We present the main directions and results of our post-GWAS studies of schizophrenia, including epigenetic studies, the search for enhancers located in schizophrenia GWAS regions and development of adequate cell models for functional studies.

Genomic and chromosomal pathology may be a mechanism for neurological and psychiatric diseases. Molecular cytogenetic studies of postmortal samples of the central nervous system have shown that genome/chromosome instability and somatic mosaicism are an element of pathogenic cascade in Alzheimer’s disease, ataxia telangiectasia, autism and schizophrenia. Using cytogenomic analysis and bioinformatics methods possible causes and functional consequences of genomic and chromosomal pathology in the diseased brain have been addressed.

The study aimed to assess the contribution of haplotypes and polyenvironmental risk scores (PERS) to DNA methylation variability in schizophrenia index loci. In peripheral blood of 70 patients, fragments within the MIR137HR and CYP17A1 genes and near SLC39A8 were studied by Pacbio-based single-molecule real-time bisulfite sequencing. Of about 1000 cytosines, only eight were variably methylated. Genotypes influenced seven of them. Additionally, in one case an interaction effect of haplotype and PERS and in another case a main effect of PERS were found. Thus, in the studied schizophrenia loci, variable methylation is mainly due to DNA structure.

CfDNA parameters of SZ patients with paranoid (N=54) and catatonic SZ (N=46) forms have been analyzed and compared with those of healthy controls. In the subjects from the both SZ forms, the mean cfDNA plasma concentration was twofold higher and NA of the plasma was higher than those in the healthy controls. In addition, peripheral blood lymphocytes of both SZ forms showed elevated levels of oxidized dna (8-OHDG) as well as increased number of double-stranded DNA breaks (flow Cytometry), and the ds-breaks level is higher in catatonic SZ. The cells with genomic DNA damages can undergo to unprogrammed cell death and contribute to circulating cfDNA. Increased DNase I activity in patients with schizophrenia promotes to cleave primarily AT-rich DNA-fragments and the accumulation of GC-rich fragments. Compared to those of healthy controls, plasma cfDNA samples of both SZ forms patients contained increased copy numbers of telomere DNA, as well as ribosomal RNA genes, and cf-rDNA concentration is higher in catatonic SZ group. Changes in cfDNA parameters was significantly higher in the catatonic SZ group, which may indicate a more pronounced inflammatory process.

The effect of INDEL polymorphism of the HLA-G gene on the risk of schizophrenia and its clinical features was studied. There was the interaction between this polymorphism and preterm birth as an environmental factor that influenced positive symptoms scores in women with the I/I genotype.

1020 DNA samples of two groups of people (schizophrenia and control) from the Russian population were analyzed using 30 SNPs. As the analyzed markers, SNPs were selected that showed an association with schizophrenia or variability of cognitive abilities in genome-wide association studies. Multiplex genotyping was performed using the MassARRAY System 4 platform. As a result of the analysis, statistically significant associations were revealed for polymorphic variants of the TCF4, LSM1, CCDC60 genes. Our results confirm the role of the TCF4 and LSM1 genes in the schizophrenia pathogenesis in world populations.

The study of the association of the genes involved in the oxytocinergic system and stressful precipitating factors with schizophrenia severity revealed as the main effects of environmental and genetic factors as well genotype-environment interactions.

Investigation of genetic predictors of antipsychotic-inducedextrapyramidal symptoms and search for usage algorithms will help treatment optimization and personalization. There was a significant association (χ2=41,6; р=0,0000001) of antipsychotic-induced extrapyramidal symptoms with quantitative distribution of risk Del-/GSTM1; Del-/ GSTT1; A2A2/rs1800497; AG/rs3892097; TT/rs1045642 genotypes from 0 to 5. The safety of antipsychotic treatment least requires genotyping of DRD2 and GSTM1 genes as well as individual selection of antipsychotics for patients with three or more risk genotypes.

The aim of the study was to analyze the role of exon II HTR2A gene transcript isoforms and rs6311 genetic variant in the development of mental pathologies and antipsychotic therapy prognosis. Alternative isoforms of exon II HTR2A are associated with the development of mental pathologies and is applicable to predict antipsychotic therapy outcome.

The search for genetic variants linking the decline in various areas of cognitive processes with age and Alzheimer’s disease is relevant. The aim was to search for the relationship of protein haplotypes of two polymorphic variants in the APOE gene with the eight cognitive function domains variability in f the elderly. Domains were determined by the battery score of the Montreal Cognitive Assessmnet (MoCA). The two most highly statistically significant associations were identified for the ε3/ε3 genotype in comparison with carriers of the ε4 allele. These are memory (p = 0.002) and visuospatial abilities (p = 0.007) domains. No statistically significant associations were revealed for cognitive domains: attention and concentration, executive functions, language, abstraction, calculations and orientation. Possibly, the identified associations determine the general genetic baseline of inheritance of Alzheimer’s disease, mental disorders, dementia and intelligence in the elderly.

For the first time in the Russian cohort of FTD patients the frequency of mutations in the most common genes associated with this disease was studied. The most frequently mutating are the genes C9orf72 and GRN. Mutations in the MAPT gene are least likely to occur, which is probably due to the uneven representation of clinical phenotypes in our sample.

The present study aimed to assess the main effects of ten polymorphisms of glucocorticoid (NR3C1) and mineralocorticoid receptor (NR3C2) genes together with gene-by-environment interactions on individual differences in personality traits in 1215 mentally healthy individuals aged 17-25 years. Multiple linear regression analysis demonstrated that prenatal solar activity level modulated the association of rs56149945 (N363S) with Persistence (β = 1.21; Р = 0.001) and rs41423247 in NR3C1 gene with emotional resistance to stress (β = -2.72; Р = 0.005).

The present study aimed to assess the main effects of IL1B (rs16944), TNF (rs1041981), CRP (rs3093077) and PCLO (rs2715157) gene polymorphisms together with G×E effects on individual differences in depression level in 999 mentally healthy individuals with sex and ethnicity as covariates. Statistical analysis revealed an association of TNF rs1041981 A-allele with a decreased depression level in Russians (p=0.04), while PCLO rs2715157 A-allele was associated with an increased depression level in Tatars (pFDR=0.03). As a result of stratification analysis we observed that place of residence and birth season significantly affected association of rs16944, rs1041981 and rs2715157 and depression level.

The difficulties frequently caused by the presence of high stress sensitivity during performing mathematical operations (mathematical anxiety, MA) in a modern high-tech society represent the important problem for both individual success and economic well-being of a society. We analyzed the interaction of 23 polymorphic variants of genes responsible for the regulation of neurotransmitter systems, working memory and synaptic plasticity, in determining inter-individual differences in the level of mathematical anxiety. As a result, we obtained two optimal statistical models of intergenic interactions associated with the level of mathematical anxiety (СREB1 (rs35349697) x DTNBP1 (rs2619522) and DRD2 (rs6277) x ВDNF (rs6265)).

Serotonin receptors are involved in regulation of mood, appetite and different aspects of behavior. 5-HT2C receptors modulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, amygdala, hypothalamus and some other brain structures. HTR2C genetic polymorphism rs6318 is known to lead to a substitution of serine for cysteine at codon 23 (Cys23Ser). There is some evidence that the Ser23 C allele is supposed to be more active than the Cys23 G allele. Despite of numerous articles about this polymorphism, the data on its contribution to substance dependence syndrome is missing. The aim of this study was to assess possible association between HTR2C rs6318 polymorphism and substance dependence syndrome. The study included 1087 participants: 773 controls and 324 patients, diagnosed with psychoactive substance dependence with withdrawal. The allele frequencies of rs6318 polymorphism were: fG= 0.861 fC = 0.139 in female patients, fG= 0.865 fC = 0.135 in female controls, in male patients fG= 0.841 fC = 0.159, and in male controls fG= 0.87 fC = 0.13.

The APOE gene is one of the most famous genes associated with the development of both cardiovascular diseases and neurodegenerative diseases of the central nervous system, accompanied by impaired cognitive functions. In the course of this study, the associations of APOE gene alleles with cognitive functions violation in the adolescent population of Novosibirsk were studied. The state of cognitive functions was evaluated in 231 boys (42.1%) and 318 girls (57.9%). Their average age was 15.66 ± 0.9 years. It was revealed that the presence of the E4 allele of the APOE gene has a negative effect on the state of working memory even in adolescence.

The rapidity of the emergence and spread of Internet addiction in adolescent populations, combined with the amount of consumed content, is associated with the emergence of a problematic dependence on uncontrolled mobile access to the network. This makes the problem of searching for molecular genetic and psychological markers of high risk of developing Internet addiction relevant. The aim of the work was to study the prevalence of Internet-dependent variants of different degrees of severity in adolescents and the distribution of polymorphic variants of the COMT and CHRNA4 genes. It was revealed that the CC variant rs1044396 CHRNA4 is associated with Internet addiction in adolescents: its prevalence progressively increases with the severity of Internet addiction. Whereas the allelic variant T has a “protective” effect against severe and uncontrolled dependence.

First Russian study of hereditary spastic paraplegias using panel MPS (or WES in few cases) detected 120 families/ with 20 SPG. Of 112 detected mutations 54 were novel. Autosomal dominant SPG were presented by 97 families/8 forms (SPG4 - 52% of the total group), autosomal recessive SPG - by 23 families/12 forms. Most interesting findings were related to SPG30 and SPG47. Few forms were unique. Yet a substantial part of tested cases remained molecularly undiscovered as in оther world studies.

CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia) is a late-onset autosomal recessive ataxia due to biallelic (AAGGG)n repeat expansion in the 2nd intron of the RFC1 gene. There is no information on the CANVAS prevalence in Russian families. We searched for biallelic expansion of AAGGG repeats in 35 Russian patients with late-onset cerebellar ataxia. Five patients (14.3%) with CANVAS syndrome and a characteristic clinical picture were verified.

Hereditary diseases of the neuromuscular system represent an extensive group of genetically heterogeneous hereditary diseases characterized by pronounced clinical polymorphism. This report shows the feasibility of using high-throughput sequencing (HTS) methods for making the most accurate diagnosis of rare neuromuscular disorders, which in turn leads to the most favorable symptomatic care and helps in genetic counselling.

NGS-based technologies play an important role in the diagnosis of diseases of the nervous system. The advantage of their using is the wide coverage of the analyzed genes, which allows to increase the detection of causes in such a clinically and genetically heterogeneous group of diseases. The purpose of this work is to determine the effectiveness of genome sequencing to identify genetic causes in patients with likely hereditary diseases of the nervous system. In our study, genome sequencing revealed the cause of the disease in 28.6%. In cases with a negative result from the analysis of the gene panel, genome sequencing revealed the cause of the disease in 9% of patients.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant myodystrophy. In approximately 95% of cases FSHD is caused by partial deletion of the D4Z4 macrosatellite tandem repeat on chromosome 4q35 (FSHD1). Here we present results FSHD1 diagnostic of patients and unaffected relatives from Russian population. We demonstrate that FSHD1 permissive alleles are bigger in size for unaffected carriers, which indicate previously reported phenomenon of inverse correlation between permissive allele size and disease penetrance and expressivity. In addition, presence of patients and unaffected carriers from one family with the same permissive allele size demonstrate importance of non-genetic factors for disease development.

Nuclear laminates are the main proteins of the nuclear membrane and provide the strength of the nuclear membrane and the interaction of extranuclear structures with the components of the cell nucleus. Despite the large number of studies in this area, there is no consensus on the mechanism underlying the pathogenesis of laminopathies. Mutations in the lamin A/C gene are the cause of the development of several clinical phenotypes, both with isolated involvement of cardiac, muscle, adipose and bone tissues, and with their combination. The most characteristic clinical manifestations of laminopathies are conduction disorders, ventricular and supraventricular rhythm disturbances, as well as systolic myocardial dysfunction. Among patients who underwent heart transplantation, approximately 10% are patients with cardiomyopathies caused by mutations in the lamin A/C gene. Often, the dominant pathology of the cardiovascular system (CVS) can mask the subclinical involvement of other tissues. Although a combination of cardiomyopathy with arrhythmic disorder and skeletal muscle disease is not uncommon, concomitant damage to the peripheral nervous system is not often reported. In this article, we present family cases of laminopathy with various involvement of the cardiac, muscle and peripheral nervous systems among members of the same family.

We present clinical description of the case of brain malformations and molecular diagnostics results. Sporadic mutation c.533C> T (p.Thr178Met) of the TUBB3 gene was detected.

The clinical picture in 196 patients with congenital malformations of the brain was analyzed. Patients were examined using neuroimaging techniques, cytogenetic and molecular genetics techniques. The spectrum of congenital brain defects was analyzed. The most frequent congenital malformations of the brain were abnormalities of cerebral commissures, the second place was occupied by cortical malformations, the third place - abnormalities of the cerebellum. Chromosomal pathology (including microdelection syndromes) was detected in 19 patients (9.7%), monogenic diseases in 27 patients (13.8%).

In patients with myotonic dystrophy, mitochondrial disorders were detected, which could be the cause of lesions of the white matter of the brain. MRI of limb muscles in patients revealed the most frequent lesion of the medial head of the calf muscle.

Hereditary diseases are often polysystemic due to the pleiotropic action of genes. There are many examples: Wilson-Konovalov disease, Marfan syndrome, many neuromuscular diseases. One of these diseases is Emery-Dreyfus muscular dystrophy (DMED). A clinical case is described when the boy was diagnosed only at the age of 18. The lack of awareness of doctors about hereditary diseases with an increased risk of SCD leads to their extremely late diagnosis or fatal outcome amid high loads, which are often the case with athletes and military servicemen. It is necessary to significantly expand the training program in residency and on the cycles of improvement of doctors in the direction of hereditary diseases in each specialty.

A family case report of Rossolimo-Steinert-Curschmann myotonic dystrophy is presented. An increased number of copies of CTG-repeats of the DMPK gene responsible for the development of MD, i.e., the diagnosis was confirmed by molecular genetic method.

Clinical observation results of 13 patients with progressive Duchene/Becker muscular dystrophy are presented, molecular-genetic method is used in all cases.

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. It was assumed that the genetic etiology of CP does not exceed 2%. The aim of this work is to determine the effectiveness of high-throughput sequencing for diagnosing the causes of CP. In our study, a genetic etiology was found in 31.8% of patients with CP, a possible cause was identified in 17.5% of patients with CP.

According to American Academy of Pediatrics recent guidelines, each family with a child diagnosed with autistic spectrum disorder should be reffered to a medical geneticist and offered genetic tests. However, an optimal genetic testing algorithm has yet to be developed. This study was conducted to compare abilities of different molecular-genetic methods to detect genetic factors of autistic spectrum disorders.

Multiple sclerosis is a chronic inflammatory demyelinating disorder of central nervous system of multifactorial origin. Genome-wide association studies identified 700 polymorphic genetic variants associated with multiple sclerosis. The aim of the current study was to analyse associations of the polymorphic markers in genes involved in the pathogenesis of the disease and those identified by genome-wide association studies in the populations of Bashkirs, Russians, and Tatars from the Republic of Bashkortostan (Russian Federation). The study group was comprised of 644 patients with multiple sclerosis and 1408 control group individuals. Genotyping of 35 polymorphic genetic markers was performed using allele-specific PCR and PCR followed by restriction fragment length polymorphism analysis. The data obtained in our study confirm the association with multiple sclerosis of the genes involved in the development of autoimmune inflammation in central nervous system.

Demyelinating diseases are heterogeneous group including multiple sclerosis (MS), acute multiple encephalomyelitis, opticoneuromyelitis (ONM), idiopathic transverse myelitis, optical neuritis. The spectrum of differential diagnostic screening in this rare autoimmune disease is variable, including hereditary/neurodegenerative diseases. The similarity of some mitochondrial diseases (MD) with MS is not accidental, since currently etiopathogenesis of MS is considered not only as autoimmune demyelination, but also as neurodegeneration, one of the important pathogenetic mechanisms of which is mitochondrial dysfunction. The article provides a brief analysis of patients with impaired visual functions and atypical clinical-diagnostic picture for MS. The selection criterion for patients was a primary clinical episode caused by a presumably inflammatory demyelinating process and complaints of decreased visual functions.

A mutation in the GRIN2A gene occurs in patients with pediatric idiopathic epilepsy. The main symptoms of the disease are acquired aphasia, auditory agnosia, dysarthria, dyspraxia with both homo- and heterozygotes. In this work a search for a variants of the GRIN2A gene was made by a patient with child epilepsy, accompanied by a developmental delay, as a result of which a mutation was detected, that led to the development of a pathological phenotype.

Assessment of hexosylsphingosine (HexSph) in the blood is currently a sensitive diagnostic test for Gaucher disease. We suggested that the assessment of this metabolite may be effective in detecting the development of Parkinson’s disease (PD) in mutation carriers in the GBA gene (GBA-PD). In the present study HexSph concentration and GBA enzymatic activity were evaluated in patients with GBA-BP, asymptomatic carriers of GBA mutations, patients with sporadic PD (sPD) and the control group in blood, as well as in the primary culture of macrophages. An assessment of HexSph level in the primary macrophage culture makes it possible to distinguish GBA mutation carriers with PD from asymptomatic mutation carriers, and though could be considered as a biomarker of PD development in carriers of GBA mutations.

An associative study identified possible clinical and genetic markers for the development of neuropsychological disorders in Parkinson’s disease, such as depression, dementia and high anxiety.

Analysis of transcriptome of fibroblasts, derived from twins, discordant in sporadic form of PD, have been conducted for the first time. We have obtained the evidence for potential utility of fibroblast studies for undrestanding the processes, underlying the PD pathogenesis. Also, our data highlights 3 possible candidate PD genes - GRIK2, PTGS2 & SCN9A.

Huntington’s disease (HD) is a neurodegenerative disease, caused by a CAG-repeat expansion in exon 1 of the HTT gene. The number of repeats more than 36 leads to HD. The range of 27-35 CAG-repeats is called as intermediate alleles (IAs). There is a growing evidence of importance of IAs for patients with other neurodegenerative diseases. In this study we have detected two cases of carriage of IAs in patients with Parkinson’s disease (PD). The analysis of clinical picture has revealed atypical clinical features of PD in these individuals. Thus, IAs of HTT gene may provide a modifying effect on clinical features of PD.

The aim of this study was to assess the level of mRNA and protein of the SNCA, DNMT1 genes, as well as intron 1 methylation of the SNCA gene in CD45 + peripheral blood cells of patients with sporadic PD and control individuals. For the first time, a decrease in the concentration of DNMT1 protein in CD45 + peripheral blood cells from PD patients compare to controls was revealed. An increase in DNMT1 gene expression in PD patients compare to controls was found. No differences in intron 1 methylation of the SNCA gene in CD45 + peripheral blood cells was found between PD patients and controls. An inverse correlations between methylation level of 21, 22 CpG island in intron1 of SNCA gene and mRNA SNCA gene and alpha-synuclein protein level were found. The study suggests the involvement of DNMT1 in the pathogenesis of PD and the lack of association of PD with intron 1 methylation of the SNCA gene.

Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder. Alpha-synuclein misfolding and aggregation resulting in neurototoxicity is a hallmark of PD. Exosomes (extrcellular vesicles 40-100 nm in size) can play a key role in the transport of pathogenic forms of alpha-synuclein. The aim of our work is to evaluate an effect of GBA and LRRK2 mutations on alpha-synuclein level in exosomes derived from peripheral blood plasma. No significant difference was found for exosomal alpha-synuclein levels patients with sporadic, GBA- and LRRK2- associated PD, PD with dementia compared to controls. Our results indicate that mutations in the LRRK2 and GBA genes do not influence on plasma exosomal alpha-synuclein level.

Parkinson’s disease (PD) is a complex systemic disease, mainly associated with the death of dopaminergic neurons. Despite the obvious progress made in the study of molecular genetic factors and mechanisms of PD pathogenesis, it has now become clear that violations in the DNA structure do not describe the entire spectrum of pathological changes observed during the development of the disease. It has now been shown that changes at the transcriptome level can have a significant effect on the pathogenesis of PD. The authors used models of the presymptomatic stage of PD with mice decapitation after 6 hours (6 h-PSS), presymptomatic stage with decapitation after 24 hours (24 h-PSS), advanced presymptomatic (Adv-PSS) and early symptomatic (ESS) stages of PD. For whole transcriptome analysis of RNA pools of the substantia nigra and mouse striatum, the MouseRef-8 v2.0 Expression BeadChip Kit microchips (Illumina, USA) were used. As a result of the analysis of whole transcriptome data, it was shown that, there are a greater number of statistically significant changes in the tissues of the brain and peripheral blood of mice with Adv-PSS and ESS models of PD compared to 6 h-PSS and 24 h-PSS models. In general, the obtained data indicate the sequential involvement of the transcriptome in the pathogenesis of PD, as well as the fact that changes at the transcriptome level of the processes of transport and mitochondrial biogenesis can play an important role in neurodegeneration in PD at an early stage.

The goal of this work was to study changes of histaminergic system genes expression level in the early symptom stage of PD. We were use MPTP mouse model of early symptom stage of PD in this study. Male mice C57BL/6 were used (n=10 in the control and experimental groups). For analysis we were choose nine genes, which associated with histaminergic system. Measuring of expression levels was carried out using reverse transcription reaction and real-time PCR (TaqMan). Changes at the mRNA level for a number of genes in the brain tissues of mice with MPTP-induced PD were founded. Based on these data, it can be suggested that histaminergic system is involve in early stage PD pathogenesis.

Mutations in the gene GBA that are encoding the lysosomal enzyme glucocerebrosidase are the most common genetic risk factor for PD. Not every carrier of GBA mutations will develop PD. Probably the dysfunction of lysosomal enzymes and membrane proteins may contribute or protect to the development of PD among carriers of GBA mutations. In the current study LAMP2, GLA, GALNS, SCARB2 and alpha-synuclein mRNA levels in CD45+ blood cells were estimated in patients with GBA-associated PD (GBA-PD), non-manifesting GBA carriers(GBA-Carriers), PD patients and controls. This is the first report estimating LAMP2, GLA, GALNS, SCARB2 and alpha-synuclein expressions in CD45+ blood cells in GBA-PD patients and GBA-Carriers. We revealed increased SNCA expression and changing expression of lysosomal genes (LAMP2, GALNS, SCARB2) that may contribute role these genes in pathogenesis of GBA-PD. Decreased of LAMP2 may be considered as trigger of GBA-PD.