Immunogenetics of Schizophrenia in the Light of Modern Genome-Wide Association Studies

Abstract

Background: Immunological and genetic studies of schizophrenia form two areas of biological psychiatry in which significant progress has been made in recent years related to understanding the role of both neuroinflammation and genetic vulnerability in the development of this disease. However, data to explain the complicity of these two factors in the etiology and pathogenesis of schizophrenia are still insufficient. The aim of the review is to assess the degree of interaction between genetic predisposition and neuroinflammation in the pathogenetic mechanisms of schizophrenia based on the currently available information on genes associated with the immune system according to genome-wide association analysis (GWAS), as well as models that involve the interaction of immunological and genetic factors, including taking into account environmental adversities. Material and method: using keywords “genome-wide association study, Mendelian randomization, regulatory regions, maternal immunity activation, synaptic pruning, microglia” both in international and domestic databases the scientific publications selected. Conclusions: recent studies have identified genomic regions that contain genes involved in the functioning of the immune system. Particular attention is paid to the MHC region, and one of the most important achievements in its study is the establishment of the role of the complement gene (component C4A) in the formation of synapses and their abnormal elimination. Other genes, both inside and outside the major histocompatibility complex (MHC) region, are of interest, and their functions in the brain and their involvement in the pathogenesis of schizophrenia have yet to be elucidated. The establishment of causal relationships between GWAS data for schizophrenia and immunological indicators of inflammation using the Mendelian randomization (MR method) indicates that the increase in the level of pro-inflammatory cytokines in patients with schizophrenia is an intrinsic symptom of the disease, and is not a consequence of the course of the pathological process. Adverse environmental factors play an important role in the interaction of genetic variants associated with schizophrenia and microglial activation, which leads to synaptic disorders.