Contemporary Genome-Wide Association Studies in Depression: The Critical Role of Phenotyping

The need to use large cohorts to identify genetic risk loci for mental disorders has led to the dilemma of phenotyping quality. This dilemma is particularly relevant to mental disorders common in the population, such as depression (prevalence throughout life up to 16.2%). On the one hand, there is the very resource-consuming method of acquiring data on patients by physicians applying diagnostic criteria for one of the classifications of mental disorders (DSM-5/ICD-10). On the other hand, there is the popular method of minimal phenotyping using patient registers, with self-assessments by respondents on the symptoms, diagnoses, and treatment of depression. There is currently no ideal method for phenotyping this disorder as a result of the understandable focus of all diagnostic methods only on its clinical symptoms. Active use of minimal phenotyping in genome-wide association studies (GWAS) has led to significant increases in both the clinical and genetic heterogeneity of depression. On the other hand, an important limitation to the use of DSM-5/ICD-10 is the high cost of phenotyping due to the involvement of medical specialists. Thus, the most rational approach is to use electronic diagnostic questionnaires based on DSM-5/ICD-10 criteria. This approach will accelerate increases in the power of studies but retain all the internal contradictions typical of the official diagnostic classifications (phenotype heterogeneity, lack of objective diagnostic criteria, the categorial approach, etc.). This increases the critical role of psychiatric epidemiology both in developing standardized tools for operationalized diagnostic criteria and in running future GWAS research by introducing new phenotypic subtypes of depression and its dimensions.