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Purpose Cystic fibrosis (CF) is one of the most common monogenic diseases with an autosomal recessive inheritance. Carrier screening leads to a reduction in the number of children born with CF disease. The aim of this study was to develop the custom panel for the diagnosis of heterozygous carriage of polymorphic variants in the CFTR gene and to establish their allelic frequencies (AF) in one of the Russian regions where ethnic Russians predominate. Patients and methods The diagnostic panel was designed on the basis of data from the register of CF patients in Russia for 2017 and validated on 22 blood samples of patients with previously genetically established CF. The study participants (n=642) for CF variants estimation were randomly selected from the population-based cohort study ESSE-Vologda. Genotypes were determined by real-time PCR on the QuantStudio 12K Flex Real-Time PCR System. Data processing was performed using the TaqMan Genotyper Software. Results The proposed diagnostic panel allowed simultaneous analysis of 60 variants of the CFTR gene. A total of 23 carriers of the following variants were identified among 642 participants: F508del (rs113993960) with a frequency of 2.02%, L138ins (rs397508686) and 394delTT (rs121908769) - 0.47%, CFTRdele2.3 (c.54-5940_273+10250del21080; p.S18Rfs*16) - 0.31%, R117H (rs78655421), and G542X (rs113993959) - 0.16%. The frequency of heterozygotes in the Russian population was 3.58% or 1:28 (CI95%: 2.28-5.33% by Clopper-Pearson exact method). Conclusion High frequency of heterozygous CFTR variants carriers and availability of highly productive diagnostic panel for detection of CFTR variants suggest the prospect of carrier screening for some common CF variants among Russian population.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. In most cases, the development of the disease is sporadic and is not associated with any currently known mutations associated with PD. It is believed that changes associated with the epigenetic regulation of gene expression may play an important role in the pathogenesis of this disease. The study of individuals with an almost identical genetic background, such as monozygotic twins, is one of the best approaches to the analysis of such changes. A whole-transcriptome analysis of dermal fibroblasts obtained from three pairs of monozygotic twins discordant for PD was carried out in this work. Twenty-nine differentially expressed genes were identified in the three pairs of twins. These genes were included in seven processes within two clusters, according to the results of an enrichment analysis. The cluster with the greatest statistical significance included processes associated with the regulation of the differentiation of fat cells, the action potential, and the regulation of glutamatergic synaptic transmission. The most significant genes, which occupied a central position in this cluster, were PTGS2, SCN9A, and GRIK2. These genes can be considered as potential candidate genes for PD. Electronic supplementary material The online version of this article (10.1007/s12031-019-01452-3) contains supplementary material, which is available to authorized users.

Background Hypertrophic cardiomyopathy (HCM), described as the presence of hypertrophy of left ventricular, is the most prevalent heritable cardiovascular disease with predominantly an autosomal dominant type of inheritance. However, pathogenic alleles are not identified in at least 25% of patients with HCM, and the spectrum of pathogenic variants that contribute to the development of HCM in Russia has not been fully described. Therefore, the goal of our study was to identify genetic variants associated with the etiopathogenesis of HCM in Russian patients. Methods The study cohort included 98 unrelated adult patients with HCM. We performed targeted exome sequencing, an analysis using various algorithms for prediction of the impact of variants on protein structure and the prediction of pathogenicity using ACMG Guidelines. Results The frequency of pathogenic and likely pathogenic variants in all HCM‐related genes was 8% in our patients. We also identified 20 variants of uncertain significance in all HCM‐related genes. Conclusions The prevalence of individual pathogenic variants in HCM‐related genes in Russian population appears to be lower than in general European population, which could be explained by ethnic features of Russian population, age characteristics of our sample, or unidentified pathogenic variants in genes previously not linked with HCM., The prevalence of individual pathogenic variants in HCM‐related genes in Russian population appears to be lower than in general European population, which could be explained by ethnic features of Russian population, age characteristics of our sample, or unidentified pathogenic variants in genes previously not linked with HCM.

Parkinson’s disease (PD) characterized with slow continuous degeneration of dopaminergic neurons in the substantia nigra is one of the most common neurodegenerative diseases, but its etiology and pathogenesis are not fully understood. The pathogenesis of PD involves the impairment of lysosomal autophagy, which also contributes to lysosomal storage disorders (LSDs). In this work, the expression of genes related to lysosomal autophagy: Hspa8, Lamp2, Tfam, Slc18a2, and Vps35, was analyzed in the brain tissues of mice with the earliest stage of MPTP-induced PD. The detected decrease in Hspa8 and Lamp2 mRNA levels suggests that dysfunction of lysosomal autophagy may be involved in the earliest stages of PD pathogenesis. A decrease in the rate of lysosomal autophagy may affect the accumulation of damaged proteins and the formation of protein inclusions in PD. Genes related to the lysosome function may be involved in development of both LSD and PD at the earliest stages of these pathophysiological processes.

BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

The mitochondrion is an extremely important organelle that performs various functions in the cell: e.g. energy production, regulation of respiration processes and maintenance of calcium homeostasis. Disruption of the biogenesis and functioning of this organelle can lead to cell damage and cell death. Mitochondrial dysfunction has been shown to possibly be involved in the pathogenesis of Parkinson's disease. However, the role of genes associated with mitochondrial biogenesis in the early stages of disease remains poorly understood. The objective of the present study was to analyze changes in the expression of activator (Nrf1, Ppargc1a, Prkn, and Kif1b) and repressor (Zfp746 and Mybbp1a) genes of mitochondrial biogenesis in the early stages of the development of neurodegeneration in an MPTP-induced model of presymptomatic and early symptomatic stages of PD. Statistically significant changes in expression at the mRNA level were detected for all studied genes. There was mainly a decrease in the expression of activator genes (Nrf1, Ppargc1a, Prkn, and Kif1b) at all stages of neurodegeneration, which seemed to be associated with impaired mitochondrial biogenesis and the development of neurodegeneration processes. A predominant decrease in the expression was detected for the Zfp746 and Mybbp1a repressor genes of mitochondrial biogenesis. However, in this case, it was associated with the emergence of compensatory mechanisms during the development of Parkinson's disease. The largest number of statistically significant changes was detected for the Nrf1 activator gene and the Mybbp1a repressor gene. Apparently, these two genes play the most important role in this disease.

Valosin-containing human protein (VCP) or p97 performs enzyme functions associated with the maintenance of protein homeostasis and control of protein quality. Disruption of its normal functioning might be associated with the development of Parkinson’s disease (PD). Tissues of mice with toxin-induced presymptomatic and early symptomatic stages of PD, as well as 52 treated and untreated patients with newly diagnosed PD and nine patients with a “predicted” form of PD, were investigated. Significant changes in Vcp gene expression were observed in almost all studied mouse tissues. A significant decrease in VCP expression specific for PD was also detected at both the late preclinical and the early clinical stages of PD in untreated patients. Thus, a decrease in VCP expression is important for changes in the function of the nervous system at early stages of PD. Analysis of changes in VCP expression in all patients with PD and in Vcp in the peripheral blood of mice used as models of PD revealed significant decreases in expression specific for PD. These data suggest that a decrease in the relative levels of VCP mRNA might serve as a biomarker for the development of pathology at the early clinical and preclinical stages of human PD.

A growing body of evidence has hinted at the involvement of the largest gene of the circadian clock family, NPAS2, in the regulatory mechanisms underlying the link between metabolic diseases and ci...

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons. A whole-transcriptome analysis of the substantia nigra and striatum of an MPTP-induced mouse models of the earliest stages of PD was performed. Functional clustering of differentially represented transcripts revealed processes associated with the functioning of synapses, dendrites, axons, and myelination of neuronal projections. All of these processes occur in both the substantia nigra and striatum, but they are aimed at the functioning of neuron terminals in the striatum. One cluster was identified at the earliest stage modeled, i.e., "neuron projection" in the substantia nigra and "transport" in the striatum, and their number increased at subsequent stages. The number of clusters in the striatum predominates over those in the substantia nigra and there is a pronounced increase in the number of clusters from the modeled early stages to the late stages. These findings indicate that the substantia nigra and striatum have unique patterns of changes at each stage. Considering the clustering of individual processes, it was seen that there is a set of hierarchical clusters that overlap only partially at different stages and in different tissues. The data indicate a consistent involvement of the transcriptome in the pathogenesis of PD and highlight the independent role of various brain structures and individual parts of nerve cells in the formation of a response to the development of neurodegeneration. Decreased myelination of neuronal projections may be associated with the development of PD in the models considered.

Sub-constructs of morning–evening preference might be differentially related to polymorphisms in circadian clock genes. We previously reported significant association between a single nucleotide po...

Polymorphisms in genes of circadian system family seem to be of most importance for understanding of mechanisms underlying self-assessed individual variation in morning–evening preference. A review of earlier reported positive findings indicated that, at least, four polymorphisms in period circadian clock 3 (PER3) showed significant association with, at least, one of sub-constructs of a morningness–eveningness scale. However, similar to other candidate gene studies, these studies suffer from increased likelihood of false positive findings. We tried to replicate some of the most recently published positive results on associations of sub-traits of morningness–eveningness with two PER3 non-synonymous single nucleotide polymorphisms. DNA from buccal swabs was collected from healthy residents of three Russian cities, Moscow (N = 149) and Novosibirsk and Stavropol (N = 248). The tested hypotheses were formulated in accord with the earlier reported positive findings: the rare alleles might be linked to a...

Identification of individuals has become an urgent problem for mankind. In the last three decades, STR-based DNA identification has actively evolved along with traditional biometric methods. Nonetheless, single-nucleotide polymorphisms (SNPs) are now of great interest and a number of relevant SNP panels have been proposed for DNA identification. Here, a simple approach to SNP data digitization that can provide assigning a unique genetic identification number (GIN) to each person is proposed. The key points of this approach are as follows: 1) SNP data are digitized as whole 4-bit boxes in the most convenient binary format, where character "1" (YES) is assigned to revealed nucleotides, and character "0" (NO) to missing nucleotides after SNP-typing; 2) all SNPs should be considered tetra-allelic. Calculations showed that a 72-plex SNP panel is enough to provide the population with unique GINs, which can be represented in digital (binary or hexadecimal) or graphic (linear or two-dimensional) formats. Simple software for SNP data processing and GINs creation in any format was written. It is likely that the national and global GIN databases will facilitate the solution of problems related to identification of individuals or human biological materials. The proposed approach may be extended to other living organisms as well.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Despite progress in the study of the molecular, genetic, and pathogenic mechanisms of PD, it is unclear which processes trigger the development of the pathology associated with PD. Models of the presymptomatic and early symptomatic stages of PD induced by MPTP have been used to analyze changes in transcriptome profile in brain tissues, to identify specific patterns and mechanisms underlying neurodegeneration in PD. The whole-transcriptome analysis in the brain tissues of the mice with MPTP-induced PD showed that striatum is involved in the pathogenesis in the earliest stages and the processes associated with vesicular transport may be altered. The expression profiles of the genes studied in the substantia nigra and peripheral blood confirm that lymphocytes from peripheral blood may reflect processes occurring in the brain. These data suggest that messenger RNA (mRNA) levels in peripheral blood may provide potential biomarkers of the neurodegeneration occurring in PD. The changes in expression at the mRNA and protein levels suggest that Snca may be involved in neurodegeneration and Drd2 may participate in the development of the compensatory mechanisms in the early stages of PD pathogenesis. Our data suggest that the brain cortex may be involved in the pathological processes in the early stages of PD, including the presymptomatic stage.

Parkinson’s disease (PD) is the second most common severe neurodegenerative disorder. It is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Unfortunately, PD remains incurable. Therapy based on regulatory peptides, particularly neuroprotective peptides, which can sustain or activate neuron plasticity to enable their survival and function in difficult environments and after violated homeostasis, is a promising approach to cure PD. Some studies show that the synthetic analogs of natural peptides may be used as an etiological or at least a complementary therapy in PD. Therefore, in the present pilot study, we investigated the effects of the synthetic peptides Semax and dopamine neuron stimulating peptide (DNSP-5), and a new synthetic Semax-DNSP-5 hybrid peptide (SD) on the functioning of brain neurons. An analysis of the levels of dopamine (DA), noradrenaline (NA), 5-hydroxytriptamine (5-HT), an expression analysis of Gdnf and Gdnf receptor genes Gfra1, Gfra2, Gfra3, Gfra4, and Gfral in various regions of the brain of rats with 6-OHDA-induced PD-like parkinsonism, and a study of the motor activity of the rats in an “open field” test showed that DNSP-5 and SD elevated the level of DA in the nonlesioned striatum. DNSP-5 also increased the expression of Gfra1 and Gfra2 in the nonlesioned striatum and lesioned substantia nigra (SN) which suggested that DNSP-5 had compensatory and neuroprotective properties. SD demonstrated similar, albeit less pronounced effects to DNSP-5 on DA metabolism and gene expression. Of the peptides studied, only SD tended to increase the horizontal and vertical activity of rats. In conclusion, these findings suggest that DNSP-5 and SD have potential neuroprotective properties and may stimulate the surviving DA neurons.

This study was conducted to explore the possibility of association between the single-nucleotide polymorphisms rs6264 of BDNF, rs5443 of GNB3, and rs1801133 of MTHFR; the In/Del polymorphism of ACE; and the e2 allele of APOE and major depressive disorder (MDD) and recurrent depressive disorder (RDD) in an East Slavic population. Generalized multifactor dimensionality reduction (GMDR) method was applied to detect gene-gene interactions. One hundred fifty patients with RDD (101 females and 49 males) and 208 patients with MDD (115 females and 93 males) were included in the study. The comparison group consisted of 200 unrelated individuals. There was no significant difference in genotype distributions or allele frequencies between the controls and any of the diagnostic groups. Nevertheless, the frequency of the G allele of rs1801133 of MTHFR was higher in the RDD group and the frequency of the C allele of rs6264 of BDNF was higher in the MDD group. The difference between the controls and specific disease groups almost reached statistical significance (P = 0.08). A GMDR did not reveal optimal two- and three-dimensional models with significant prediction accuracies (P ˃ 0.05) for the MDD or RDD groups.

Heritability analyses of genome-wide association study (GWAS) cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here we analyze the genetic architectures of schizophrenia in 49,806 samples from the PGC and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which >= 71% of 1-Mb genomic regions harbor >= 1 variant influencing schizophrenia risk. We also observe significant enrichment of heritability in GC-rich regions and in higher-frequency SNPs for both schizophrenia and GERA diseases. In bivariate analyses, we observe significant genetic correlations (ranging from 0.18 to 0.85) for several pairs of GERA diseases; genetic correlations were on average 1.3 tunes stronger than the correlations of overall disease liabilities. To accomplish these analyses, we developed a fast algorithm for multicomponent, multi-trait variance-components analysis that overcomes prior computational barriers that made such analyses intractable at this scale. Refereed/Peer-reviewed

Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss consisting of 116 variants in the CFTR, PAH, SERPINA1, and GJB2 genes. The approach is based on the cheapest and fastest method, on using a small number of genes, and on the estimation of the effectiveness of carriers&rsquo, detection. The custom panel was tested on a population-based cohort that included 1244 participants. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The frequency of heterozygotes in the Russian population was 16.87% or 1:6 (CI95%: 14.76&ndash, 19.00% by Clopper-Pearson exact method): in CFTR&mdash, 2.81% (1:36), PAH&mdash, 2.33% (1:43), SERPINA1&mdash, 4.90% (1:20), and GJB2&mdash, 6.83% (1:15). The data on allele frequencies were obtained for the first time on a Russian population. The panel allows us to identify the vast majority of carriers of recessive diseases in the population. It is an effective approach to carrier screening for common recessive diseases.

Aim of the study: It was found that the mutations in the SDHD gene, encoding one of subunits of the succinate dehydrogenase complex, lead to the development of head and neck paraganglioma (HNPGL). We analyzed this gene in 91 patients with HNPGL from Russia. Materials and methods: DNA was isolated from the whole blood. A screening for mutations was performed by Sanger sequencing. Results: We revealed three missense mutations that have been described previously: p.Pro81Leu, p.His102Arg, p.Tyr114Cys. Moreover, we identified a novel potentially pathogenic variant (p.Trp105*). Conclusions: We found that mutations in the SDHD gene were less common in Russian patients compared with the majority of European populations. It was shown that the p.His102Arg mutation is a major mutation in Russia. We confirmed the previous suggestion that a bilateral localization of the tumor and the carotid type represent a marker of the genetically determined form of HNPGL.

Depressive disorders (DDs) are one of the most widespread forms of psychiatric pathology. According to the World Health Organization, about 350 million people in the world are affected by this condition. Family and twin studies have demonstrated that the contribution of genetic factors to the risk of the onset of DDs is quite large. Various methodological approaches (analysis of candidate genes, genome-wide association analysis, genome-wide sequencing) have been used, and a large number of the associations between genes and different clinical DD variants and DD subphenotypes have been published. However, in most cases, these associations have not been confirmed in replication studies, and only a small number of genes have been proven to be associated with DD development risk. To ascertain the role of genetic factors in DD pathogenesis, further investigations of the relevant conditions are required. Special consideration should be given to the polygenic characteristics noted in whole-genome studies of the heritability of the disorder without a pronounced effect of the major gene. These observations accentuate the relevance of the analysis of gene-interaction roles in DD development and progression. It is important that association studies of the inherited variants of the genome should be supported by analysis of dynamic changes during DD progression. Epigenetic changes that cause modifications of a gene's functional state without changing its coding sequence are of primary interest. However, the opportunities for studying changes in the epigenome, transcriptome, and proteome during DD are limited by the nature of the disease and the need for brain tissue analysis, which is possible only postmortem. Therefore, any association studies between DD pathogenesis and epigenetic factors must be supplemented through the use of different animal models of depression. A threefold approach comprising the combination of gene association studies, assessment of the epigenetic state in DD patients, and analysis of different “omic” changes in animal depression models will make it possible to evaluate the contribution of genetic, epigenetic, and environmental factors to the development of different forms of depression and to help develop ways to decrease the risk of depression and improve the treatment of DD.

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed

J. Lönnqvist on työryhmän Psychiat Genomics Consortium jäsen. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on similar to 150,000 individuals give a higher accuracy than LDSC estimates based on similar to 400,000 individuals (from combinedmeta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.

Publisher's version (útgefin grein), Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is −0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health., This research is supported by the Australian National Health and Medical Research Council (1080157, 1087889, 1103418, 1127440), and the Australian Research Council (DP160102126, FT160100229). This research has been conducted using the UK Biobank Resource. UK Biobank (http://www.ukbiobank.ac.uk) Research Ethics Committee (REC) approval number is 11/NW/0382. Our reference number approved by UK Biobank is 14575.

A role of nicotinic acetylcholine receptors (nAChR) in the development of Parkinson's disease (PD) has been investigated using two mouse models corresponding to the presymptomatic stage and the early symptomatic stage of PD. Quantitative determination of nAChR in the striatum and substantia nigra (SN) was performed using the radioactive derivatives of epibatidine, -conotoxin MII, and -bungarotoxin as ligands. The number of ligand-binding sites changed differently depending on their location in the brain, the stage of the disease and the receptor subtype. Epibatidine binding decreased in the striatum to 66% and 70% at the presymptomatic and early symptomatic stages, respectively, whereas in SN a 160% increase was registered at the presymptomatic stage. The -conotoxin MII binding on striatal dopaminergic axonal terminals at the presymptomatic stage decreased by 20% and at the symptomatic stage it demonstrated a further decrease. The increase in -bungarotoxin binding at the presymptomatic stage and a decrease at the early symptomatic stage was observed in the striatum. In SN, the level of -bungarotoxin binding decreased at the presymptomatic stage and kept constant at the symptomatic stage. The significant decrease in the expression of Chrna4 and Chrna6 genes encoding 4 and 6 nAChR subunits was observed in SN at the early symptomatic stage, while a 13-fold increase in expression of the Chrna7 gene encoding the 7 nAChR subunit was detected at the presymptomatic stage. The data obtained suggest possible involvement of nAChR in compensatory mechanisms at early PD stages.Issledovana rol' nikotinovykh atsetilkholinovykh retseptorov (nAKhR) na rannikh stadiiakh bolezni Parkinsona (BP) na éksperimental'nykh modeliakh u mysheĭ, sootvetstvuiushchikh dosimptomnoĭ i ranneĭ simptomnoĭ stadiiam BP. Kolichestvennoe opredelenie nAKhR v preparatakh striatuma i chernoĭ substantsii (ChS) provodili s pomoshch'iu ligandov, selektivnykh dlia razlichnykh podtipov nAKhR: radioaktivnykh proizvodnykh épibatidina, -konotoksina MII i -bungarotoksina. Kolichestvo vyiavlennykh ligand-sviazyvaiushchikh saĭtov zaviselo ot ikh tipa, lokalizatsii v golovnom mozge i stadii zabolevaniia. V striatume sviazyvanie épibatidina na dosimptomnoĭ i ranneĭ simptomnoĭ stadiiakh snizheno na 66% i 70% sootvetstvenno, a v ChS – povysheno do 160% na dosimptomnoĭ stadii po sravneniiu s kontrolem. Sviazyvanie -konotoksina MII na terminaliakh aksonov dofaminergicheskikh neĭronov na dosimptomnoĭ stadii bylo snizheno na 20%, i snizhenie ikh kolichestva prodolzhilos' na ranneĭ simptomnoĭ stadii. Sviazyvanie -bungarotoksina v striatume povysheno na dosimptomnoĭ i snizheno na ranneĭ simptomnoĭ stadiiakh, a v ChS umen'shalos' uzhe na dosimptomnoĭ stadii i ostavalos' postoiannym. Znachitel'noe snizhenie ékspressii genov neĭronal'nykh nAKhR Chrna4 i Chrna6, kodiruiushchikh 4 i 6 sub"edinitsy nAKhR, otmecheno v ChS na ranneĭ simptomnoĭ stadii, a dlia gena Chrna7, kodiruiushchego 7 sub"edinitsu, obnaruzheno 13-kratnoe uvelichenie na dosimptomnoĭ stadii. Poluchennye dannye ob izmeneniiakh urovnia mRNK ili funktsional'nykh kholinoretseptorov svidetel'stvuiut o vozmozhnom uchastii nAKhR v kompensatornykh mekhanizmakh na rannikh stadiiakh BP.

Public transport driving is a highly demanding activity requiring high skills and responsibility. Shift work, problems with regular sleep schedule negatively impact psychomotor reactions, cognitive functions and ability to react appropriately to the changing environment. For professional drivers all these factors may lead to the increased risk of a road accident. Individual differences in chronotype, cognitive and emotional control are partially genetically determined.Our study aimed to investigate the possible associations between chronotype parameters, traffic accident history and single nucleotide polymorphisms (SNPs) in a number of genes: RORA (rs1159814), CLOCK (rs12649507), PER3 (rs2640909), NPSR1 (rs324981), NPAS2 (rs4851377), DRD3 (rs6280), SLC6A3 (rs6347), DBH (rs1611125).We have studied 303 professional bus drivers working on rolling shifts in the Moscow region who had a recorded history of road accidents. The studied group was genotyped on selected SNPs and has filled out two chronotype questionnaires: MCTQ and shortened SWPAQ (Putilov A.A, 2014).A mixed chronotype with high levels of morning and evening alertness prevailed in the group. A prominent social jetlag caused by shift work was found. For SNP in PER3 gene there was an association with morning activation. SNP in CLOCK gene was associated with social jetlag and the risk to cause a crash. Minor alleles of SNPs in NPSR1and SLC6A3 correlated with later chronotype and increased risk of a road accident. We suppose that these polymorphisms may be amongst the genetic factors connecting chronotype and road accident risk.Цель исследования. Изучение ассоциаций между однонуклеотидными полиморфизмами (ОНП) генов RORA (rs1159814), CLOCK (rs12649507), PER3 (rs2640909), NPSR1 (rs324981), NPAS2 (rs4851377), DRD3 (rs6280), SLC6A3 (rs6347), DBH (rs1611125), параметрами хронотипа и статистики дорожно-транспортных происшествий (ДТП) водителей. Материал и методы. В исследование включили 303 водителей подмосковных междугородных автобусов, работающих по скользящему графику. Был проведен анализ связи результатов генотипирования по ОНП, Мюнхенского опросника хронотипа, сокращенного опросника для самооценки индивидуальных особенностей цикла сон-бодрствование (SWPAQ), данных о ДТП по официальной статистике. Результаты и заключение. В выборке преобладал смешанный хронотип, склонный поздно ложиться и способный рано вставать, наблюдался ярко выраженный сдвиг между режимами сна в будние и выходные дни. Для ОНП гена PER3 обнаружены ассоциации с параметрами утренней активности. ОНП гена CLOCK связан со сдвигом режима и риском стать виновником ДТП, минорные аллели ОНП генов NPSR1и SLC6A3 - с более поздним хронотипом и повышенным риском ДТП. Высказано предположение, что эти полиморфизмы могут быть одним из генетических факторов, связывающих хронотип и работоспособность.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

Natural regulatory peptides are biologically active compounds that are produced by various cells and provide a link among the main regulatory systems of the body. The field of research into the biologic activity of endogenous regulatory peptides is extremely vast. These peptides affect the cardiovascular, immune, reproductive, endocrine, digestive, and other systems, alter energy metabolism, and are especially effective in the regulation of the central nervous system. Despite of the wide range of preventive and therapeutic effects of natural regulatory peptides and proteins, their application in clinical practice is difficult. This is primarily because of their extreme instability, as they are rapidly degraded by proteases of the gastrointestinal tract, blood, cerebrospinal fluid, and other biologic media. Compounds with higher stability (i.e., a considerably longer half-life compared with that of natural molecules) and the ability to provide a directional effect on the various body systems were obtained from modifications of endogenous regulatory peptides. Synthetic analogs of regulatory peptides, as a rule, contain only natural amino acids in their composition, and their biodegradation does not lead to the formation of toxic products; thus, they have fewer side effects. This review focuses on the consideration of two synthetic regulatory peptides, Semax and Selank, which were the bases for the creation of new drugs that are used effectively in the treatment of various diseases of the nervous system. The synthetic analog of an adrenocorticotropic hormone 4-10 fragment (ACTH4-10) Semax is a powerful neuroprotective agent that is particularly effective as a therapy for stroke. Selank was synthesized on the basis of the natural immunomodulator tuftsin. Selank is a powerful anxiolytic that is used as a therapy for generalized anxiety disorder and neurasthenia without sedative and muscle-relaxant effects. This review presents the results of research aimed at studying the influence of these peptides on the transcriptome of brain cells. The problems of drugs developed based on the clinical activities of Semax and Selank are discussed separately.

Analysis of monogenic forms and candidate genes of Parkinson’s disease (PD) does not allow to describe completely the contribution of genetic factors to the etiopathogenesis of the disorder. An approach associated with an analysis of changes in a transcriptome pattern during the development of the disease in model objects can be used to identify new candidate genes that are involved in the pathogenesis of PD. In this work, we performed a transcriptome analysis of a PD model, created via stereotaxic unilateral introduction of the 6-hydroxidopamine (6-OHDA) into the substantia nigra pars compacta (SNpc) of a rat brain, to identify new candidate genes for PD. We studied transcriptome alterations in the substantia nigra of the rat brains 2 weeks after toxin administration, when the rats developed the Parkinson-like phenotype, and 4 weeks after toxin administration, when maximal changes in the behavior of animals were observed. The transcriptome analysis of the substantia nigra of the rat brains at the first time point (2 weeks) revealed changes in expression of genes that were clustered with high significance (p

Parkinson’s disease (PD) is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons in the brain. The α-synuclein (SNCA) gene is one of the most studied genes involved in the pathogenesis of PD. In our study, we conducted a genetic analysis of promoter and intron single-nucleotide polymorphisms (SNPs) in the SNCA gene. We also analyzed the association of genotypes of these SNPs with expression levels of SNCA mRNA. One of four SNPs in the SNCA gene, and the rs2736990 polymorphism, associates with the risk of the sporadic form of PD in Russian population. The risk of PD was increased almost twofold in carriers of allele C (odds ratios = 1.9, 95% confidence interval: 1.2-2.91, p = 0.003). However, no association was found between any of the genotypes of SNPs tested (rs2583988, rs2619363, rs2619364 and rs2736990) and alterations in SNCA levels. Our findings support the hypothesis that the rs2736990 polymorphism is associated with PD. SNPs rs2583988, rs2619363 and rs2619364 in the promoter region of the SNCA gene themselves do not significantly influence the expression of SNCA. Most likely, SNCA gene expression is a very complex process that is affected by different genetic and epigenetic factors.

Mutations in PARK2 are one of the causes of Parkinson's disease (PD). Deletions and duplications/triplications of one exon or exon groups account for a large proportion of mutations in the gene. At the present time, it is still not fully clear whether heterozygous mutations cause the development of PD. Our study aimed at conducting screening for mutations in PARK2 in patients with a sporadic form of PD to clarify the role of PARK2 in the development of PD.The cohort of 327 patients with PD was screened by quantitative real-time polimerase chain reaction (PCR) with subsequent Sanger sequencing.It was found that a sufficiently large proportion of these patients (21 patients, 6.4%) were carriers of heterozygous deletions or duplications in PARK2. Analysis of PARK2 exon rearrangement carriers for the presence of point mutations in PARK2 did not reveal any variants with pathogenic significance.Thus, our data indicate that heterozygous deletions and duplications can play an important role in the pathogenesis of PD and can be considered as dominant mutations with low penetrance.

Aim of study: Since the discovery of microRNAs (miRNAs) in the 1990s, our knowledge about their biology has grown considerably. The increasing number of studies addressing the role of miRNAs in development and in various diseases emphasizes the need for a comprehensive catalogue of accurate sequence, expression and conservation information regarding the large number of miRNAs proposed recently in all organs and tissues. The objective of this study was to provide data on the levels of miRNA expression in 15 tissues of the normal human brain. Materials and methods: We conducted an analysis of the relative levels of 88 of the most abundantly expressed and best characterized miRNA derived postmortem from well-characterized samples of various regions of the brains from five normal individuals. Results: The cluster analysis revealed some differences in the relative levels of these miRNAs among the brain regions studied. Such diversity can be explained by different functioning of these brain regions. Conclusion: We hope that the data from the current study are a resource that will be useful to our colleagues in this exciting field, as more hypotheses will be generated and tested with regard to small noncoding RNA in the human brain in healthy and disease states.

Clinical studies have shown that Selank had an anxiolytic effect comparable to that of classical benzodiazepine drugs, which can enhance the inhibitory effect of GABA by allosteric modulation of GABAA receptors. These data suggest that the molecular mechanism of the effect of Selank may also be related to its ability to affect the performance of the GABAergic system. To test this hypothesis, we studied the changes in expression of 84 genes involved in the functioning of the GABAergic system and in the processes of neurotransmission in the culture of neuroblastoma IMR-32 cells using qPCR method. As test substances, in addition to Selank, we selected the major GABAA receptor ligand, GABA, the atypical antipsychotic, olanzapine, and combinations of these compounds (Selank and GABA; Selank and olanzapine). We found no changes in the mRNA levels of the genes studied under the effect of Selank. The combined effect of GABA and Selank led to nearly complete suppression of changes in expression of genes in which mRNA levels changed under the effect of GABA. When Selank was used in conjunction with olanzapine, the expression alterations of more genes were observed compared with olanzapine alone. The data obtained indicate that Selank has no direct effect on the mRNA levels of the GABAergic system genes in neuroblastoma IMR-32 cells. At the same time, our results partially confirm the hypothesis that the peptide may affect the interaction of GABA with GABAA receptors. Our data also suggest that Selank may enhance the effect of olanzapine on the expression of the genes studied.

Clinical studies have shown the similarity of the spectrum of physiological effects of Selank and classical benzodiazepines, such as diazepam and phenazepam. These data suggest that there is a similar basis of their mechanism of action. To test this hypothesis we studied the effect of Selank and GABA on the expression of genes involved in the neuroreсeption and neurotransmission. We analyzed the expression of 84 genes involved in neuroreсeption (e.g., major subunit of the GABA receptor, transporters, ion channels, dopamine and serotonin receptors) in the frontal cortex of rats 1 and 3 hours after the administration of Selank or GABA (300 μg/kg) using real-time PCR method. We found significant changes in the expression of 45 genes 1 hour after the administration of the compounds. Three hours after Selank or GABA administration, 22 genes changed their expression. We found positive correlation between the changes in genes expression within 1 hour after administration of Selank or GABA. Our results showed that Selank caused a number of alterations in the expression of genes involved in neuroreсeption. The data obtained indicate that Selank is characterized by its complex effects on nerve cells, and one of its possible molecular mechanisms is associated with allosteric modulation of the GABAergic system.

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia. This work was supported by R01 HG 006855 (to S.A.M), by the Stanley Center for Psychiatric Research (to S.A.M and B.S.), by R01 MH077139 (to the PGC), and by T32 GM007753 (to A.S. and M.B.).

Parkinson's disease is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons from the substantia nigra pars compacta of human brain. However, causes and mechanisms of the progression of the disease are not yet fully clarified. To date, investigation of the role of miRNAs in norm and pathology is one of the most intriguing and actively developing areas in molecular biology. MiRNAs regulate expression of a variety of genes and can be implicated in pathogenesis of various diseases. Possible role of miRNAs in pathogenesis of Parkinson's disease is discussed in this review.

Previous studies have shown that synthetic tuftsin analogue Selank causes a transcriptomic response in the rat hippocampus and in spleen cells and may participate in the regulation of inflammatory processes in the body. In this work we studied the effect of Selank and two of its fragments on the expression of genes involved in processes of inflammation. We analyzed the expression of 84 genes involved in processes of inflammation (e.g., chemokines, cytokines, and its receptors) in mouse spleen 6 and 24 h after Selank single intraperitoneal injection (100 μg/kg) using real-time PCR method. We found significant changes in the expression of 34 genes involved in inflammation processes. The detailed analysis of quantitative data showed that the Bcl6 gene, which plays a main role in the formation and development of the immune system, exhibited significant changes in its expression levels in response to injection of each of the peptides. Also, we observed expression changes for Bcl6 target and corepressor genes under the influence of Selank and its fragments. Our results showed that Selank and its fragments caused a number of alterations in the expression of genes involved in inflammation. The data obtained confirmed the participation of Selank in the processes of regulation of inflammation in the body. The complex biological effect of Selank may be partially determined by the systematic effect of this peptide on genomic expression.

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Detecting changes in gene expression in untreated de novo patients with PD is important for understanding the disease pathogenesis and for identifying biomarkers of the preclinical stage of PD. In this study, the expression of the glycogen synthase kinase-3 beta gene (GSK3B) was investigated in the peripheral blood of several groups of neurological patients using reverse transcription reaction and real-time PCR. Our results suggest that the GSK3B expression level cannot serve as a biomarker for early stages of PD.

Parkinson’s disease (PD) is a severe neurological disorder pathogenesis of which involves various genetic systems and environmental factors. However, despite extensive research on this disease, its causes remain incompletely elucidated and the exact range of genes and mutations involved in pathogenesis of the hereditary forms of PD has not yet been fully clarified. The present work is devoted to the analysis of mutations that lead to development of monogenic forms of PD in patients with the suspected autosomal dominant form of PD using multiplex ligation-dependent probe amplification (MLPA). We have identified several mutations (G2019S in LRRK2, heterozygous deletions of 2–3, 3–4 exons and heterozygous duplication of 2–4 exons in the PARK2 gene, deletion of the 3 exon in the PARK7 gene) that lead to development in only 7 people out of 70 (18.4%), which suggests the need for further research on new mutations, for example, using exome sequencing. In the future, this will help in developing molecular genetic tests for early preclinical diagnostics and risk evaluation of PD and understanding the causes and mechanisms of this disease better.

Neurotrophins are a family of structurally related proteins that regulate the survival, differentiation, and maintenance of function of different neuron populations. Some peptides are able to affect the production and activity of neurotrophins. One of these synthetic peptides is heptapeptide Semax, an analog of the N-terminal adrenocorticotropic hormone fragment 4-10. It is known that Semax has effects on learning and memory formation and exerts some neuroprotective effects in rodents and humans. Male Wistar rats were treated for 20 min, 40 min, 90 min, 3 h, 8 h, and 24 h with Semax. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) gene expression in rat brain and retina was analyzed by real-time polymerase chain reaction. It was revealed that after Semax administration the multidirectional activation of the expression of the genes under investigation in the hippocampus, frontal cortex, and retina was observed. The expression of both neurotrophin genes was decreased in rat hippocampus and retina 20 min after Semax administration and was increased in the frontal cortex. The expression levels of NGF remained practically constant in the retina at the initial stage, whereas the expression levels of BDNF were significantly increased 90 min after Semax administration.

Parkinson’s disease is a complex disorder that is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Its development is determined by the interaction between the genetic constitution of a body and environmental factors. Analysis of the genes associated with monogenic forms of Parkinson’s disease implicated proteasomal degradation, differentiation of dopaminergic neurons, mitochondrial dysfunction, and oxidative damage in its pathogenesis. The review considers ample data that suggest a key role for mitochondrial dysfunction and oxidative stress.

The heptapeptide Semax, an analogue of the N-terminal adrenocorticotropic hormone fragment (4–10) (ACTH 4–10 ), has been shown to exert a number of neuroprotective effects. There are some investigations that connected these effects with the increase of neurotrophin gene expression under the peptide drug application in neuron cell cultures [M.I. Shadrina, O.V. Dolotov, I.A. Grivennikov, P.A. Slominsky, L.A. Andreeva, L.S. Inozemtseva, S.A. Limborska, N.F. Myasoedov, Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analogue, Neurosci. Lett. 308 (2001) (2) 115–118]. In this work, we examined the action of Semax on rapid changes of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) gene expression in vivo. Male Wistar rats were treated for 1 h with Semax (50 μg/kg, single intranasal application) and neurotrophin gene expression in rat brain was analyzed by real-time polymerase chain reaction (PCR). It was revealed that an intranasal application of Semax increased the expression of both neurotrophin genes in rat hippocampus. Bdnf gene expression also increased in the brainstem and cerebellum. Ngf gene expression decreased in rat frontal cortex. Thus, Semax induces rapid, gene- and region-specific changes in neurotrophin gene expression in normal rat brain.

Parkinson’s disease (PD) is a widespread neurodegenerative disorder. Despite the intensive studies of this pathology, in general, the picture of the etiopathogenesis has still not been clarified fully. To understand better the mechanisms underlying the pathogenesis of PD, we analyzed the expression of 10 genes in the peripheral blood of treated and untreated patients with PD. 35 untreated patients with PD and 12 treated patients with Parkinson’s disease (Hoehn and Yahr scores 1-2) were studied. An analysis of the mRNA levels ofATP13A2,PARK2,PARK7,PINK1,LRRK2,SNCA,ALDH1A1,PDHB,PPARGC1A, andZNF746genes in the peripheral blood of patients was carried out using reverse transcription followed by real-time PCR. A statistically significant and specific increase by more than 1.5-fold in the expression of theATP13A2,PARK7, andZNF746genes was observed in patients with PD. Based on these results, it can be suggested that the upregulation of the mRNA levels ofATP13A2,PARK7, andZNF746in untreated patients in the earliest clinical stages can also be observed in the preclinical stages of PD, and that these genes can be considered as potential biomarkers of the preclinical stage of PD.

Background: Parkinson’s disease (PD) is caused by complex interactions between genetic and environmental factors. Mendelian forms of PD rarely occur in practice, but respective genes may play some role in pathogenesis of a common sporadic form of the disease. Methods: We analyzed most frequent known point mutations (PMs) and single-nucleotide polymorphisms (SNPs) in genes responsible for monogenic PD in 408 Russian patients, using arrayed primer extension (APEX), real-time PCR, and restriction fragment length polymorphism analysis. Results: We detected only three heterozygous PMs in the PARK2 gene in three non-related patients with early-onset sporadic PD. No association between PD and the studied SNPs was identified. Conclusion: The examined PMs and SNPs in genes responsible for monogenic PD do not contribute significantly to the development of sporadic PD in Russia.

1 Abstract The sequence of the first hypervariable segment (HVS-I) of mi- tochondrial DNA (mtDNA) was determined in 251 individuals from three eastern Slavonic populations, two Russian and one Belorussian. Within HVS-I, 78 polymorphic positions were revealed. Within-population diversity of HVS-I varies slightly among three samples; its estimates do not differ strongly from those for European populations. Haplotype diversity for three populations calculated in this study is 0.949; mean pairwise differences esti- mate is 3.59. To assign mtDNA sequences to major phylogenetic clusters, haplogroup-specific restriction polymorphisms were selectively typed in most samples. The haplogroup distribution in the total Eastern Slavonic sam- ple is similar to that reported for the European sample. However, the separate consideration of three Slavonic samples reveals the complicated structure of the mitochondrial gene pool in the Eastern European area. Data of this study support the proposed model of the origin of modern Eastern Slavs, which im- plies the admixture of ancient Slavonic tribes with pre-Slavonic populations of Eastern Europe. These data should contribute to general studies of mito- chondrial DNA variations in Europe.

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease that arises as a result of the destruction of dopaminergic neurons. Reasons for the development of PD are not completely clarified and, at present, a number of genes involved in the development of both familial and sporadic PD forms have been detected. According to recent data from genome-wide association studies, single nucleotide polymorphisms (SNPs) in these genes (including the MAPT locus) can play a significant role in the development of PD. In connection with the above, we analyzed the distribution of genotype frequencies of SNP rs415430 in WNT3 gene in Russian patients with sporadic PD and in Russian population controls (OR = 0.84, Confidence Interval (95% CI) 0.58–1.23, p = 0.39). We conclude that the WNT3 gene rs415430 SNP does not influence the risk of the development of PD in the Russian population.