Bierut L, Dinwiddie SH et al. Suicidal behaviour: an epidemiological and genetic study. Psychol Med 1998; 28: 839–885.
Higley JD, Thompson WW, Champoux M, Goldman D, Hasert MF, Kraemer GW et al. Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoamine metabolites in rhesus monkeys (Macaca mulatta). Arch Gen Psychiatry 1993; 50: 615–623.
Rogers J, Martin LJ, Comuzzie AG, Mann JJ, Manuck SB, Leland M et al. Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid. Biol Psychiatry 2004; 55: 739–744.
Mann JJ, Arango V, Marzuk PM, Theccanat S, Reis DJ . Evidence for the 5-HT hypothesis of suicide. A review of post-mortem studies. Br J Psychiatry 1989; 155 (Suppl 8): 7–14.
Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H et al. Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology 2006; 31: 814–824.
Underwood MD, Khaibulina AA, Ellis SP, Moran A, Rice PM, Mann JJ et al. Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims. Biol Psychiatry 1999; 46: 473–483.
Boldrini M, Underwood MD, Mann JJ, Arango V . More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides. Brain Res 2005; 1041: 19–28.
Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG . Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 2004; 305: 217.
Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB et al. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 2005; 45: 11–16.
Glatt CE, Carlson E, Taylor TR, Risch N, Reus VI, Schaefer CA . Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45 11–16. Neuron 2005; 48: 704–705; author reply 705–706.
Van Den Bogaert A, De Zutter S, Heyrman L, Mendlewicz J, Adolfsson R, Van Broeckhoven C et al. Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major Depression. Neuron 45, 11–16. Neuron 2005; 48: 704; author reply 705–706.
Zhou Z, Peters EJ, Hamilton SP, McMahon F, Thomas C, McGrath PJ et al. Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Neuron 2005; 48: 702–703; author reply 705–706.
Bicalho MA, Pimenta GJ, Neves FS, Correa H, de Moraes EN, De Marco L et al. Genotyping of the G1463A (Arg441His) TPH2 polymorphism in a geriatric population of patients with major depression. Mol Psychiatry 2006; 11: 799–800.
Kelly TM, Mann JJ . Validity of DSM-III-R diagnosis by psychological autopsy: a comparison with clinician ante-mortem diagnosis. Acta Psychiatr Scand 1996; 94: 337–343.
Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R et al. SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004; 9: 1030–1036.
Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M . Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 2004; 56: 581–586.
Keilp JG, Waniek C, Goldman RG, Zemishlany Z, Alexander GE, Gibbon M et al. Reliability of post-mortem chart diagnoses of schizophrenia and dementia. Schizophr Res 1995; 17: 221–228.
First MB, Spitzer RL, Gibbon M, Williams JMG, Benjamin L . Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID II), Version 2.0. Biometrics Research Department, New York State Psychiatric Institute: New York, 1996.
Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE (eds). Reducing Suicide: A National Imperative. National Academies Press: Washington, D.C., 2002.
Spitzer RL, Williams JBW, Gibbon M, First MB . Structured Clinical Interview for DSM-III-R. Patient edition (SCID-P). American Psychiatric Press: Washington, D.C., 1990.
Emahazion T, Feuk L, Jobs M, Sawyer SL, Fredman D, St Clair D et al. SNP association studies in Alzheimer's disease highlight problems for complex disease analysis. Trends Genet 2001; 17: 407–413.
Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.
Purcell S, Cherny SS, Sham PC . Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.
Hubbard T, Barker D, Birney E, Cameron G, Chen Y, Clark L et al. The Ensembl genome database project. Nucleic Acids Res 2002; 30: 38–41.
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R et al. Complete sequencing and characterization of 21 243 full-length human cDNAs. Nat Genet 2004; 36: 40–45.
Kruglyak L, Nickerson DA . Variation is the spice of life. Nat Genet 2001; 27: 234–236.
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999; 22: 231–238.
Halushka MK, Fan JB, Bentley K, Hsie L, Shen N, Weder A et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22: 239–247.
Wang N, Akey JM, Zhang K, Chakraborty R, Jin L . Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am J Hum Genet 2002; 71: 1227–1234.
Zeggini E, Barton A, Eyre S, Ward D, Ollier W, Worthington J et al. Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition. BMC Genet 2005; 6: 21.
Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8–19.
Lopez AJ . Developmental role of transcription factor isoforms generated by alternative splicing. Dev Biol 1995; 172: 396–411.
Stasiv Y, Regulski M, Kuzin B, Tully T, Enikolopov G . The Drosophila nitric-oxide synthase gene (dNOS) encodes a family of proteins that can modulate NOS activity by acting as dominant negative regulators. J Biol Chem 2001; 276: 42241–42251.
Zhang K, Jin L . HaploBlockFinder: haplotype block analyses. Bioinformatics 2003; 19: 1300–1301.
Acknowledgements
This study was supported by PHS Grants MH40210, MH64168, MH63749, HG002915 and MH62185. We thank Drs A Dumas, B Mancevski and T Serafimova for contributing to collection of specimens and psychological autopsies.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Haghighi, F., Bach-Mizrachi, H., Huang, Y. et al. Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression. Mol Psychiatry 13, 813–820 (2008). https://doi.org/10.1038/sj.mp.4002127
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4002127
Keywords
This article is cited by
-
Modulation of depression-related behaviors by adiponectin AdipoR1 receptors in 5-HT neurons
Molecular Psychiatry (2021)
-
Effect of childhood general traumas on suicide attempt depends on TPH2 and ADARB1 variants in psychiatric patients
Journal of Neural Transmission (2017)
-
Association of TPH-1 and TPH-2 gene polymorphisms with suicidal behavior: a systematic review and meta-analysis
BMC Psychiatry (2014)
-
Serotonin Transporter Gene: A New Polymorphism May Affect Response to Antidepressant Treatments in Major Depressive Disorder
Molecular Diagnosis & Therapy (2014)
-
Tryptophan hydroxylase2 gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans
Molecular Psychiatry (2012)