[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.