Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis

Abstract

BackgroundHomovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis.MethodsWe have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder.ResultsThere were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls.ConclusionsThe present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.

Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis

“…However, we failed to identify significant changes in metabolites of this pathway in blood, and the majority of these metabolites were not detectable in human CSF (5-hydroxytryptophan, kynurenine and tryptophan being the exceptions). Previous studies have shown that single nucleotide polymorphisms in tryptophan 5-monooxygenase could be linked to neuropsychiatric disorders [56]. A substantial increase in 5-hydroxytryptophan is seen in aromatic L-amino acid decarboxylase deficiency, where patients are rendered in a vegetative state [57] and treatments with 5-hydroxytryptophan have been used to treat depression caused by serotonin deficiencies [58].…”

Genetic variability of serotonin pathway associated with schizophrenia onset, progression, and treatment

“…Enzymes involved in 5‐HT metabolism are less well‐studied than 5‐HT transporters and HTRs. However, they can importantly affect the concentration of 5‐HT breakdown products (Andreou et al, ). Some enzymes involved in 5‐HT metabolism also play a role in other neurotransmitter pathways, such as MAOA which breaks down dopamine as well as 5‐HT (Qiu et al, ).…”

Molecular aspects of monoamine oxidase B

“…Other studies have examined the changes in metabolites associated with polymorphisms confirming that higher activity alleles show more metabolism of dopamine, noradrenaline and serotonin (Aklillu et al, 2009, Andreou et al, 2014. Elevated MAO activity had already been observed in AD-type dementia in 1980 (Adolfsson et al, 1980).…”