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Background: Psychosis, particularly schizophrenia (SZ), is influenced by genetic and environmental factors. The neurodevelopmental hypothesis suggests that genetic factors affect neuronal circuit connectivity during perinatal periods, hence causing the onset of the diseases. In this study, we performed a genome-wide association study (GWAS) in a sample of the first episode of psychosis (FEP). Methods: A sample of 147 individuals diagnosed with non-affective psychosis and 102 controls were recruited and assessed. After venous blood and DNA extraction, the samples were genotyped. Genetic data underwent quality controls, genotype imputation, and a case-control genome-wide association study (GWAS). After the GWAS, results were investigated using an in silico functional mapping and annotation approach. Results: Our GWAS showed the association of 27 variants across 13 chromosomes at genome-wide significance (p < 1 × 10⁻⁷) and a total of 1976 candidate variants across 188 genes at suggestive significance (p < 1 × 10⁻⁵), mostly mapping in non-coding or intergenic regions. Gene-based tests reported the association of the SUFU (p = 4.8 × 10⁻⁷) and NCAN (p = 1.6 × 10⁻⁵) genes. Gene-sets enrichment analyses showed associations in the early stages of life, spanning from 12 to 24 post-conception weeks (p < 1.4 × 10⁻³) and in the late prenatal period (p = 1.4 × 10⁻³), in favor of the neurodevelopmental hypothesis. Moreover, several matches with the GWAS Catalog reported associations with strictly related traits, such as SZ, as well as with autism spectrum disorder, which shares some genetic overlap, and risk factors, such as neuroticism and alcohol dependence. Conclusions: The resulting genetic associations and the consequent functional analysis displayed common genetic liability between the non-affective psychosis, related traits, and risk factors. In sum, our investigation provided novel hints supporting the neurodevelopmental hypothesis in SZ and—in general—in non-affective psychoses. Full article

Epidemiological and clinical studies have uniformly reported an overrepresentation of females with very-late-onset schizophrenia-like psychotic disorder (VLOS), in stark contrast to the sex distribution of early-onset schizophrenia. Various explanatory models have been proposed to account for these sex differences, including (a) antidopaminergic effects of estrogen, (b) differential vulnerability to subtypes, (c) neurodegenerative differences between the sexes, and (d) and sex differences in age-related psychosocial and neurological risk factors; however, these models have not yet been critically evaluated for their validity. Keywords related to VLOS symptomatology, epidemiology, and sex/gender were entered into the PubMed, MEDLINE, and Google Scholar databases spanning all years. Through a narrative review of symptomatology and pathophysiology of VLOS, we examine the strengths and limitations of the proposed models. We present a comprehensive biopsychosocial perspective to integrate the above models with a focus on the role of neuroinflammation. There is significant room for further research into the mechanisms of VLOS that may help to explain the female preponderance; the effects of estrogen and menopause, neuroinflammation, and dopaminergic transmission; and their interaction with age-related and lifetime psychosocial stressors and underlying biological vulnerabilities. Full article