Tryptophan hydroxylase2 gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans

Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[(11)C]methyl-L-tryptophan (11C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized 11C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH2). In all, 46 healthy controls had PET 11C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH2 gene and its 5′ upstream region. Several TPH2 SNPs were associated with lower normalized blood-to-brain clearance of 11C-AMT in the OBFC. Dose–effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5′ upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC.

[1]  G. Rosoklija,et al.  Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression , 2008, Molecular Psychiatry.

[2]  Andreas Büttner,et al.  Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: a post-mortem study. , 2007, Journal of psychiatric research.

[3]  F. McMahon,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 , 2005, Neuron.

[4]  M. Gill,et al.  Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD , 2006, Molecular Psychiatry.

[5]  K. Sleegers,et al.  Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population. , 2006, Archives of General Psychiatry.

[6]  M Diksic,et al.  Image generation of serotonin synthesis rates using alpha-methyltryptophan and PET. , 1998, Journal of computer assisted tomography.

[7]  David A. Schwartz,et al.  Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression , 2005, Neuron.

[8]  Mirko Diksic,et al.  Image generation of serotonin synthesis rates using α-methyltryptophan and PET , 1998 .

[9]  Michael Bader,et al.  Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform , 2003, Science.

[10]  M. Phillips,et al.  A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder , 2008, Molecular Psychiatry.

[11]  R. Handa,et al.  Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei , 2009, Neuroscience.

[12]  D. Hommer,et al.  Brain Serotonin Synthesis Rates in Rhesus Monkeys Determined by [11C;[alpha;-Methyl-L-Tryptophan and Positron Emission Tomography Compared to CSF 5-Hydroxyindole-3-Acetic Acid Concentrations , 1998, Neuropsychopharmacology.

[13]  Pedro Rosa-Neto,et al.  Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. , 2004, Archives of general psychiatry.

[14]  Bengt Långström,et al.  5-Hydroxy-l-[β-11C]tryptophan versus α-[11C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain , 2007 .

[15]  R. T. Constable,et al.  Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation , 2005, Journal of Neural Transmission.

[16]  D. Veltman,et al.  Neuroimaging of response interference in twins concordant or discordant for inattention and hyperactivity symptoms , 2009, Neuroscience.

[17]  D. Goldman,et al.  Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. , 2005, Archives of general psychiatry.

[18]  M Diksic,et al.  Cortical trapping of alpha-[(11)C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males. , 2006, NeuroImage.

[19]  A C Roberts,et al.  Selective prefrontal serotonin depletion impairs acquisition of a detour‐reaching task , 2006, The European journal of neuroscience.

[20]  M. First,et al.  Structured clinical interview for DSM-IV axis II personality disorders : SCID-II , 1997 .

[21]  M Diksic,et al.  Differences between males and females in rates of serotonin synthesis in human brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Rodriguiz,et al.  Role of GSK3β in behavioral abnormalities induced by serotonin deficiency , 2008, Proceedings of the National Academy of Sciences.

[23]  R. Kahn,et al.  Genetic influences on human brain structure: A review of brain imaging studies in twins , 2007, Human brain mapping.

[24]  Alexander Strobel,et al.  Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation. , 2007, The international journal of neuropsychopharmacology.

[25]  J. Kennedy,et al.  Analysis of the novel TPH2 gene in bipolar disorder and suicidality , 2004, Molecular Psychiatry.

[26]  Mirko Diksic,et al.  Study of the brain serotonergic system with labeled α‐methyl‐l‐tryptophan , 2001 .

[27]  T. Lanthorn,et al.  Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants , 2008, PloS one.

[28]  M. Diksic,et al.  The inhibition of tryptophan hydroxylase, not protein synthesis, reduces the brain trapping of α-methyl-l-tryptophan: an autoradiographic study , 2002, Neurochemistry International.

[29]  Joel Paris,et al.  Brain Regional α-[11C]Methyl-l-Tryptophan Trapping in Impulsive Subjects With Borderline Personality Disorder , 2001 .

[30]  Dennis L. Murphy,et al.  Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter , 2005, Neuropharmacology.

[31]  Edgar Erdfelder,et al.  G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences , 2007, Behavior research methods.

[32]  Masami Nishikawa,et al.  An index of 5-HT synthesis changes during early antidepressant treatment: α-[11C]methyl-l-tryptophan PET study , 2008, Neurochemistry International.

[33]  S. Cichon,et al.  Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder. , 2007, Human molecular genetics.

[34]  Marco Leyton,et al.  Brain regional alpha-[11C]methyl-L-tryptophan trapping correlates with post-mortem tissue serotonin content and [11C]5-hydroxytryptophan accumulation. , 2005, The international journal of neuropsychopharmacology.

[35]  L. Siever.  Neurobiology of aggression and violence. , 2008, The American journal of psychiatry.

[36]  Pedro Rosa-Neto,et al.  A-( 11 C)Methyl-L-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide , 2006 .

[37]  O. Muzik,et al.  α[C-11]Methyl-l-Tryptophan PET Maps Brain Serotonin Synthesis and Kynurenine Pathway Metabolism , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[38]  T. Sotnikova,et al.  Tryptophan Hydroxylase-2 Controls Brain Serotonin Synthesis , 2004, Science.

[39]  H. Möller,et al.  SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression , 2004, Molecular Psychiatry.

[40]  G. Miller,et al.  Rhesus monkey tryptophan hydroxylase-2 coding region haplotypes affect mRNA stability , 2008, Neuroscience.

[41]  M. Novak,et al.  Tryptophan hydroxylase-2 gene polymorphisms in rhesus monkeys: association with hypothalamic–pituitary–adrenal axis function and in vitro gene expression , 2006, Molecular Psychiatry.

[42]  J. Dalley,et al.  Opposing effects of 5,7-DHT infusions into the orbitofrontal cortex and amygdala on flexible responding. , 2010, Cerebral cortex.

[43]  C. Benkelfat,et al.  Brain Serotonin Synthesis in Adult Males Characterized by Physical Aggression during Childhood: A 21-Year Longitudinal Study , 2010, PloS one.

[44]  M. Diksic,et al.  The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with α-[14C]methyl-l-tryptophan: An autoradiographic study , 2005, Brain Research Bulletin.

[45]  M. Lautenschlager,et al.  Characterization of a Functional Promoter Polymorphism of the Human Tryptophan Hydroxylase 2 Gene in Serotonergic Raphe Neurons , 2007, Biological Psychiatry.

[46]  T. Robbins,et al.  Differential Contributions of Dopamine and Serotonin to Orbitofrontal Cortex Function in the Marmoset , 2008, Cerebral cortex.

[47]  M. Alda,et al.  Effect of Tryptophan Hydroxylase-2 Gene Variants on Suicide Risk in Major Depression , 2007, Biological Psychiatry.

[48]  C. Benkelfat,et al.  Pet studies of serotonin synthesis in the human brain. , 1999, Advances in experimental medicine and biology.

[49]  G. Huether.  Tryptophan, serotonin, and melatonin : basic aspects and applications , 1999 .

[50]  R. Rothermel,et al.  Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children , 1999, Annals of neurology.

[51]  毛利 健太朗.  TPH2 is not a susceptibility gene for suicide in Japanese population , 2010 .

[52]  M Diksic,et al.  Statistical mapping analysis of serotonin synthesis images generated in healthy volunteers using positron-emission tomography and alpha-[11C]methyl-L-tryptophan. , 2000, Journal of psychiatry & neuroscience : JPN.

[53]  M. Nishikawa,et al.  Increasing blood oxygen increases an index of 5-HT synthesis in human brain as measured using α-[11C]methyl-l-tryptophan and positron emission tomography , 2005, Neurochemistry International.

[54]  M. Furey,et al.  Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression , 2008, Brain Structure and Function.

[55]  K. Lesch,et al.  Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals , 2009, Molecular Psychiatry.

[56]  Serotonergic Changes Produced by Repeated Exposure to Forced Swimming , 2008, Annals of the New York Academy of Sciences.

[57]  K. Lesch,et al.  Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice , 2008, Journal of Neural Transmission.

[58]  P. Blier,et al.  Effects of serotine receptors agonists, TFMPP and CGS12066B, on regional serotonin synthesis in the rat brain: an autoradiographic study , 2002, Journal of neurochemistry.

[59]  A. Hariri,et al.  A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity , 2005, Molecular Psychiatry.

[60]  C. Broeckhoven,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 , 2005, Neuron.

[61]  T. Lai,et al.  Association of functional polymorphisms of the human tryptophan hydroxylase 2 gene with risk for bipolar disorder in Han Chinese. , 2007, Archives of general psychiatry.

[62]  Yasuyuki Sakai,et al.  Cortical trapping of α-[11C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males , 2006, NeuroImage.

[63]  D. Collins,et al.  Automatic 3D Intersubject Registration of MR Volumetric Data in Standardized Talairach Space , 1994, Journal of computer assisted tomography.

[64]  Sylvain Houle,et al.  Seasonal variation in human brain serotonin transporter binding. , 2008, Archives of general psychiatry.

[65]  S. Kõks,et al.  Variation in tryptophan hydroxylase-2 gene is not associated to male completed suicide in Estonian population , 2009, Neuroscience Letters.

[66]  R. Plehm,et al.  Growth retardation and altered autonomic control in mice lacking brain serotonin , 2009, Proceedings of the National Academy of Sciences.

[67]  M L Phillips,et al.  Neural systems underlying voluntary and automatic emotion regulation: toward a neural model of bipolar disorder , 2008, Molecular Psychiatry.

[68]  T. Shinkai,et al.  Promoter polymorphism of second tryptophan hydroxylase isoform (TPH2) in schizophrenia and suicidality , 2005, Psychiatry Research.

[69]  M Diksic,et al.  Study of the brain serotonergic system with labeled α‐methyl‐l‐tryptophan , 2001, Journal of neurochemistry.

[70]  Jacqueline Spiegel-Cohen,et al.  F]fluorodeoxyglucose Positron Emission Tomography , 1999 .

[71]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[72]  M Diksic,et al.  Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder. , 2001, The American journal of psychiatry.

[73]  K. Sugden,et al.  Genes within the serotonergic system are differentially expressed in human brain , 2009, BMC Neuroscience.