Interactions between variation in candidate genes and environmental factors in the etiology of schizophrenia and bipolar disorder : a systematic review

Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein 5 (FKBP5) have been explored. Almost consistently, these studies revealed that polymorphisms in COMT, BDNF, and FKBP5 genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD

Thyroid hormones in persons with schizophrenia: A systematic review and meta-analysis.

There is accumulating evidence that individuals with schizophrenia show altered levels of thyroid hormones. However, a qualitative and quantitative synthesis of findings in this field has not been performed so far. Therefore, we aimed to perform a systematic review and meta-analysis of studies investigating the levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4), total thyroxine (tT4), free triiodothyronine (fT3) and total triiodothyronine (tT3) in multiple-episode schizophrenia (MES) and first-episode psychosis (FEP). Electronic databases were searched from their inception until 30th May 2020 by two independent reviewers. Random-effects meta-analyses and meta-regression analyses were performed. Altogether, 19 studies were included. Persons with FEP had significantly lower TSH levels (5 studies, g = −0.26, 95%CI: −0.47 to −0.06, p = 0.013, I2 = 21.3%), higher fT4 levels (3 studies, g = 0.58, 95%CI: 0.15–1.01, p = 0.008, I2 = 64.6%) and lower tT3 levels (2 studies, g = −0.60, 95%CI: −0.82 to −0.37, p < 0.001, I2 = 0%) compared to controls. Elevated TSH levels were found in persons with MES (13 studies, g = 0.20, 95%CI: 0.02–0.39, p = 0.031, I2 = 50.0%). Our findings imply that the levels of TSH might be decreased in persons with FEP and increased in those with MES. Other alterations need to be confirmed by additional studies. These findings imply the need to monitor the levels of TSH and thyroid hormones from the onset of psychosis

Adverse childhood experiences and methylation of the FKBP5 gene in patients with psychotic disorders

Altered methylation of the FKBP5 gene has been observed in various mental disorders and attributed to the effects of adverse childhood experiences (ACEs). However, the level of FKBP5 methylation has not been investigated in patients with psychotic disorders. Therefore, in this study we aimed to determine the FKBP5 methylation in patients with psychosis and controls, taking into account the effects of ACEs. Participants were 85 patients with psychotic disorders, including first-episode psychosis (FEP) patients and acutely relapsed schizophrenia (SCZ-AR) patients, as well as 56 controls. The level of four CpG sites at the FKBP5 gene was determined in the peripheral blood leukocytes using pyrosequencing. After controlling for potential confounding factors, the level of FKBP5 methylation at one out of four tested CpG sites was significantly lower in FEP patients compared to other groups of participants. Significant main effects of parental antipathy and sexual abuse on the level of FKBP5 methylation were observed at the differentially methylated CpG site. Participants reporting this category of ACEs had significantly lower levels of FKBP5 methylation at this CpG site. Lower levels of FKBP5 methylation were associated with better cognitive performance and higher functional capacity in patients with psychosis. In controls, lower methylation of FKBP5 was related to worse performance of immediate memory and language skills. Our findings suggest that hypomethylation of the FKBP5 appears at early stages of psychosis and might be associated with a history of ACEs as well as less severe clinical manifestation

Genetic variants in transforming growth factor-β gene (TGFB1) affect susceptibility to schizophrenia

Immense body of evidence indicates that dysfunction of immune system is implicated in the etiology of schizophrenia. The immune theory of schizophrenia is supported by alterations in cytokine profile in the brain and peripheral blood. Given the strong genetic background of schizophrenia, it might be assumed that aberrant production of cytokines might be the consequence of genetic factors. This study aimed at investigating the association between schizophrenia susceptibility and selected functional polymorphisms in genes encoding cytokines including: interleukin-2 (IL2 −330T>G, rs2069756), interleukin-6 (IL-6 −174G>C, rs1800795), interferon-γ (IFNG +874T>A, rs2430561) as well as for the first time transforming growth factor-β1 (TGFB1 +869T>C, rs1800470 and +916G>C, rs1800471). We recruited 151 subjects with schizophrenia and 279 controls. There was a significant difference in the genotype distribution and allelic frequency of the TGFB1 +869T>C between patients with schizophrenia and healthy controls (p < 0.05). The risk of schizophrenia was more than two-fold higher in carriers of T allele (CT+TT genotypes) than individuals with CC genotype. Given documented gender differences in incidence of schizophrenia, we conducted separate analyses of male and female participants. We have shown that the association was significant in females, while in males it reached a trend toward statistical significance. To the best of our knowledge, it is the first report showing the association between TGFB1 +869T>C polymorphism and schizophrenia

Immune-inflammatory markers and psychosis risk: A systematic review and meta-analysis.

Abstract Subclinical inflammation has been associated with psychosis; however, it remains unknown whether this phenomenon appears also in the premorbid phase. Therefore, we performed a systematic review and meta-analysis of studies comparing peripheral blood levels of C-reactive protein (CRP) and cytokines between individuals at risk of psychosis and controls. Moreover, we tested the hypothesis that the levels of these markers may be different in high-risk converters versus non-converters. Two independent reviewers searched electronic databases until Dec 16th, 2020. After reviewing publication records, 16 studies (548 high-risk individuals and 559 controls) were included. Random-effects meta-analyses with Hedges' g as the effect size estimate were performed. Individuals at clinical risk of psychosis had significantly higher levels of interleukin-6 (IL-6) compared to controls (g = 0.33, 95%CI: 0.06–0.60, p = 0.018). Heterogeneity was not significant in this subgroup analysis. Changes in the levels of IL-6 in subjects at familial risk of psychosis were not significant (g = 0.04, 95%CI: −0.24 to 0.31, p = 0.798). The use of antidepressants was associated with significantly higher levels of IL-6 in high-risk individuals (Beta = 1.56, 95%CI: 0.60–2.53, p = 0.001). No significant differences in the levels of immune-inflammatory markers were found between high-risk converters and non-converters. Our findings suggest that individuals at clinical risk of psychosis show subclinical inflammation in terms of elevated IL-6 levels. This phenomenon might be related to the use of antidepressants. The present meta-analysis does not support the usefulness of single immune-inflammatory markers in predicting transition to psychosis

Effects of interactions between variation in dopaminergic genes, traumatic life events, and anomalous self-experiences on psychosis proneness : results from a cross-sectional study in a nonclinical sample

Background: there is a growing number of studies showing interactions between genetic polymorphisms associated with dopaminergic neurotransmission and traumatic life events (TLEs) on a risk of psychotic-like experiences (PLEs). Anomalous self-experiences (ASEs) have been associated both with TLEs as well as with PLEs. However, it remains unknown what is the role of ASEs in the complexity of gene - environment interactions on the emergence of PLEs. Patients and methods: we included 445 young adults - university students from three big cities in Poland. We used the Traumatic Events Checklist to assess TLEs, the Inventory of Psychotic-Like anomalous self-experiences in order to measure ASEs, and the Prodromal Questionnaire (PQ16) to record the level of PLEs. The following gene polymorphisms, related to dopaminergic neurotransmission, were determined: the catechol-O-methyltransferase (COMT) rs4680 polymorphism, the dopamine D2 receptor (DRD2) rs6277 polymorphism, and the dopamine transporter 1 (DAT1) rs28363170 polymorphism. Results: there was a significant effect of the interaction between the DAT1 polymorphism, a severity of ASEs, and a history of TLEs on the level of PLEs. Among the DAT1 10R/10R homozygotes with low level of ASEs, a severity of PLEs was significantly higher in individuals with a history of any TLEs. Higher scores of the PQ16 were associated with a greater severity of ASEs both in the DAT1 9R allele carriers and the DAT1 10R/10R homozygotes. Conclusion: our findings imply that genetic liability related to aberrant dopamine transport might impact the association between TLEs and PLEs in subjects with high levels of ASEs

Depression following major life transitions in women: a review and theory

Depression can occur due to common major life transitions, such as giving birth, menopause, retirement, empty-nest transition, and midlife crisis. Although some of these transitions are perceived as positive (e.g., giving birth), they may still lead to depression. We conducted a systematic literature review of the factors underlying the occurrence of depression following major life transition in some individuals. This review shows that major common life transitions can cause depression if they are sudden, major, and lead to loss (or change) of life roles (e.g., no longer doing motherly or fatherly chores after children leave family home). Accordingly, we provide a theoretical framework that explains depression caused by transitions in women. One of the most potential therapeutic methods of ameliorating depression associated with life transitions is either helping individuals accept their new roles (e.g., accepting new role as a mother to ameliorate postpartum depression symptoms) or providing them with novel life roles (e.g., volunteering after retirement or children leave family home) may help them overcome their illness