[Anhedonia in mood disorders and somatic diseases: results of exploratory Mendelian randomization analysis]. / Angedoniya pri rasstroistvakh nastroeniya i somaticheskikh zabolevaniyakh: rezul'taty razvedochnogo Mendelevskogo randomizatsionnogo analiza.

OBJECTIVE: To conduct an exploratory Mendelian randomization analysis of the causal relationships of anhedonia with a wide range of psychiatric and somatic phenotypes based on the genetic data of participants in a population study. MATERIAL AND METHODS: This cross-sectional study included 4520 participants, of which 50.4% (n=2280) were female. The mean age was 36.8 (S.D.=9.8) years. Participants were pheno-nailed based on the DSM-5 criteria for anhedonia in the framework of depression. An episode of anhedonia exceeding 2 weeks during life was reported by 57.6% (n=2604) of participants. A genome-wide association study (GWAS) of the anhedonia phenotype was performed, as well as a Mendelian randomization analysis using summary statistics of large-scale GWASs on psychiatric and somatic phenotypes. RESULTS: The GWAS on anhedonia did not reveal the variants with genome-wide significant association (p<10-8). The most significant (p=9.71×10-7) was the variant rs296009 (chr5:168513184) in an intron of the slit guidance ligand 3 (SLIT3) gene. Using Mendelian randomization, nominally significant (p<0.05) causal associations of anhedonia with 24 phenotypes were identified, which can be divided into 5 main groups: psychiatric/neurological diseases, inflammatory diseases of the digestive system, respiratory diseases, oncological diseases and metabolic disorders. The most significant causal effects of anhedonia were found for breast cancer (p=0.0004, OR=0.9986, 95% confidence interval (CI) (0.9978-0.999)), minimal depression phenotype (p=0.009, OR=1.004, 95% CI (1.001-1.007)), as well as for apolipoprotein A (p=0.01, OR=0.973, 95% CI (0.952-0.993)) and respiratory diseases (p=0.01, OR=0.9988, 95% CI (0.9980-0.9997)). CONCLUSION: The polygenic nature of anhedonia may cause the risks of comorbidity of this phenotype with a wide range of somatic diseases, as well as may be associated with mood disorders.

[Association of depression and anxiety with somatic diseases: negative lifestyle factors impact]. / Svyaz' depressii i trevogi s somaticheskimi zabolevaniyami: rol' negativnykh vneshnikh faktorov.

OBJECTIVE: To assess the associations of various depression and anxiety phenotypes with manifestations of different somatic disorders and negative lifestyle factors. MATERIAL AND METHODS: The study involved 5116 people. In the online questionnaire, participants provided information about age, sex, height and weight, as well as a history of smoking, alcohol use, physical activity and diagnoses/symptoms of various physical diseases. Self-questions based on the DSM-5 criteria and the online version of the HADS were used to screen for phenotypes of affective and anxiety disorders in a population sample. RESULTS: An association of both subclinical and clinical depressive symptoms on HADS-D was noted for respondents with weight gain (OR 1.43; CI: 1.29-1.58, p<0.05 and OR 1,CI: 1.05-1.52, p<0.05, respectively), increased BMI (OR 1.36; CI: 1.24-1.48, p<0.05 OR 1.27; CI: 1.09-1.47, p<0.05 respectively), and decreased physical activity (OR 1.67; CI: 1.35-2.07, p<0.05 and OR 2.35; CI: 1.59-3.57, p<0.05, respectively) at the time of testing. The phenotypes of depression, anxiety disorders, and bipolar disorder by DSM criteria were associated with a history of smoking. (OR 1.37; CI: 1.18-1.62, p<0.001; OR 1.36; CI: 1.24-1.48, p<0.05 and OR 1.59; CI: 1.26-2.01, p<0.001, respectively). For higher BMI the association was reported only for the bipolar depression phenotype (OR 1.16; CI: 1.04-1.29, p<0.05), and with a decrease in physical activity - for the phenotypes of major depression and anxiety disorders (OR 1.27; CI: 1.07-1.52, p<0.05 and OR 1.61; CI: 1.31-1.99, p<0.001, respectively). A significant association with various somatic disorders was noted for all phenotype variants, but to the greatest extent for those based on DSM criteria. CONCLUSIONS: The study confirmed the association of negative external factors and various somatic disorders with depression. These associations were noted for various phenotypes of anxiety and depression, both in severity and structure, and may be due to complex mechanisms that have shared biological and environmental mechanisms.

Genome assembly using quantum and quantum-inspired annealing.

Recent advances in DNA sequencing open prospects to make whole-genome analysis rapid and reliable, which is promising for various applications including personalized medicine. However, existing techniques for de novo genome assembly, which is used for the analysis of genomic rearrangements, chromosome phasing, and reconstructing genomes without a reference, require solving tasks of high computational complexity. Here we demonstrate a method for solving genome assembly tasks with the use of quantum and quantum-inspired optimization techniques. Within this method, we present experimental results on genome assembly using quantum annealers both for simulated data and the [Formula: see text]X 174 bacteriophage. Our results pave a way for a significant increase in the efficiency of solving bioinformatics problems with the use of quantum computing technologies and, in particular, quantum annealing might be an effective method. We expect that the new generation of quantum annealing devices would outperform existing techniques for de novo genome assembly. To the best of our knowledge, this is the first experimental study of de novo genome assembly problems both for real and synthetic data on quantum annealing devices and quantum-inspired techniques.

[GWAS-based polygenic risk scores for depression with clinical validation: methods and study design in the Russian population]. / Poligennye shkaly riska razvitiya depressii na osnove GWAS s klinicheskoi validatsiei: metodologiya i dizain issledovaniya v rossiiskoi populyatsii.

Depression is one of the leading causes of decreased quality of life and social functioning of patients. In the context of preventive medicine, the prevention of depression becomes a priority. To achieve the goals of prevention, it is necessary to identify specific population risk groups - individuals with a high genetic risk of depression. The paper describes the project aimed at developing a genetic test system based on polygenic risk scores (PRS) for depression, considering the multi-ethnicity and multicultural diversity of the Russian population. As a result of the study, data on the genetic architecture of depression (GWAS) and PRS for depression will be obtained for the first time. The emergence of a genetic test system developed in the study of the Russian population and in the conditions of a constant decrease in the cost of genetic research will allow an effective transition to preventive medicine in the area of mental health.

[Perspectives of the use of pharmacogenetic tests in neurology and psychiatry]. / Perspektivy primeneniia farmakogeneticheskikh testov v psikhiatrii i nevrologii.

The review is devoted to the analysis of the current state of pharmacogenetic research and their use in psychiatric practice. The main genes responsible for the pharmacodynamics and pharmacokinetics of drugs used in psychiatry are listed. Foreign pharmacogenetic clinical recommendations and progress on their implementation in medical practice in various countries of Europe and the USA are analyzed. The need to create Russian clinical guidelines on pharmacogenomics to improve the effectiveness of patient care and to implement a personalized approach to therapy is discussed.

A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.

BACKGROUND: Cutis laxa (CL) is a rare connective tissue disorder characterized by loose, redundant, inelastic and wrinkled skin. Patients develop a prematurely aged appearance. Inheritance can be autosomal dominant or autosomal recessive. The X-linked form is now classified in the group of copper transport diseases. Autosomal dominant CL is characterized by wrinkled, redundant and sagging, inelastic skin and in some cases is associated with internal organ involvement. CASE PRESENTATION: We report a familial case of autosomal dominant CL, which includes a 33-year-old woman and her 11-year-old son with dry, thin and wrinkled skin that appeared prematurely aged. No serious involvement of internal organs was found. In both patients, we identified novel heterozygous mutation c.2323delG (p.Ala775fs) in exon 34 of elastin transcript NM_001278939.1. Similar frameshift mutations in the last exons of elastin gene were previously reported in patients with autosomal dominant CL. CONCLUSIONS: Our results show a novel frameshift mutation that was found in patients with cutis laxa. Exome sequencing is effective and useful technology for properly diagnosis of diseases with similar phenotype to ensure proper treatment is provided.

[A bioinformatic pipeline for NGS data analysis and mutation calling in human solid tumors]. / Bioinformaticheskii protokol dlia obrabotki NGS-dannykh i identifikatsii mutatsii v solidnykh opukholiakh cheloveka.

We aimed to develop a pipeline for the bioinformatic analysis and interpretation of NGS data and detection of a wide range of single-nucleotide somatic mutations within tumor DNA. Initially, the NGS reads were submitted to a quality control check by the Cutadapt program. Low-quality 3¢-nucleotides were removed. After that the reads were mapped to the reference genome hg19 (GRCh37.p13) by BWA. The SAMtools program was used for exclusion of duplicates. MuTect was used for SNV calling. The functional effect of SNVs was evaluated using the algorithm, including annotation and evaluation of SNV pathogenicity by SnpEff and analysis of such databases as COSMIC, dbNSFP, Clinvar, and OMIM. The effect of SNV on the protein function was estimated by SIFT and PolyPhen2. Mutation frequencies were obtained from 1000 Genomes and ExAC projects, as well as from our own databases with frequency data. In order to evaluate the pipeline we used 18 breast cancer tumor biopsies. The MYbaits Onconome KL v1.5 Panel ("MYcroarray") was used for targeted enrichment. NGS was performed on the Illumina HiSeq 2500 platform. As a result, we identified alterations in BRCA1, BRCA2, ATM, CDH1, CHEK2, TP53 genes that affected the sequence of encoded proteins. Our pipeline can be used for effective search and annotation of tumor SNVs. In this study, for the first time, we have tested this pipeline for NGS data analysis of samples from patients of the Russian population. However, further confirmation of efficiency and accuracy of the pipeline is required on NGS data from larger datasets as well as data from several types of solid tumors.

[Application of whole exome sequencing in the diagnosis of hereditary neurological diseases].

Whole Exome Sequencing (WES) is a promising method in human genetics. Because the majority of pathogenic mutations that lead to the development of diseases are localized in exons and splice sites, WES could become a major tool for the diagnosis of diseases with a complex hereditary nature. This tool appears to be particularly useful for hereditary neurological diseases, such as autism spectrum disorders, Charcot-Marie-Tooth disease and others. In our review, we discuss the clinical application of WES, with special emphasis on the diagnosis of hereditary neurological diseases.