d-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians

Abstract

The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.

Specific and common genes implicated across major mental disorders: A review of meta-analysis studies

“…DAOA (also known as G72/G30) encodes a protein that activates D-amino acid oxidase, which in turn degrades the gliotransmitter D-serine, an activator of NMDA type glutamate receptors. More recent studies suggest it also modulates DAO function as a negative effector, deaminating D-DOPA to a-keto acid which is transmitted to L-DOPA, which then enters the pathway to dopamine and homovanillic acid (Andreou et al, 2012). Of the rs3918342 polymorphism, the T variant, here associated with SZ and BD, has been shown to be associated with decreased homovanillic acid concentrations and disturbed dopamine turnover (Andreou et al, 2012).…”

Genetic variation in the G72 gene is associated with increased frontotemporal fiber tract integrity

“…Thus, variation at the G72 locus may also have influence on the dopaminergic system. For M23 and M24, the variants analyzed in the present study, association has been found with the concentration of the dopamine metabolite homovanillic acid in the cerebrospinal fluid of healthy individuals [25].…”

A microchip electrophoresis-mass spectrometric platform for fast separation and identification of enantiomers employing the partial filling technique

“…L-DOPA is a popular therapeutic drug to treat Parkinson's disease [6-8]. However, it's antipode, D-DOPA, is not only inactive, but also toxic [9-10]. Therefore, study of chirality in biological systems receives an increasing research attention, which has promoted method development for chiral analysis.…”