دانلود رایگان مقاله انگلیسی ژنتیک اسکیزوفرنی - اشپرینگر 2018

Abstract

Schizophrenia is a complex multifactorial disease, in most cases manifested as a result of the interaction of genetic and psychological factors, as well as certain environmental conditions. However, genetic factors certainly play a determining role in the predisposition to schizophrenia. The coefficient of heritability of schizophrenia is about 80%, which is typical of the most highly inherited multifactorial diseases. This review presents the results of the latest world studies of genetic factors in the development of schizophrenia, including epigenetic, genome-wide association studies, and next generation sequencing.

Next Generation Sequencing.

De novo Mutations and Schizophrenia

Exome-wide and genome-wide sequencing technologies can be used for case-control studies or search for de novo mutations by sequencing of the genomes of healthy parents and their sick child (trio). In the study by Xu et al. [82], exomes of 53 trios with a sporadic form of the disease were sequenced, as well as of 20 individuals of the control group. A total of 40 de novo mutations were found in 27 schizophrenic patients, including a potentially destructive mutation in the DGCR2 gene located in the 22q11.2 microdeletion region, which is known to have a significant genetic factor in the development of schizophrenia [82]. The results of the exome sequencing of genomic DNA in 399 individuals, including 105 probands with schizophrenia, 84 healthy siblings, and 210 healthy parents, suggest that a disturbance of neurogenesis in the prefrontal cortex of embryos can play a decisive role in the pathophysiology of schizophrenia [83]. Exome sequencing of 57 trios with sporadic or familial disease showed a 3.5-fold increase in the proportion of de novo nonsense mutations in the case of sporadic schizophrenia. Moreover, mutations were found in the genes also involved in autism (AUTS2, CHD8, and MECP2) and mental retardation (HUWE1 and TRAPPC9) and demonstrate the common genetic etiology of these diseases. Functionally the CHD8, MECP2, and HUWE1 genes participate in epigenetic regulation of transcription, which presumably can be an important risk mechanism [84]. The most wide-ranging exomewide studies have confirmed the cross of not only genes, but even mutations with similar functional effects for schizophrenia, autism spectrum disorders, and mental retardation [85, 86]. According to another UK10K multicenter study involving a total of 4264 patients with schizophrenia, 9343 healthy individuals, and 1077 trios, a genome-wide significance level (p = E5.6-09) was achieved with a rare polymorphic variant in the gene encoding the histone-methyltransferase complex SETD1A [87]. The same group showed the involvement of this SETD1A gene also in the pathogenesis of other mental diseases and established a crossover of schizophrenia with other diseases of neuronal development [87].