Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci from published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent singlenucleotide polymorphisms were genome-wide significant (P < 5 × 10 -8 ) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis and 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.The lives lost, impacts on individuals and families, and socioeconomic costs attributable to substance use reflect a growing public health crisis 1 . For example, in the United States, 13.5% of deaths among young adults 2 are attributable to alcohol, smoking is the leading risk factor for mortality in males 3 , and the odds of dying by opioid overdose are greater than those of dying in a motor vehicle crash 4 . Despite the large impact of substance use and substance use disorders 5 , there is limited knowledge of the molecular genetic underpinnings of addiction broadly.

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In a cohort of schizophrenia inpatients CYP2D6 metabolic activity affects mean AP daily dose only in the presence of DRD2 Taq1A polymorphic allele. CYP2D6 metabolic activity correlates independently from DRD2 Taq1A polymorphism with hospital stay duration. Subpopulation of schizophrenia inpatients with altered CYP2D6 activity (PMs and UMs) carriers of Taq1A polymorphisms needs special attention of clinicians in aligning of AP treatment.

We provide an overview of the recent achievements in psychiatric genetics research in the Russian Federation and present genotype-phenotype, population, epigenetic, cytogenetic, functional, ENIGMA, and pharmacogenetic studies, with an emphasis on genome-wide association studies. The genetic backgrounds of mental illnesses in the polyethnic and multicultural population of the Russian Federation are still understudied. Furthermore, genetic, genomic, and pharmacogenetic data from the Russian Federation are not adequately represented in the international scientific literature, are currently not available for meta-analyses and have never been compared with data from other populations. Most of these problems cannot be solved by individual centers working in isolation but warrant a truly collaborative effort that brings together all the major psychiatric genetic research centers in the Russian Federation in a national consortium. For this reason, we have established the Russian National Consortium for Psychiatric Genetics (RNCPG) with the aim to strengthen the power and rigor of psychiatric genetics research in the Russian Federation and enhance the international compatibility of this research.The consortium is set up as an open organization that will facilitate collaborations on complex biomedical research projects in human mental health in the Russian Federation and abroad. These projects will include genotyping, sequencing, transcriptome and epigenome analysis, metabolomics, and a wide array of other state-of-the-art analyses. Here, we discuss the challenges we face and the approaches we will take to unlock the huge potential that the Russian Federation holds for the worldwide psychiatric genetics community.

BackgroundAntipsychotic action of haloperidol is due to blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) are described.ObjectiveThe objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol.Patients and methodsThe study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and “SNP-Screen” sets of “Syntol” (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every “SNP-Screen” set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels.ResultsResults of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p < 0.001) and in the Simpson-Angus Scale (SAS) score of 5.04 ± 1.59 (10/10) versus 6.41 ± 1.33 (9/10; p = 0.006) were revealed.ConclusionPolymorphism of the SCL6A3 gene can affect the safety of haloperidol, and this should be taken into account during the choice of drug and its dosage regimen.

Background Eating Disorders pose a serious health risk to individuals. Often, eating disorder symptoms are overlooked when assessing obesity risk. The current cross-sectional study was focused on the search of association between disordered eating behaviors evaluated by Eating Attitudes Test 26 (EAT-26) and obesity in a large cohort of Russian-speaking adults seeking online assistance with medical weight correction. Methods The web-based cross-sectional study evaluated the data of online Eating Attitudes Test 26 (EAT-26) completed by 13,341 registered adult visitors of weight loss clinic website. The EAT-26 provides an overall score for potential eating disorders risk, as well as scores for three subscales: Bulimia, dieting, and oral control. Additional self-reported information about sex, weight, height, and age of respondents was used for analysis. The nonparametric analysis of variance and binominal logistic regression modeling were applied to search for an association between obesity and EAT-26 total score and subscales scores. The critical level of the significance was considered as α = 0.05. Results Women (94%) had lower BMI values but higher EAT-26 total score than men, which was indicated as statistically significant by a Wilcoxon Signed-Ranks Test (Z = − 11.80, p < 0.0001). Logistic regression for the whole cohort revealed that Bulimia subscale score was associated with higher risk of obesity (OR = 1.03, 95% CI 1.02–1.05) whereas higher score of EAT-26 oral control subscale was associated with decreased risk of obesity (OR = 0.93, 95% CI 0.91–0.95). Separate analysis for men and women showed that in men higher obesity risk was associated with higher oral control subscale scores (OR = 1.08, 95% CI 1.06–1.11); while in women both dieting and bulimia subscales scores were associated with higher obesity risk (OR = 1.02, 95% CI 1.01–1.03 and OR = 1.03, 95% CI 1.02–1.05, respectively). Older age was associated with obesity risk for both women and men. Conclusions In a large cohort of individuals seeking medical weight correction assistance, the risk of obesity was associated with the higher EAT-26 scores, age, and sex. Moreover, different eating disorder risk profiles were associated with obesity in men and women. Higher oral control subscale score was associated with decreased risk of obesity in women, but with higher risk in men. Older age was a shared obesity risk factor for both sexes. Therefore, the use of EAT-26 would facilitate individual diagnostic assessment for specific eating disorders in different sub-cohorts. Further assessment of separate EAT-26 subscales may be important to predict sex-/age-specific risks of obesity that implies their study in the future. Plain English summary Obesity is a significant health problem. Different factors (e.g. social, biological, and behavioral) are important for their successful treatment. Abnormal eating behaviors may be one of the most likely predictors of increased body weight. This study aims to determine whether there is a significant association between obesity and scores on the eating behavior questionnaire-Eating Attitudes Test-26 (EAT-26)-in a large cohort of adults seeking medical weight correction assistance at a private weight loss clinic web-site. According to the study results, the association was shown for the male sex, older age, and higher Bulimia scores as measured on the EAT-26. Moreover, different EAT-26 scales were associated with obesity risks in women and men subgroups, while older age was a shared risk factor for obesity in both sexes. The findings may suggest sex-/age-specific diagnostic approach and treatment strategies for individuals with obesity.

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