Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission

Abstract

Schizophrenia is a severe mental disorder, with a highly complex and heterogenous clinical presentation. Our current perspectives posit that the pathogenic mechanisms of this illness lie in complex arrays of gene × environment interactions. Furthermore, several findings indicate that males have a higher susceptibility for schizophrenia, with earlier age of onset and overall poorer clinical prognosis. Based on these premises, several authors have recently begun exploring the possibility that the greater schizophrenia vulnerability in males may reflect specific gene × sex (G×S) interactions. Our knowledge on such G×S interactions in schizophrenia is still rudimentary; nevertheless, the bulk of preclinical evidence suggests that the molecular mechanisms for such interactions are likely contributed by the neurobiological effects of sex steroids on dopamine (DA) neurotransmission. Accordingly, several recent studies suggest a gender-specific association of certain DAergic genes with schizophrenia. These G×S interactions have been particularly documented for catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), the main enzymes catalyzing DA metabolism. In the present review, we will outline the current evidence on the interactions of DA-related genes and sex-related factors, and discuss the potential molecular substrates that may mediate their cooperative actions in schizophrenia pathogenesis.

MB-COMTpromoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

“…Third, our sample was not matched for sex and COMT genotype by sex interaction effects have been reported for schizophrenia risk and a range of schizophrenia-associated traits (for a review see ref. 32). Although we could not identify a sex effect on MB-COMT methylation, which is in line with previous studies, 12,13 or a sex by methylation effect on DLPFC activity, sex remains an important variable when studying COMT.…”

Association between Silent Information Regulator 1 (SIRT1) gene polymorphisms and schizophrenia in a Chinese Han population

“…Historically, the predominant explanation for schizophrenia has been the "dopamine hypothesis", which states that genes involved in the dopaminergic signal transduction system contribute to the pathogenesis of schizophrenia and (or) to the expression of symptoms (Godar and Bortolato, 2014).…”

Childhood trauma, BDNF Val66Met and subclinical psychotic experiences. Attempt at replication in two independent samples

“…There is evidence of sex differences in healthy brain structure, function, and neurotransmission (Cosgrove et al, 2007). These differences can also be observed in relation to risk for psychopathology (Aleman et al, 2003;Cahill, 2006), showing males to have a higher susceptibility for schizophrenia, with earlier age of onset and an overall poorer clinical prognosis (Godar and Bortolato, 2014). Moreover, several studies have shown a different genetic effect on psychosis risk depending on the subject's sex, for example with the COMT gene (e.g.…”

“…All these studies point out the existence of a gender-specific mechanism underlying brain development and functioning, that may be led by sexual hormones (i.e. : estrogens and androgens) (see review by Godar and Bortolato, 2014). In addition, these biological differences may interact with gender-dimorphic sociocultural factors influencing the impact of childhood trauma on the brain-mind development and gene expression patterns.…”