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


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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    • "These observations suggest a role for nongenetic and random genetic factors (O'Reilly & Singh, 1996; Singh & O'Reilly, 2009), including random developmental events (Singh et al., 2004), epigenetic mechanisms (Singh et al., 2002), and environmental factors (Torrey et al., 1997). Over 30 years of genetic research using linkage and association analysis have identified a number of promising linkages (Sullivan, 2005) and candidate genes (Hamilton, 2008; Karayiorgou & Gogos, 2006). Most of these results have been difficult to reliably replicate except in the case of a few variants, which have been associated across multiple studies, typically when large sample sizes are employed (Ripke et al., 2013; Torkamani et al., 2010). "
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    ABSTRACT: We have evaluated copy number variants (CNVs) in six monozygotic twin pairs discordant for schizophrenia. The data from Affymetrix® Human SNP 6.0 arrays™ were analyzed using Affymetrix® Genotyping Console™, Partek® Genomics Suite™, PennCNV, and Golden Helix SVS™. This yielded both program-specific and overlapping results. Only CNVs called by Affymetrix Genotyping Console, Partek Genomics Suite, and PennCNV were used in further analysis. This analysis included an assessment of calls in each of the six twin pairs towards identification of unique CNVs in affected and unaffected co-twins. Real time polymerase chain reaction (PCR) experiments confirmed one CNV loss at 7q11.21 that was found in the affected patient but not in the unaffected twin. The results identified CNVs and genes that were previously implicated in mental abnormalities in four of the six twin pairs. It included PYY (twin pairs 1 and 5), EPHA3 (twin pair 3), KIAA1211L (twin pair 4), and GPR139 (twin pair 5). They represent likely candidate genes and CNVs for the discordance of four of the six monozygotic twin pairs for this heterogeneous neurodevelopmental disorder. An explanation for these differences is ontogenetic de novo events that differentiate in the monozygotic twins during development.
    Twin Research and Human Genetics 02/2014; 17(02):1-13. DOI:10.1017/thg.2014.6 · 2.30 Impact Factor
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