Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers Dimitrios Andreou a , Peter Saetre a , Thomas Werge b , Ole A. Andreassen c,d , Ingrid Agartz a,e,f , Göran C. Sedvall a , Håkan Hall a,g , Lars Terenius a , Erik G. Jönsson a, ⁎ a Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, R5:00, SE-171 76 Stockholm, Sweden b Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark c TOP project, Division of Psychiatry, Ullevål University Hospital, University of Oslo, Oslo, Norway d TOP project, Institute of Psychiatry, University of Oslo, Oslo, Norway e Department of Psychiatry, Section Vinderen, University of Oslo, Oslo, Norway f Institute of Psychiatry, University of Oslo, Oslo, Norway g Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden abstract article info Article history: Received 19 June 2009 Received in revised form 6 November 2009 Accepted 16 November 2009 Keywords: Genetics Cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) Homovanillic acid (HVA) 3-methoxy-4-hydroxyphenylglycol (MHPG) Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. We investigated possible relationships between five TPH1 gene polymorphisms and cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the major dopamine metabolite homovanillic acid (HVA), and the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 132). The G-allele of the TPH1 rs4537731 (A-6526G) polymorphism was associated with 5-HIAA and HVA, but not MHPG concentrations. None of the other four TPH1 polymorphisms (rs211105, rs1800532, rs1799913 and rs7933505) were significantly associated with any of the monoamine metabolite concentrations. Two (rs4537731G/rs211105T/rs1800532C/rs1799913C/rs7933505G and rs4537731A/rs211105T/rs1800532C/rs1799913C/rs7933505G) of five common TPH1 five-allele haplotypes were associated with 5-HIAA and HVA concentrations in opposite directions. None of the common haplotypes was associated with MHPG concentrations in the CSF. The results suggest that TPH1 gene variation participates in the regulation of serotonin and dopamine turnover rates in the central nervous system of healthy human subjects. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Tryptophan hydroxylase (TPH) catalyses the first and rate-limiting reaction in the biosynthesis of serotonin (Cooper and Melcer, 1961). Two active isoforms (TPH1 and TPH2) of the enzyme have been identified (Kuhn et al., 1980; Hasegawa and Ichiyama, 1987; Walther et al., 2003; Zhang et al., 2004), and these are encoded by the TPH1 (11p15.3–p14) and TPH2 (12q21.1) genes, respectively. In humans both TPH1 and TPH2 are expressed in the central nervous system, including cortex, hypothalamus, thalamus, hippocampus, amygdale, cerebellum and raphe nuclei, with an approximately four-fold higher expression level of TPH2 mRNA in the raphe nuclei (Zill et al., 2007). In mice TPH2 mRNA is preferentially expressed in the brain, whereas TPH1 mRNA is mainly expressed in the pineal gland and the periphery (Walther et al., 2003). However, TPH1 is expressed preferentially during the late developmental stage in the mouse brain, and kinetic comparison in rats demonstrate that TPH1 shows higher affinity to tryptophan and stronger enzyme activity than TPH2 under conditions reflecting that of the developing brainstem (Nakamura et al., 2006). Together, this indicates that TPH1 may affect serotonin levels specifically in the developing brain. Concentrations of the major serotonin metabolite 5-hydroxyindo- leacetic acid (5-HIAA), the major dopamine metabolite homovanillic acid (HVA), and the major norepinephrine metabolite 3-methoxy-4- hydroxyphenylglycol (MHPG) in cerebrospinal fluid (CSF) have been used as indirect indices of monoamine turnover rate. Studies of human twins indicate that CSF 5-HIAA, HVA and MHPG concentra- tions are partly under genetic influence (Oxenstierna et al., 1986). CSF 5-HIAA and HVA concentrations are also heritable in other primates Psychiatry Research 180 (2010) 63–67 ⁎ Corresponding author. Tel.: +46 8 51772626; fax: +46 8 346563. E-mail address: erik.jonsson@ki.se (E.G. Jönsson). 0165-1781/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2009.11.018 Contents lists available at ScienceDirect Psychiatry Research journal homepage: www.elsevier.com/locate/psychres