title: Why schizophrenia genetics needs epigenetics: a review.
abstract: Schizophrenia (SZ) is a highly heritable disorder, with about 80% of the variance attributable to genetic factors. There is accumulating evidence that both common genetic variants with small effects and rare genetic lesions with large effects determine risk of SZ. As recently shown, thousands of common single nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of the underlying genetic risk of SZ. On the other hand, rare and large copy number variants (CNVs) with high but incomplete penetrance, variable in different individual, could explain about additional 30% of SZ cases. Although these rare CNVs frequently develop de novo, it is not clear whether they affect risk independently or via interaction with a polygenic liability in the background. Finally, the role of environmental risk factors has been well established in SZ. Environmental factors are rarely sufficient to cause SZ independently, but act in parallel or in synergy with the underlying genetic liability. Epigenetic misregulation of the genome and direct CNS injury are probably the main mechanism to mediate prenatal environmental effects (e.g., viruses, ethanol, or nutritional deficiency) whereas postnatal risk factors (e.g., stress, urbanicity, cannabis use) may also affect risk via use-based potentiation of vulnerable CNS pathways implicated in SZ. In this review, we outline a general theoretical background of epigenetic mechanisms involved in GxE interactions, and then discuss epigenetic and neurodevelopmental features of SZ based on available information from genetics, epigenetics, epidemiology, neuroscience, and clinical research. We argue that epigenetic model of SZ provides a framework to integrate a variety of diverse empirical data into a powerful etiopathogenetic synthesis. The promising future of this model is the possibility to develop truly specific prevention and treatment strategies for SZ.
authors.affiliation: Faculty of Medicine, University Belgrade, Serbia. nadjamaric@yahoo.com
authors.forename: Nadja P
authors.initials: NP
authors.lastname: Maric
authors.forename: Dragan M
authors.initials: DM
authors.lastname: Svrakic
mesh_terms: D001921:Brain / Q000503:physiopathology; D056915:DNA Copy Number Variations / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics* / Q000502:physiology; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics / Q000523:psychology; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology; D012307:Risk Factors; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012565:Schizophrenic Psychology