Modern genome-wide association studies of mental disorders: focus on the mechanisms of inflammation

The objective of the analytical review is to analyze modern data on the genomics of mental disorders of various methodologies and designs with a focus on the results demonstrating the important role of inflammation mechanisms in the formation and implementation of genetic risk for the most common mental disorders. The analysis of the most important modern comparative genomic studies of several nosological forms of mental disorders (schizophrenia, bipolar disorder, and depression) showed that the mechanisms of formation of genetic risks for those nosological forms were largely associated with various aspects of inflammation. At the same time, the level of association and the direction of the effect differed significantly. Most genetic markers associated with C-reactive protein (CRP), which is an important and informative indicator of inflammatory processes, overlap with genetic markers of mental disorders. There are genetic markers associated simultaneously with CRP and mental disorders with mixed directions of effect. A stable and reproducible causal protective effect of genetically determined CRP level on the risk for developing schizophrenia and, conversely, a risk-increasing effect on the risk for developing bipolar disorder was found in several studies. In addition, schizophrenia and depression demonstrate opposite genomic associations with inflammation. Of extreme importance are the published data on a significant association of CRP levels with suicidal behavior in patients with mood disorders and with the first psychotic episode, in whom genetically determined high CRP levels exceed those in individuals with the probability of suicidal behavior. The results of modern genome-wide association studies, the creation and use of polygenic risk scores, and Mendelian randomization provide convincing direct and indirect evidence of a deep link at the genomic level between the mechanisms of formation of genetic risk of mental disorders and inflammation. The use of direct measurement of the main informative peripheral indicators of the inflammatory process, in particular the level of CRP, demonstrates broad possibilities for the analysis of cause-and-effect relationships between inflammation and mental disorders, the formation of which occurs at the genomic level and forms the pathophysiological phenomena of the etiology and pathogenesis of mental disorders. There is a number of methodological limitations in assessing the cause-and-effect relationships using genomic tools associated with the quality of phenotyping in assessing the clinical phenotypes, as well as with the characteristics of clinical biobank collections.