Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia, part III: Molecular mechanisms

Schmitt, Andrea; Martins-de-Souza, Daniel; Akbarian, Schahram; Cassoli, Juliana S.; Ehrenreich, Hannelore; Fischer, André; Fonteh, Alfred N.; Gattaz, Wagner F.; Gawlik, Michael; Gerlach, Manfred; Grünblatt, Edna; Halene, Tobias B.; Hasan, Alkomiet; Hashimoto, K.; Kim, Yong Ku; Kirchner, Sophie-Kathrin; Kornhuber, Johannes; Kraus, Theo; Malchow, Berend; Nascimento, Juliana; Rossner, Moritz J.; Schwarz, Markus J.; Steiner, Johann; Talib, Leda Leme; Thibaut, Florence; Riederer, Peter; Falkai, Peter

doi:10.1080/15622975.2016.1224929

Cited by 32 publications

(23 citation statements)

References 260 publications

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“…Interestingly, we also observed increased HDAC1 levels in blood samples from mice exposed to ELS and in patients with schizophrenia. Although increased HDAC1 levels in blood are unlikely to contribute to schizophrenia-like phenotypes, this finding is in line with the view that adverse early life events and other risk factors induce similar gene expression changes in various cell types (46).…”

Section: Discussionsupporting

confidence: 72%

HDAC1 links early life stress to schizophrenia-like phenotypes

Bahari‐Javan

Varbanov

Halder

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

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Section: Discussionsupporting

confidence: 72%

HDAC1 links early life stress to schizophrenia-like phenotypes

Bahari‐Javan

Varbanov

Halder

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Blood-based studies of the ARMS and UHR, focusing on inflammation markers, have been undertaken and have shown largely consistent changes implicating a proinflammatory process in both psychosis and affective disorder [8,9]. These findings are supported and extended by discovery proteomic studies of first episode psychosis and schizophrenia implicating the acute-phase response, glucocorticoid receptor signalling, coagulation, and lipid and glucose metabolism [10,11]. Furthermore, inflammatory cytokines, chemokines, and growth factors have been assessed in the blood during the perinatal periods and during childhood in subjects who subsequently developed schizophrenia, and in those with a first episode psychosis [12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 86%

Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

et al. 2019

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The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.

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“…These conflicting results could at least partly be explained by differences in durations of illness between study samples since a positive correlation was observed between duration of illness and betaine concentrations [16] . Despite this research, a generally approved biomarker (panel) for schizophrenia still remains to be identified [18] .…”

Section: Introductionmentioning

confidence: 99%

The role of genetic variation of human metabolism for BMI, mental traits and mental disorders

Peters

Schijven

Hebebrand

et al. 2018

Molecular Metabolism

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ObjectiveThe aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disordersMethodsWe first assessed the number of single nucleotide polymorphisms (SNPs) with genome-wide significance for human metabolism (NHGRI-EBI Catalog). These 516 SNPs (216 independent loci) were looked-up in genome-wide association studies for association with body mass index (BMI) and the mental traits/disorders educational attainment, neuroticism, schizophrenia, well-being, anxiety, depressive symptoms, major depressive disorder, autism-spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's disease, bipolar disorder, aggressive behavior, and internalizing problems. A strict significance threshold of p < 6.92 × 10−6 was based on the correction for 516 SNPs and all 14 phenotypes, a second less conservative threshold (p < 9.69 × 10−5) on the correction for the 516 SNPs only.Results19 SNPs located in nine independent loci revealed p-values < 6.92 × 10−6; the less strict criterion was met by 41 SNPs in 24 independent loci. BMI and schizophrenia showed the most pronounced genetic overlap with human metabolism with three loci each meeting the strict significance threshold. Overall, genetic variation associated with estimated glomerular filtration rate showed up frequently; single metabolite SNPs were associated with more than one phenotype. Replications in independent samples were obtained for BMI and educational attainment.ConclusionsApproximately 5–10% of the regions involved in the regulation of blood/urine metabolite levels seem to also play a role in BMI and mental traits/disorders and related phenotypes. If validated in metabolomic studies of the respective phenotypes, the associated blood/urine metabolites may enable novel preventive and therapeutic strategies.

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Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia, part III: Molecular mechanisms

Cited by 32 publications

References 260 publications

HDAC1 links early life stress to schizophrenia-like phenotypes

HDAC1 links early life stress to schizophrenia-like phenotypes

Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

The role of genetic variation of human metabolism for BMI, mental traits and mental disorders

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