Review article

WHY SCHIZOPHRENIA GENETICS NEEDS EPIGENETICS: A REVIEW

Nadja Maric orcid.org/0000-0002-7051-853X ; Faculty of Medicine, University Belgrade, Serbia
Dragan Svrakic ; Department of Psychiatry, Washington University School of Medicine in St Louis, USA

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 usebased
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.

Keywords

schizophrenia; SZ; epigenetics; gene-environment interactions; review

Hrčak ID:

106199

URI

https://hrcak.srce.hr/106199

Publication date:

25.3.2012.

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