The Genetics of Schizophrenia

Department of Genetics, Psychiatry, and Epidemiology, University of North Carolina, Chapel Hill, USA.
PLoS Medicine (Impact Factor: 14.43). 08/2005; 2(7):e212. DOI: 10.1371/journal.pmed.0020212
Source: PubMed

ABSTRACT Research into the etiology of schizophrenia, particularly the possible genetic basis, has never been as interesting and as provocative as in the past three years. Sullivan looks critically at the key research.

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    • "Genetics may help to identifying the biological hallmarks of schizophrenia. The heritability of schizophrenia is around 80% (Sullivan, 2005). Thus, the analysis of the genetic variations that segregate patients vs. controls may inform the biological events that drive schizophrenia. "
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    ABSTRACT: schizophrenia is a complex mental disorder marked by severely impaired thinking, delusional thoughts, hallucinations and poor emotional responsiveness. The biological mechanisms that lead to schizophrenia may be related to the genetic background of patients. Thus, a genetic perspective may help to unravel the molecular pathways disrupted in schizophrenia. In the present work, we used a molecular pathway analysis to identify the molecular pathways associated with schizophrenia. We collected data of genetic loci previously associated with schizophrenia, identified the genes located in those positions and created the metabolic pathways that are related to those genes' products. These pathways were tested for enrichment (a number of SNPs associated with the phenotype significantly higher than expected by chance) in a sample of schizophrenic patients and controls (4,486 and 4,477, respectively). The molecular pathway that resulted from the identification of all the genes located in loci previously found to be associated with schizophrenia was found to enriched, as expected (permutated p(10(6))=9.9999e-06).We found 60 SNPs amongst 30 different genes with a strong association with schizophrenia. The genes are related to the pathways related to neurodevelopment, apoptosis, vesicle traffic, immune response and MAPk cascade. The pathway related to the toll-like receptor family seemed to play a central role in the modulation/connection of various pathways whose disruption leads to schizophrenia. This pathway is related to the innate immune system, further stressing the role of immunological-related events in increasing the risk to schizophrenia. Copyright © 2014. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2014; 59. DOI:10.1016/j.pnpbp.2014.12.009 · 3.69 Impact Factor
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    • "Increased Cell-to-Cell Variation in the HSF1 Activation Level among NPCs Differentiated from hiPSCs Derived from Subjects Diagnosed with SZ Lastly, we examined the possibility that HSF1 activation is altered in patients with neuropsychiatric disorders that are thought to be linked to exposure to harsh prenatal environmental conditions. We used iPSCs derived from patients with SZ (Brennand et al., 2011) as a model because a number of prenatal environmental risk factors have been reported to potentially cause or contribute to SZ (Sullivan, 2005) and because abnormalities in HSF1-Hsp70 signaling have been demonstrated in SZ (see Discussion). Two independent NPC lines from four patients with SZ were employed in the experiments. "
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    ABSTRACT: Prenatal exposure of the developing brain to various environmental challenges increases susceptibility to late onset of neuropsychiatric dysfunction; still, the underlying mechanisms remain obscure. Here we show that exposure of embryos to a variety of environmental factors such as alcohol, methylmercury, and maternal seizure activates HSF1 in cerebral cortical cells. Furthermore, Hsf1 deficiency in the mouse cortex exposed in utero to subthreshold levels of these challenges causes structural abnormalities and increases seizure susceptibility after birth. In addition, we found that human neural progenitor cells differentiated from induced pluripotent stem cells derived from schizophrenia patients show higher variability in the levels of HSF1 activation induced by environmental challenges compared to controls. We propose that HSF1 plays a crucial role in the response of brain cells to prenatal environmental insults and may be a key component in the pathogenesis of late-onset neuropsychiatric disorders.
    Neuron 04/2014; 82(3). DOI:10.1016/j.neuron.2014.03.002 · 15.05 Impact Factor
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    • "Maternal stress during the prenatal period has been related to schizophrenia, depression, and anxiety (Markham and Koenig, 2011), which also applies to autism spectrum disorder and attention deficit hyperactivity disorder (Class et al., 2014). It includes maternal psychological stress exposure e.g., due to bereavement, unwantedness of a pregnancy, natural disaster or war experience (Brown, 2002; Spauwen et al., 2004; Sullivan, 2005; Meli et al., 2012). Children of mothers who experienced e.g., death of relatives or other serious life events developed schizophrenia to a higher degree (Khashan et al., 2008). "
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    ABSTRACT: During the last decades, schizophrenia has been regarded as a developmental disorder. The neurodevelopmental hypothesis proposes schizophrenia to be related to genetic and environmental factors leading to abnormal brain development during the pre- or postnatal period. First disease symptoms appear in early adulthood during the synaptic pruning and myelination process. Meta-analyses of structural MRI studies revealing hippocampal volume deficits in first-episode patients and in the longitudinal disease course confirm this hypothesis. Apart from the influence of risk genes in severe psychiatric disorders, environmental factors may also impact brain development during the perinatal period. Several environmental factors such as antenatal maternal virus infections, obstetric complications entailing hypoxia as common factor or stress during neurodevelopment have been identified to play a role in schizophrenia and bipolar disorder, possibly contributing to smaller hippocampal volumes. In major depression, psychosocial stress during the perinatal period or in adulthood is an important trigger. In animal studies, chronic stress or repeated administration of glucocorticoids have been shown to induce degeneration of glucocorticoid-sensitive hippocampal neurons and may contribute to the pathophysiology of affective disorders. Epigenetic mechanisms altering the chromatin structure such as histone acetylation and DNA methylation may mediate effects of environmental factors to transcriptional regulation of specific genes and be a prominent factor in gene-environmental interaction. In animal models, gene-environmental interaction should be investigated more intensely to unravel pathophysiological mechanisms. These findings may lead to new therapeutic strategies influencing epigenetic targets in severe psychiatric disorders.
    Frontiers in Neuroscience 02/2014; 8(8):19. DOI:10.3389/fnins.2014.00019 · 3.66 Impact Factor
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