BACKGROUND:Alcohol use disorder (AUD) significantly affects over 200 health conditions, causing about 3 million deaths annually worldwide and is approximately 50 % heritable. METHODS:We conducted a genome-wide association study (GWAS) on self-reported alcohol consumption and alcohol-related challenges (AUDIT score) in a large East Slavs cohort (N = 41,575). Genetic correlations with diverse phenotypes were assessed, and a polygenic risk score (PRS) for alcohol use disorder (AUD) was built and tested in an independent clinical cohort. GWAS and PRS associations were validated across various genetic ancestries. RESULTS:The East Slavs GWAS identified a highly significant association (p = 2.5 ×10-18) between the rs1229984 SNP and AUD. Transancestral modeling revealed significant associations in Ashkenazi Jews, Tatars, Siberian, and other populations. Additional subthreshold associations (p < 10-6) were found in SNPs within KIF26, OCA2, DLGAP2, and miRNA AL161421 gene regions. SNP-based heritability was estimated at hg = 6.4 % (SE = 1.1 %). Genetic correlation analysis revealed the strongest positive associations with psychiatric traits. We trained the PRS using external summary statistics and individual-level genomic data from our cohort (R2 = 0.013). It outperformed other external PRSs included in the analysis. Validation in the independent clinical cohort showed an AUC of 0.6 (95 % CI = 0.56-0.64), and integrating PRS with non-genetic models increased the AUC by 1.33 %, resulting in 0.762 (p = 8 × 10⁻⁵). CONCLUSIONS:Our findings suggest a genetic basis for AUD involving genes related to alcohol metabolism and the reward system. The applicability of the PRS across diverse genetic ancestries supports its integration into non-genetic prediction models, enhancing AUD prediction accuracy in diverse populations.

BackgroundPolygenic risk score (PRS) prediction is widely used to assess the risk of diagnosis and progression of many diseases. Routinely, the weights of individual SNPs are estimated by the linear regression model that assumes independent and linear contribution of each SNP to the phenotype. However, for complex multifactorial diseases such as Alzheimer’s disease, diabetes, cardiovascular disease, cancer, and others, association between individual SNPs and disease could be non-linear due to epistatic interactions. The aim of the presented study is to explore the power of non-linear machine learning algorithms and deep learning models to predict the risk of multifactorial diseases with epistasis.MethodsSimulated data with 2- and 3-loci interactions and tested three different models of epistasis: additive, multiplicative and threshold, were generated using the GAMETES. Penetrance tables were generated using PyTOXO package. For machine learning methods we used multilayer perceptron (MLP), convolutional neural network (CNN) and recurrent neural network (RNN), Lasso regression, random forest and gradient boosting models. Performance of machine learning models were assessed using accuracy, AUC-ROC, AUC-PR, recall, precision, and F1 score.ResultsFirst, we tested ensemble tree methods and deep learning neural networks against LASSO linear regression model on simulated data with different types and strength of epistasis. The results showed that with the increase of strength of epistasis effect, non-linear models significantly outperform linear. Then the higher performance of non-linear models over linear was confirmed on real genetic data for multifactorial phenotypes such as obesity, type 1 diabetes, and psoriasis. From non-linear models, gradient boosting appeared to be the best model in obesity and psoriasis while deep learning methods significantly outperform linear approaches in type 1 diabetes.ConclusionOverall, our study underscores the efficacy of non-linear models and deep learning approaches in more accurately accounting for the effects of epistasis in simulations with specific configurations and in the context of certain diseases.

BackgroundCOVID-19 disease has infected more than 772 million people, leading to 7 million deaths. Although the severe course of COVID-19 can be prevented using appropriate treatments, effective interventions require a thorough research of the genetic factors involved in its pathogenesis.MethodsWe conducted a genome-wide association study (GWAS) on 7,124 individuals (comprising 6,400 controls who had mild to moderate COVID-19 and 724 cases with severe COVID-19). The inclusion criteria were acute respiratory distress syndrome (ARDS), acute respiratory failure (ARF) requiring respiratory support, or CT scans indicative of severe COVID-19 infection without any competing diseases. We also developed a polygenic risk score (PRS) model to identify individuals at high risk.ResultsWe identified two genome-wide significant loci (P-value <5 × 10−8) and one locus with approximately genome-wide significance (P-value = 5.92 × 10−8-6.15 × 10−8). The most genome-wide significant variants were located in the leucine zipper transcription factor like 1 (LZTFL1) gene, which has been highlighted in several previous GWAS studies. Our PRS model results indicated that individuals in the top 10% group of the PRS had twice the risk of severe course of the disease compared to those at median risk [odds ratio = 2.18 (1.66, 2.86), P-value = 8.9 × 10−9].ConclusionWe conducted one of the largest studies to date on the genetics of severe COVID-19 in an Eastern European cohort. Our results are consistent with previous research and will guide further epidemiologic studies on host genetics, as well as for the development of targeted treatments.

BACKGROUND: Anhedonia is characterized by a reduced ability to anticipate, experience, and/or learn about pleasure. This phenomenon has a transdiagnostic nature and is one of the key symptoms of mood disorders, schizophrenia, addictions, and somatic conditions. AIM: To evaluate the genetic architecture of anhedonia and its overlap with other mental disorders and somatic conditions. METHODS: We performed a genome-wide association study of anhedonia on a sample of 4,520 individuals from a Russian non-clinical population. Using the available summary statistics, we calculated polygenic risk scores (PRS) to investigate the genetic relationship between anhedonia and other psychiatric or somatic phenotypes. RESULTS: No variants with a genome-wide significant association were identified. PRS for major depression, bipolar disorder, and schizophrenia were significantly associated with anhedonia. Conversely, no significant associations were found between PRS for anxiety and anhedonia, which aligns well with existing clinical evidence. None of the PRS for somatic phenotypes attained a significance level after correction for multiple comparisons. A nominal significance for the anhedonia association was determined for omega-3 fatty acids, type 2 diabetes mellitus, and Crohn’s disease. CONCLUSION: Anhedonia has a complex polygenic architecture, and its presence in somatic diseases or normal conditions may be due to a genetic predisposition to mood disorders or schizophrenia.

We present the results of the depression Genome-wide association studies study performed on a cohort of Russian-descent individuals, which identified a novel association at chromosome 7q21 locus. Gene prioritization analysis based on already known depression risk genes indicated MAGI2 (S-SCAM) as the most probable gene from the locus and potential susceptibility gene for the disease. Brain and gut expression patterns were the main features highlighting functional relatedness of MAGI2 to the previously known depression risk genes. Local genetic covariance analysis, analysis of gene expression, provided initial suggestive evidence of hospital anxiety and depression scale and diagnostic and statistical manual of mental disorders scales having a different relationship with gut-brain axis disturbance. It should be noted, that while several independent methods successfully in silico validate the role of MAGI2, we were unable to replicate genetic association for the leading variant in the MAGI2 locus, therefore the role of rs521851 in depression should be interpreted with caution.

Background Overweight is the scourge of modern society and a major risk factor for many diseases. For this reason, understanding the genetic component predisposing to high body mass index (BMI) seems to be an important task along with preventive measures aimed at improving eating behavior and increasing physical activity. Methods We analyzed genetic data of a European cohort ( n = 21,080, 47.25% women, East Slavs ancestry >80%) for 5 frequently found genes in the context of association with obesity: IPX3 (rs3751723), MC4R (rs17782313), TMEM18 (rs6548238), PPARG (rs1801282) and FTO (rs9939609). Results Our study revealed significant associations of FTO (rs9939609) (β = 0.37 (kg/m 2 )/allele, p = <2 × 10 −16 ), MC4R (rs17782313) (β = 0.28 (kg/m 2 )/allele, p = 5.79 × 10 −9 ), TMEM18 (rs6548238) (β = 0.29 (kg/m 2 )/allele, p = 2.43 × 10 −8 ) with BMI and risk of obesity. Conclusions The results confirm the contribution of FTO, M4CR, and TMEM18 genes to the mechanism of body weight regulation and control.

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.

BackgroundLactase persistence-the ability to digest lactose through adulthood-is closely related to evolutionary adaptations and has affected many populations since the beginning of cattle breeding. Nevertheless, the contrast initial phenotype, lactase non-persistence or adult lactase deficiency, is still observed in large numbers of people worldwide.MethodsWe performed a multiethnic genetic study of lactase deficiency on 24,439 people, the largest in Russia to date. The percent of each population group was estimated according to the local ancestry inference results. Additionally, we calculated frequencies of rs4988235 GG genotype in Russian regions using the information of current location and birthplace data from the client's questionnaire.ResultsThe attained results show that among all studied population groups, the frequency of GG genotype in rs4988235 is higher than the average in the European populations. In particular, the prevalence of lactase deficiency genotype in the East Slavs group was 42.8% (95% CI: 42.1-43.4%). We also investigated the regional prevalence of lactase deficiency based on the current place of residence.ConclusionsOur study emphasizes the significance of genetic testing for diagnostics, i.e., specifically for lactose intolerance parameter, as well as the scale of the problem of lactase deficiency in Russia which needs to be addressed by the healthcare and food sectors.

Charcot–Marie–Tooth disease (CMT) is a genetically heterogeneous group of peripheral neuropathies most of which are associated with mutations in four genes including peripheral myelin protein-22 ( PMP22) , myelin protein zero ( MPZ ), gap junction protein beta1 ( GJB1 ) and mitofusin2 ( MFN2 ). This current case report describes the clinical and genetic characteristics of a 6-year-old male proband. A physical examination revealed muscular hypotonia. He started walking on his own at 18 months. A nerve conduction study with needle electromyography revealed conduction block. A novel MPZ mutation (c.398C > T, p.Pro133Leu) was revealed in the proband. This mutation was also found in the 32-year-old father of the proband. The father had had deformity of the feet and distal muscle weakness since childhood. The novel p.Pro133Leu pathogenic mutation was responsible for early onset but slowly progressive CMT1B. We assume that this site is an intolerant to change region in the MPZ gene. This variant in the MPZ gene is an important contributor to hereditary neuropathy with reduced nerve conduction velocity in the Russian population. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of CMT associated with a mutation in the MPZ gene. Keywords Charcot-Marie-Tooth disease , MPZ gene , neuropathy

Abstract The Minusinsk Basin in Southern Siberia had unique conditions for the development of ancient societies, thanks to its geographical location, favorable climatic conditions, and relative isolation. Located at the northern periphery of the eastern Eurasian steppe, surrounded by the Altai-Sayan Mountains this area witnessed numerous ancient human migrations with specific types of interaction between outside and local archaeological cultures. The genomic history of the human population of Southern Siberia from the Chalcolithic to the middle Bronze Age has been relatively well described in the recent genome-wide studies, while the genetic ancestry of populations, represented by diverse archaeological cultures of the Late Bronze and Early Iron Ages, remains a blank spot for modern paleogenomics. Here, for the first time, we present two ancient nuclear genomes of the individuals buried in the Oglakhty cemetery (early Tashtyk culture, 2nd to 4th centuries AD). Our pilot study is undertaken within a multidisciplinary project on this noteworthy site with well-preserved organic remains and provides fresh paleogenomic data on the ancient societies of Southern Siberia.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of peripheral neuropathies most of which are associated with mutations in four genes including peripheral myelin protein-22 (PMP22), myelin protein zero (MPZ), gap junction protein beta1 (GJB1) and mitofusin2 (MFN2). This current case report describes the clinical and genetic characteristics of a 6-year-old male proband. A physical examination revealed muscular hypotonia. He started walking on his own at 18 months. A nerve conduction study with needle electromyography revealed conduction block. A novel MPZ mutation (c.398C > T, p.Pro133Leu) was revealed in the proband. This mutation was also found in the 32-year-old father of the proband. The father had had deformity of the feet and distal muscle weakness since childhood. The novel p.Pro133Leu pathogenic mutation was responsible for early onset but slowly progressive CMT1B. We assume that this site is an intolerant to change region in the MPZ gene. This variant in the MPZ gene is an important contributor to hereditary neuropathy with reduced nerve conduction velocity in the Russian population. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of CMT associated with a mutation in the MPZ gene.

In our previous study, we found that high doses of several substances with antioxidant capacities (Tempol, resveratrol, diphenyleneiodonium) can cause genotoxic stress and induce premature senescence in the human mesenchymal stem cells (MSCs). Here, using whole-transcriptome analysis, we revealed the signs of endoplasmic reticulum stress and unfolded protein response (UPR) in MSCs stressed with Tempol and resveratrol. In addition, we found the upregulation of genes, coding the UPR downstream target APC/C, and E3 ubiquitin ligase that regulate the stability of cell cycle proteins. We performed the molecular analysis, which further confirmed the untimely degradation of APC/C targets (cyclin A, geminin, and Emi1) in MSCs treated with antioxidants. Human fibroblasts responded to antioxidant applications similarly. We conclude that endoplasmic reticulum stress and impaired DNA synthesis regulation can be considered as potential triggers of cell damage and premature senescence stimulated by high-dose antioxidant treatments.

Identification of the genetic cause of a hereditary disease is a necessary step in the differential diagnosis, because plays an important role in evaluation of genetic risk, and in some cases also helps to determine the method of treatment, for example, for some hereditary metabolic diseases. The subsequent choice of molecular genetic testing method can be very difficult due to the presence of a number of advantages and limitations for each of these approaches. Methods of molecular genetic testing in order to identify the genetic causes of a hereditary disease, first of all, differ in diagnostic efficiency, time and cost of the study. In addition, the characteristics of different methods can also vary significantly for different groups of genetic diseases. Using the wrong method can significantly increase the time and cost of diagnosis. Recently, several data indicate that one of the next generation sequencing (NGS) methods - exome sequencing - has high efficacy for identification of the genetic cause of certain groups of hereditary diseases. Exome sequencing provides information about changes in gene coding regions - exons. A trio exome sequencing in families further increases the effectiveness of such analysis. The article describes the examples of clinical and financial feasibility of exome sequencing to identify the genetic cause of a hereditary disease. Such cases include: rare genetic diseases, heterogeneous diseases in children 0-3 years old, recently established connection of a gene with a disease, testing after negative results of other studies, for prenatal diagnosis, for financial reasons.

Background Epilepsy with intellectual disability limited to females (Epileptic encephalopathy, early infantile, 9; EIEE9) is a rare early infantile epileptic encephalopathy characterized by an unusual X-linked inheritance: females with heterozygous mutations are affected, while hemizygous males are not. Case presentation We describe the clinical and molecular characteristics of 2 Russian patients with EIEE9 (females, ages 3 years and 7 years). In these patients seizures developed at the age of 3 years. Additionally, for our patients and for cases described in the literature we searched for a possible relationship between the type and localization of the mutation and the EIEE9 clinical phenotype. Conclusions We identified two novelPCDH19mutations in EIEE9 patients: a missense mutation in exon 1 (c.1236C > A, p.Asp412Glu) and a frameshift in exon 3 (c.2386_2387insGTCT, p.Thr796fs). We conclude that the age of seizure onset and the presence of intellectual disability may depend not on the type and localization ofPCDH19mutations, but on the X-inactivation status. The study also highlights the need to screen for EIEE9 among young female epilepsy patients.

Abstract Background Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision. Methods We describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). The clinical features of these patients include cognitive and motor deterioration, seizures, stereotypies, and magnetic resonance imaging signs of brain atrophy. Exome sequencing was performed to identify the genetic variants of patients with NCL. Additionally, we tested 6,396 healthy Russians for NCL alleles. Results We identified five distinct mutations in four NCL‐associated genes of which two mutations are novel. These include a novel homozygous frameshift mutation in the CLN6 gene, a compound heterozygous missense mutation in the KCTD7 gene, and previously known mutations in KCTD7, TPP1, and MFSD8 genes. Furthermore, we estimated the Russian population carrier frequency of pathogenic and likely pathogenic variants in 13 genes associated with different types of NCL. Conclusion Our study expands the spectrum of mutations in lipofuscinosis. This is the first study to describe the molecular basis of NCLs in Russia and has profound and numerous clinical implications for diagnosis, genetic counseling, genotype–phenotype correlations, and prognosis.

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