A current view of the genetics of substance use disorders and development of metabolic comorbidities

The review focuses on the main challenges and achievements of genomic research on substance use disorders (SUDs), which include drug dependence, alcohol abuse, and smoking, as well as the state-of-the-art of the comorbidity of this spectrum with metabolic disorders, on the example of metabolic syndrome.A particular emphasis is placed on genomic studies of SUDs and related health conditions in Eastern European countries, which are traditionally not or poorly included in large genome-wide association studies (GWASs).SUDs have a high degree of comorbidity and significantly increase the risk of many diseases, including other psychiatric and metabolic disorders.The question of pathophysiological and genetic causes of comorbidity attracts attention in current research and some results are already shown (genetic correlation and pleiotropic effects).At the same time, genomic studies of SUDs, even in well-studied populations, are still not sufficiently informative, and polygenic risk scores only slightly improves performance of the existing SUDs risk prognostic models.This might be partly due to the fact that SUDs represent a complex set of interrelated phenotypes rather than a set of distinct nosologic forms, which is usually not taken into account in the design of the majority of GWASs.The high level of polygenicity of these phenotypes also increases the sample number expectations to ensure sufficient statistical power.A multi-phenotype approach to genomic studies of such complex, highly correlated phenotypes can increase their efficiency.