At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in patients with AD and eight related clinical measures. A genome-wide significant association of rs220677 with AD (p-value = 1.33 × 10⁻⁸ calculated with the Yates-corrected χ² test under the assumption of dominant inheritance) was discovered in female patients. Associations of AD and related clinical measures with seven other single nucleotide polymorphisms listed in previous GWASs of psychiatric and addiction traits were differently replicated in male and female patients. The bioinformatic analysis showed that regulatory elements in the eight associated linkage disequilibrium blocks define the expression of 80 protein-coding genes. Nearly 68% of these and of 120 previously published coding genes associated with alcohol phenotypes directly interact in a single network, where BDNF is the most significant hub gene. This study indicates that several genes behind the pathogenesis of AD are different in male and female patients, but implicated molecular mechanisms are functionally connected. The study also reveals a central role of BDNF in the pathogenesis of AD.

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.

BACKGROUND:Recentlyasignificant part of schizophrenia studies have been focused on the role of cytokines, especially interleukin-6 (IL-6). Some authors have suggestedapathogenetic role for IL-6 in schizophrenia and concluded that therapy that centers on suppressing IL-6 activity may prove beneficial for certain categories of patients with the disorder. However, many questions about whether the changes in IL-6 levels in schizophrenia are primary, related to symptoms or caused by therapy, are concomitant metabolic disorders, are related to smoking or other secondary factors remain unanswered. AIM:To assess the level of serum IL-6 in patients with schizophrenia in comparison with healthy controls, as well as to study its association with clinical and socio-demographic characteristics. METHODS:Some 125 patients with schizophrenia and 95 healthy volunteers were examined.Theevaluation of IL-6 was performed by enzyme immunoassay. All patients were assessed using standardized psychometric instruments. Information from patient medical records on the course of the disease and treatment wasanalyzed. RESULTS:Thelevel of IL-6 was significantly higher in the patients than in the healthy volunteers (z=2.58;p=0.0099), but among men the difference between the patients and volunteers was not significant. Statistically significant correlations were found between the level of serum IL-6 and the severity of the cognitive impairment of patients: (auditory [ρ=–0.31;p=0.00063] and working memory [ρ=−0.25;p=0.0065], hand-eye coordination [ρ=−0.29;p=0.0011], verbal fluency [ρ=−0.28;p=0.0019] and problem-solving capacity [ρ=−0.22;p=0.013]), total severity of schizophrenia symptoms (PANSS, ρ=0.22;p=0.016), PANSS positive subscale (ρ=0.18;p=0.048), and the age of manifestation (ρ=0.20;p=0.025) and disease duration (ρ=0.18;p=0.043).Thelevel of IL-6 was the lowest in patients treated with third-generation antipsychotics, and the highest in those treated withfirst-generation antipsychotics (H=6.36;p=0.042). Moreover, in hospital patients, the level of IL-6 was significantly higher than in outpatients and inpatients hospitals (H=18.59;p=0.0001). CONCLUSION:Thestudy confirmed that there are associations between the serum IL-6 level and schizophrenia, the age of the patient, duration of the disease and how late in one's life cycle it began manifesting itself, as well asanumber of clinical characteristics. Considering that IL-6isassociated withawide range of symptoms that are loosely controlled by antipsychotics, this biochemical marker needs to be studied to look into how closely its level tracks with an unfavorable course of schizophrenia. That would require further prospective studies.

A wide range of studies have demonstrated that hyperhomocysteinemia is associated with the risk of schizophrenia, but currently available assumptions about the direct involvement of homocysteine (Hcy) in the pathogenesis of schizophrenia are hypothetical. It is possible that in vivo Hcy is only a marker of folate metabolism disturbances (which are involved in methylation processes) and is not a pathogenetic factor per se. Only one study has been conducted in which associations of hyperhomocysteinemia with oxidative stress in schizophrenia (oxidative damage to protein and lipids) have been found, and it has been suggested that the oxidative stress may be induced by the elevated Hcy in schizophrenic patients. But the authors did not study the level of reduced glutathione (GSH), as well as possible causes of hyperhomocysteinemia—disturbances of folate metabolism. The aim of this work is to analyze the association of Hcy levels with the following: (1) redox markers in schizophrenia GSH, markers of oxidative damage of proteins and lipids, and the activity of antioxidant enzymes in blood serum; (2) with the level of folate and cobalamin (В12); and (3) with clinical features of schizophrenia measured using the Positive and Negative Syndrome Scale (PANSS). 50 patients with schizophrenia and 36 healthy volunteers, matched by sex and age, were examined. Hcy in patients is higher than in healthy subjects (p = 0.0041), and this may be due to the lower folate level in patients (p = 0.0072). In patients, negative correlation was found between the level of Hcy both with the level of folate (ρ = −0.38, p = 0.0063) and with the level of B12 (ρ = −0.36, p = 0.0082). At the same time, patients showed higher levels of oxidative modification of serum proteins (p = 0.00046) and lower catalase (CAT) activity (p = 0.014). However, Hcy is not associated with the studied markers of oxidative stress in patients. In the group of patients with an increased level of Hcy (>10 μmol/l, n = 42) compared with other patients (n = 8), some negative symptoms (PANSS) were statistically significantly more pronounced: difficulty in abstract thinking (N5, p = 0.019), lack of spontaneity and flow in conversation (N6, p = 0.022), stereotyped thinking (N7, p = 0.013), and motor retardation (G7, p = 0.050). Thus, in patients with schizophrenia, hyperhomocysteinemia caused by deficiency of folate and B12 is confirmed and can be considered a marker of disturbances of vitamin metabolism. The redox imbalance is probably not directly related to hyperhomocysteinemia and is hypothetically caused by other pathological processes or by an indirect effect of Hcy, for example, on the enzymatic antioxidant defence system (CAT activity), which requires further exploration. Further study of the role of Hcy in the pathogenesis of schizophrenia is relevant, since the proportion of patients with hyperhomocysteinemia is high and correlations of its level with negative symptoms of schizophrenia are noted.