[A perspective on the application of CRISPR/CAS9 genome editing system to study of molecular-genetic basis of mental disorders]. / Perspektivy ispol'zovaniya sistemy genomnogo redaktirovaniya CRISPR/Cas9 dlya izucheniya molekulyarno-geneticheskikh osnov psikhicheskikh rasstroistv.

Schizophrenia, depression, bipolar disorder and autism spectrum disorders are common mental disorders that are among the leading causes of disability worldwide. The major complication to effective therapies for mental disorders is the poor understanding of their pathogenic mechanisms. Currently, an increasing number of research groups are focusing on uncovering the molecular mechanisms of mental disorders and developing novel therapies using the CRISPR/Cas9 (Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR) - CRISPR-associated system 9 (Cas9)) system to determine the molecular mechanisms of developing mental disorders and novel therapy. The CRISPR/Cas9 system is the most promising among genome editing tools. Numerous advantages of the CRISPR/Cas9 system and its successful application in some studies provide wide opportunities for genome therapy and regeneration medicine. In this review we shortly describe structure and function of the CRISPR/Cas9 system and its application to study the molecular-genetic basis of mental disorders in human.

Individual Differences in Relative Telomere Length in Mentally Healthy Subjects: The Effect of TERT Gene Polymorphism and Urban Residency.

The changes in the telomere length caused by the terminal underreplication in the existing literature are related to depressive disorders. However, the use of the telomere length as a biomarker of depressive states is ambiguous, which is due to the effect of various environmental factors on both the psychoemotional state and cellular aging of an organism. In order to identify the possible use of the relative telomere length (RTL) measured in peripheral blood leukocytes as a biomarker of enhanced liability to depression prior to the clinical symptoms, as well as to determine the link between telomere length, sociodemographic factors, allelic variants of the genes involved in the regulation of telomere elongation, and depression level, the association analysis of reverse transcriptase (TERT rs7726159), telomerase RNA component (TERC rs1317082), and the CST complex encoding protein (OBFC1 rs2487999) gene polymorphisms was performed with RTL and depression level in mentally healthy individuals (N = 1065) aged 18-25 years. Together with genetic variants, the examined regression models included various sociodemographic parameters as predictors. As a result of statistical analysis, we failed to observe the association between RTL and individual differences in depression level in the studied sample. Nevertheless, multiple regression analysis allowed us to construct a statistically significant model of individual variance in RTL (P = 4.3е-4; r 2 = 0.018), which included rs7726159 in the TERT gene (P = 0.020; ß = 0.078) and such environmental predictors as age (P = 0.001; ß = -0.027) and place of residence in childhood (urban/rural area) (P = 0.048; ß = 0.063). The data obtained confirm the involvement of TERT gene variants and age in telomere length in mentally healthy individuals aged 18-25 years and indicate a negative effect of urban residency on telomere length shortening, which reflects the cellular aging of an organism.

The role of inflammatory system genes in individual differences in nonverbal intelligence.

Nonverbal intelligence represents one of the components of brain cognitive functions, which uses visual images and nonverbal approaches for solving required tasks. Interaction between the nervous and immune systems plays a specif ic role in individual differences in brain cognitive functions. Therefore, the genes encoding pro- and antiinflammatory cytokines are prospective candidate genes in the study of nonverbal intelligence. Within the framework of the present study, we conducted the association analysis of six SNPs in the genes that encod proteins involved in inf lammatory response regulation in the central nervous system (CRP rs3093077, IL1А rs1800587, IL1B rs16944, TNF/ LTA rs1041981, rs1800629, and P2RX7 rs2230912), with nonverbal intelligence in mentally healthy young adults aged 18- 25 years without cognitive decline with inclusion of sex, ethnicity and the presence of the "risky" APOE ε4 allele as covariates. Considering an important role of environmental factors in the development of brain cognitive functions in general and nonverbal intelligence in particular, we conducted an analysis of gene-by-environment (G × E) interactions. As a result of a statistical analysis, rs1041981 and rs1800629 in the tumor necrosis factor gene (TNF) were shown to be associated with a phenotypic variance in nonverbal intelligence at the haplotype level (for АА-haplotype: ßST = 1.19; p = 0.033; pperm = 0.047) in carriers of the "risky" APOE ε4 allele. Gene-by-environment interaction models, which determined interindividual differences in nonverbal intelligence, have been constructed: sibship size (number of children in a family) and smoking demonstrated a modulating effect on association of the TNF/LTA (rs1041981) (ß = 2.08; ßST = 0.16; p = 0.001) and P2RX7 (rs2230912) (ß = -1.70; ßST = -0.10; p = 0.022) gene polymorphisms with nonverbal intelligence. The data obtained indicate that the effect of TNF/LTA on the development of cognitive functions is evident only in the presence of the "unfavorable" APOE ε4 variant and/or certain environmental conditions.

The role of the KIBRA and APOE genes in developing spatial abilities in humans.

In the contemporary high-tech society, spatial abilities predict individual life and professional success, especially in the STEM (Science, Technology, Engineering, and Mathematics) disciplines. According to neurobiological hypotheses, individual differences in cognitive abilities may be attributed to the functioning of genes involved in the regulation of neurogenesis and synaptic plasticity. In addition, genome-wide association studies identified rs17070145 located in the KIBRA gene, which was associated with individual differences in episodic memory. Considering a significant role of genetic and environmental components in cognitive functioning, the present study aimed to estimate the main effect of NGF (rs6330), NRXN1 (rs1045881, rs4971648), KIBRA (rs17070145), NRG1 (rs6994992), BDNF (rs6265), GRIN2B (rs3764030), APOE (rs7412, rs429358), and SNAP25 (rs363050) gene polymorphisms and to assess the effect of gene-environment interactions on individual differences in spatial ability in individuals without cognitive decline aged 18-25 years (N = 1011, 80 % women). Spatial abilities were measured using a battery of cognitive tests including the assessment of "3D shape rotation" (mental rotation). Multiple regression analysis, which was carried out in the total sample controlling for sex, ethnicity and the presence of the "risk" APOE ε4 allele, demonstrated the association of the rs17070145 Т-allele in the KIBRA gene with enhanced spatial ability (ß = 1.32; pFDR = 0.037) compared to carriers of the rs17070145 CC-genotype. The analysis of gene-environment interactions revealed that nicotine smoking (ß = 3.74; p = 0.010) and urban/rural residency in childhood (ß = -6.94; p = 0.0002) modulated the association of KIBRA rs17070145 and АРОЕ (rs7412, rs429358) gene variants with individual differences in mental rotation, respectively. The data obtained confirm the effect of the KIBRA rs17070145 Т-allele on improved cognitive functioning and for the first time evidence the association of the mentioned genetic variant with spatial abilities in humans. A "protective" effect of the APOE ε2 allele on enhanced cognitive functioning is observed only under certain conditions related to childhood rearing.

Longitudinal genetic studies of cognitive characteristics.

The present review describes longitudinal studies of cognitive traits and functions determining the causes of their variations and their possible correction to prevent cognitive impairment. The present study reviews the involvement of such environmental factors as nutrition, prenatal maternal stress, social isolation and others in cognitive functioning. The role of epigenetic factors in the implementation of environmental effects in cognitive characteristics is revealed. Considering the epigenome significance, several studies were focused on the design of substances affecting methylation and histone modification, which can be used for the treatment of cognitive disorders. The appropriate correction of epigenetic factors related to environmental differences in cognitive abilities requires to determine the mechanisms of chromatin modifications and variations in DNA methylation. Transposons representing stress-sensitive DNA elements appeared to mediate the environmental influence on epigenetic modifications. They can explain the mechanism of transgenerational transfer of information on cognitive abilities. Recently, large-scale meta-analyses based on the results of studies, which identified genetic associations with various cognitive traits, were carried out. As a result, the role of genes actively expressed in the brain, such as BDNF, COMT, CADM2, CYP2D6, APBA1, CHRNA7, PDE1C, PDE4B, and PDE4D in cognitive abilities was revealed. The association between cognitive functioning and genes, which have been previously involved in developing psychiatric disorders (MEF2C, CYP2D6, FAM109B, SEPT3, NAGA, TCF20, NDUFA6 genes), was revealed, thus indicating the role of the similar mechanisms of genetic and neural networks in both normal cognition and cognitive impairment. An important role in both processes belongs to common epigenetic factors. The genes involved in DNA methylation (DNMT1, DNMT3B, and FTO), histone modifications (CREBBP, CUL4B, EHMT1, EP300, EZH2, HLCS, HUWE1, KAT6B, KMT2A, KMT2D, KMT2C, NSD1, WHSC1, and UBE2A) and chromatin remodeling (ACTB, ARID1A, ARID1B, ATRX, CHD2, CHD7, CHD8, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SRCAP, and SS18L1) are associated with increased risk of psychiatric diseases with cognitive deficiency together with normal cognitive functioning. The data on the correlation between transgenerational epigenetic inheritance of cognitive abilities and the insert of transposable elements in intergenic regions is discussed. Transposons regulate genes functioning in the brain due to the processing of their transcripts into non-coding RNAs. The content, quantity and arrangement of transposable elements in human genome, which do not affect changes in nucleotide sequences of protein encoding genes, but affect their expression, can be transmitted to the next generation.

[The organizational aspects of health care of students of institutions of higher professional education].

In recent decades, both in the Russian Federation and in the Sverdlovsk oblast decreasing of population size of adolescents and deterioration of their physical development and health status were established. In Russia, the organization of medical care of college students is insufficiently organized and requires additional improvements. The selective assessment of activities of medical offices in six colleges in Yekaterinburg was implemented. The sociological surveys were organized on the basis of the international HBSC questionnaire to study opinions of the minors about organization of medical care in colleges (653 students interviewed) and prevalence of health risk factors among students (1142 students were interviewed). In the Sverdlovsk region in 2018, only 53.6% of colleges were licensed for carrying out medical activities. According to the study, medical care in colleges was provided by medical assistant of medical office. This condition resulted in that not all the students underwent preventive examinations or underwent them not in required fullness. The medical personnel of colleges provided no analysis of health status of adolescents and health education is insufficient. The analysis of the data of sociological surveys established high prevalence of behavioral risk factors among underage students. Almost half of respondents noted the presence of harmful habits and only quarter of respondents paid attention to healthy diet. The percentage of respondents claimed that they tasted and consumed "spices" and "surfactants" was high against the background of low awareness of dangers of these habits. To amend this situation, it is necessary to organize auditing of quality of medical care of students in colleges, to analyze quality of preventive examinations, to develop a set of preventive measures of promoting health of students of colleges, based on their motivation and psychological characteristics, involving students themselves in the process, applying interactive forms.

[Genetic and environmental aspects of mathematical disabilities].

Mathematics has become highly important in today's high-tech life. Success in everyday life requires the presence of mathematical knowledge, which, in turn, appears to be the basis for any innovative scientific activity. However, a large percentage of the population demonstrates mathematical disabilities. Mathematical abilities and disabilities represent a complex and multifactorial phenomenon caused by the influence of both genetic and environmental factors. The present review is focused on studies based on a candidate gene approach and on genome-wide association studies previously reporting associations between gene polymorphisms and cognitive impairments, particularly mathematical disabilities. According to the first approach, learning and memory formation are influenced by variants in neurotransmitter system genes, genes involved in the working memory and synaptic plasticity. The results of the second approach demonstrates that the matrix metalloproteinase 7 gene (MMP7), the glutamate receptor ionotropic kainate 1 gene (GRIK1), and the dynein axonemal heavy chain 5 gene (DNA H5) are responsible for developing mathematical disabilities.

[Arginine-vasopressin receptor gene (AVPR1A, AVPR1B) polymorphisms and their relation to personality traits].

The present study aimed to assess the main effects ofAVPRIA (rs11174811, RSI) and AVPRIB (rs28632197, rs33911258) gene polymorphisms, as well as haplotypic, GxE and GxG effects on personality trait variation in 1018 healthy individuals, considering gender and ethnicity confounding. Haplotype analysis revealed an association ofAVPRIA C*S- and C*L-haplotype (rs11174811 and RS1, respectively) and increased (PFDR= 0.016) or decreased (PFDR = 0.031) Extraversion (EPI) in Bashkirs, respectively. The association of AVPR1B G*A-haplotype (rs28632197 and rs33911258, respectively) and decreased Self-transcendence (TCI-125) (P(FDR) = 0.040) was demonstrated in the total sample and in Udmurts. GxE analysis revealed that the birth season modulated the involvement of the AVPR1A (rs11174811) gene marker in the variation of Persistence (TCI-125) in the total sample (P(FDR) = 0.012). The modulating effect of several environmental factors (ethnicity and birth season) on the association of AVPR1A and AVPR1B gene polymorphisms and personality traits was established.

[Role of dopamine transporter gene (DAT1) polymorphisms in personality traits variation].

According to psychobiological model of personality proposed by Cloninger, personality traits characterizing enhanced tendency to novel stimuli, impulsivity and sociability are influenced by dopaminergic system functioning. The present study considered both the main effect of two polymorphic loci (VNTR and 2319G>A) in dopamine transporter gene (DAT1) and the role of distinct DAT1 gene haplotypes in personality traits variation in 592 healthy individuals belonging to different ethnicities (men and women). The results of the study revealed the involvement of VNTR and 2319G>A polymorphisms in Novelty Seeking variation and the main effect of 2319G>A polymorphism on Reward Dependence (TCI) observed in Russian females. Moreover, DAT1 gene haplotype effect on Novelty Seeking in Russian females and on Persistence (TCI) in Tatar females was demonstrated. Reported in the current study results pointed to the involvement of dopaminergic system (DAT1 gene in particular) in variation of personality traits characterizing the tendency to novel stimuli, purposefulness, and sociability specifically in women.

[Association of several polymorphic loci of serotoninergic genes with unipolar depression].

Serotoninergic system is one of the major brain neurotransmitter systems that is involved in the development of depression disorders. Regulatory genes of this system are the principle candidate genes predisposing to unipolar depression. Using PCR-RFLP analysis, we have conducted a study of polymorphic loci of several genes of this system: C1019G of serotonin receptor 1A gene, (HTR1A); A438G of serotonin receptor 2A gene, (HTR2A); G861C of serotonin receptor 1B gene, (HTR1B); Stin2VNTR and 5-HTTLPR of serotonin transporter gene (SLC6A4) in patients with unipolar depression among ethnic Tatars and Russians. The results of the study suggest that genotype 10/10 of the SLC6A4 gene as well as genotype G/G and allele G of the HTR2A gene can predispose for increased risk of unipolar depression development in ethnic Russians. In contrast, genotype 12/10 of the SLC6A4 gene is a marker of low risk of the disease development in both ethnic groups.