Candidate genes for psychosis and their interaction with environmental factors: impact on psychosis-proneness = Gens candidats per psicosi i la seva interacció amb factors ambientals: impacte sobre la vulnerabilitat per a psicosi

Abstract

Schizophrenia is a severe and complex mental disorder that results in an inability to cope with life’s ordinary demands and routines. Normally, it appears in late adolescence, more frequently and developing earlier in males. It seems that disruption of the factors and pathways involved in brain development may cause modifications in neural structure, function or connectivity, leading to a final brain more susceptible to develop psychotic symptoms. The high diversity of symptoms intra- and inter-patient, makes the exploration of the aetiology and biological pathways underlying this illness, as well as its treatment, substantially difficult and suggests that alternative strategies may be more helpful for the study of such disease. Despite the psychotic phenotype has traditionally been thought as a dichotomous entity (i.e. “healthy” and “ill” subjects), evidence shows that psychosis exists as a distribution of symptoms expressed across a continuum ranging from nonclinical, subclinical to clinical manifestations with shared underlying etiological and developmental processes. Schizotypy and psychotic-like experiences are intermediate phenotypes of psychosis that measure the liability for psychosis-proneness. They can be found in healthy people and, although they are non-destabilising in the daily life, represent an increased risk for psychosis and are believed to share risk factors with the illness. The predisposition to develop psychopathology is determined by a complex combination and/or interplay between genetic, environmental, personal and epigenetic factors. The genes responsible for schizophrenia susceptibility have been tried to identify using classic candidate-gene research strategies and, more recently genome-wide association studies (GWAS), but despite interesting genes have been reported, the variance in liability explained by these genes is low. It seems thus, that these approaches are be missing epistatic and gene-environment interactions (GxE), which could explain part of the phenotype. Additionally, the study of intermediate phenotypes related with the disorder, instead of the illness itself, seems to be a good strategy that allows a better definition of the phenotype under study. Environmental factors also play a significant role in the aetiology of the disorder. Exposure to childhood trauma is a robust risk factor for psychosis that has been associated to increased schizotypy and psychotic-like experiences. It seems to affect mental health though alterations in the stress-related systems (i.e. HPA axis), however, not all subjects who experience these adverse events will develop psychosis, pointing out that other factors are modulating this response. Gene-environment interaction may be an important variable explaining the observed differential risk to develop psychosis. In this sense, genetic vulnerability predisposes an individual to the development of psychopathology and, when a level of stressors exceeds this vulnerability threshold, symptoms emerge. In this sense, polymorphic variants in genes involved in stress-response related genes (e.g. FKPB5), as well as those involved in neurodevelopment or neurotransmitter systems (e.g. COMT, BDNF, RGS4, ZNF804A), are interesting candidate genes. According to this, the present thesis aimed to explore the involvement of several schizophrenia candidate gens (i.e. COMT, RGS4 and ZNF804A) on the development of psychosis-related phenotypes in nonclinical samples, as well as the modulating role of some of these genes (i.e. BDNF, FKBP5, COMT) in the association between childhood trauma and psychosis-proneness phenotypes. In line with previous published research, the results of the present thesis showed interesting associations between COMT, RGS4 and ZNF804A genes and the psychosis-proneness phenotype (i.e. schizotypy and/or psychotic-like experiences) in nonclinical subjects, which seem to be sex-specific in some cases. Moreover, BDNF and FKBP5 show a modulating role on the association between childhood trauma and psychopathology in nonclinical subjects. In the case of FKBP5 we found that it modulates this association in relation to depressive-anxious symptoms. This thesis, shows the interest of exploring schizophrenia candidate genes in relation to psychosis-related phenotypes in nonclinical samples to study the underlying mechanisms involved in the development of psychopathology. The findings support the existence of a continuum psychotic phenotype with a multifactorial aetiology involving genes, environment and possibly other factors that are active agents in the formation of an individuals’ level of vulnerability. Moreover, they encourage future studies in samples across the psychosis continuum considering the multifactorial nature of the disorder and related traits by implementing the new developed methodologies and considering adequate sample sizes, appropriate statistical models, accurate phenotypic and environmental measures and also sexual differences.

L’objectiu de la present tesi doctoral era estudiar el paper de diversos gens candidats per esquizofrènia (COMT, RGS4 i ZNF804A) en la vulnerabilitat a patir psicosis en individus no clínics, així com en estudiar al paper modulador d’alguns d’aquests ganes (BDNF, FKBP5, COMT) en l’associació entre el trauma durant la infància i els fenotips de vulnerabilitat a psicosi. D’acord amb estudis previs, els resultats obtinguts mostraren una associació entre els gens COMT, RGS4 i ZNF804A i els fenotips de vulnerabilitat estudiats. A més, vam detectar que els gens BDNF i FKBP5 tenien un paper modulador en l’associació entre el trauma i la psicopatologia en els individus no clínics estudiats. En el cas de l’FKBP5 vam observar que estava modulant aquesta associació en relació amb símptomes depressius-ansiosos. Aquesta tesi mostra l’interès d’explorar gens candidats per esquizofrènia en relació a fenotips de vulnerabilitat pe psicosi en mostres no clíniques per estudiar els mecanismes subjacents al desenvolupament de psicopatologia. Els nostres resultats recolzen l’existència d’un fenotip contínuum de les psicosis que presenta una etiologia multifactorial, incloent gens, ambient i probablement altres factors que són agents actius en la formació del nivell de vulnerabilitat de cada individu. Addicionalment, mostren la necessitat de realitzar nous estudis futurs en mostres al llarg del contínuum (no clíniques, subclíniques i clíniques) considerant la naturalesa multifactorial de les psicosis i fenotips relacionats mitjançant l’ús de les noves metodologies desenvolupades i considerant mides mostrals adequades, mesures fenotípiques i ambientals acurades, així com diferències sexuals.