Serotonin-Related Gene Polymorphisms and Central Nervous System Serotonin Function

Abstract

Central nervous system (CNS) serotonergic function affects a wide range of biological and behavioral functions affecting health and disease. Our objective in this study was to determine whether functional polymorphisms of the genes that encode for the serotonin transporter promoter (5HTTLPR) and monoamine oxidase A (MAOA-uVNTR) are associated with CNS serotonin turnoverFindexed by cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)Fin a community sample of healthy adults. Subjects were 165 community volunteers without current medical or psychiatric illness, stratified with respect to ethnicity, gender, and socioeconomic status who underwent inpatient evaluation in the General Clinical Research Center of a university medical center. A significant ethnicity  genotype interaction (P ¼ 0.008) indicated that, compared to the long/long and long/short genotypes, the 5HTTLPR short/short genotype was associated with higher CSF 5-HIAA levels in African Americans, but with lower levels in Caucasians. A gender  genotype interaction (P ¼ 0.04) indicated that 5HTTLPR short/short genotype was associated with higher 5-HIAA levels in women but with lower levels in men. MAOA-uVNTR 3.5 and 4 repeat alleles were associated with higher 5-HIAA (P ¼ 0.03) levels in men, but were unrelated to 5-HIAA levels in women. These findings suggest that effects of serotonin-related gene polymorphisms on CNS serotonergic function vary as a function of both ethnicity and gender. Further research will be required to determine the mechanism(s) underlying these differential effects. In the meanwhile, both ethnicity and gender should be taken into account in research evaluating effects of these and related polymorphisms on CNS serotonergic function, as well as the broad range of biological and behavioral functions that are regulated by CNS serotonergic function.

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…No reliable association was found between 5-HTLPR and the level of serotonin metabolite in the cerebrospinal fluid. 83,84 Lower availability of the 5-HT1A receptor in 5-HTTLPR s allele carriers has been reported and awaits replication. 85 While single measurements of 5-HTT availability and serotonin turnover have not provided a consistent picture, specific challenge tests may be better suited to reveal differences in central nervous reactivity associated with 5-HTTLPR.…”

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

“…In a sample of 165 healthy volunteers, males with high activity alleles displayed higher 5-HIAA than males with low activity alleles, whereas no differences were detected among women. 29 Zahlsman et al 31 in a clinical sample of 98 subjects found that high activity genotypes were associated with high HVA among males. Finally, in a study conducted on 88 healthy volunteers Jonsson et al 30 found that high activity genotypes were associated with higher HVA and 5-HIAA metabolite levels in women, but with lower CSF HVA levels in men.…”

“…28 Since MAOA is one of the major enzymes responsible for monoamine degradation within the CNS, it is plausible to assert that functional variants within the gene might contribute to interindividual differences in brain monoamine activity that, in turn, might alter the risk of developing antisocial-related disorders. To date, only a few studies [29][30][31] have evaluated the influence of MAOA-LPR on CSF monoamine metabolite levels in humans, with controversial results. In a sample of 165 healthy volunteers, males with high activity alleles displayed higher 5-HIAA than males with low activity alleles, whereas no differences were detected among women.…”

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

“…Some studies suggested that 5-HTTLPR polymorphisms moderate other monoamine metabolites, such as MHPG and HVA. Jonsson et al (1998) reported the relationship between 5-HTT polymorphisms and MHPG, although their results were not replicated (Williams et al, 2003). Furthermore, Å gren et al (1986) observed positive correlations between 5-HIAA and HVA in CSF and suggested a unidirectional relationship between 5-HIAA and HVA, from the former to the latter.…”