Hereditary factors contribute significantly to the development of schizophrenia. However, despite many years of research, the genetic architecture and mechanisms of the participation of genetic ...factors in the development of schizophrenia are not well understood. Genome-wide analyzes of genetic associations in various non-coding regions of the genome, including gene enhancers, revealed many loci associated with an increased risk of schizophrenia. In the course of the analysis of the spatial structure of the genome, we revealed the interaction of these enhancers with the promoter regions of genes involved in the metabolism of neurons. To study in more detail the functions of these genes and the participation of enhancers in their regulation, we obtained plasmid and lentiviral constructs of a functionally active transcription repressor based on the CRISPR / SpyCas9 system, as well as the endonuclease system. The use of these constructs in studies of the functions of enhancers and genes associated with the metabolism and regulation of gene expression in neurons is discussed.
Dopamine transmission is known to play an important role in the reinforcement system of the brain. Studies have identified dopamine system genes whose polymorphic variants have been linked with the ...intensity of psychological traits reflecting the tendency to form behaviors characterized by impulsivity and the need for additional stimulation. The aim of the present work was to seek associations between polymorphisms in the catechol-O-methyltransferase (COMT) and D4 dopamine receptor (DRD4) genes and personality traits in the Russian population. Studies of 130 subjects showed that carriers of the Met/Met genotype of the COMT gene had a greater intensity of the novelty-seeking trait than carriers of the Val/Val and Val/Met genotypes, though this association was seen only in women. In addition, the presence of the C allele of the DRD4 gene in carriers of the Met/Met genotype showed high levels of extraversion and hypomania. These results are consistent with current theoretical concepts of the regulation of dopamine transmission in the brain.
There is growing evidence that serum levels of various inflammation markers are associated with personality traits. However, only few studies investigated the link between genetic variants of ...cytokine encoding genes and psychological characteristics. In this study, we examined genotypes in 297 individuals to assess the association between common variants of interleukin 4 (
IL
-4) and interleukin 10 (
IL
-10) genes and basic personality traits of extraversion and neuroticism, measured using the Eysenck Personality Questionnaire (EPQ). We found that, in homozygous female carriers of high expression alleles Т (
IL-4
C-589T) and G (
IL-10
G-1082A), neuroticism scores were higher (
p
= 0.045 and
p
= 0.08, respectively). In turn, extraversion scores were significantly higher in both male and female carriers of heterozygous variants CT and GA (
p
= 0.01). Our results are in accordance with the behavioral immune system hypothesis, and the general paradigm on the role of personality traits in health and longevity.
Associations of
BDNF Val66Met
polymorphism with such components of executive functions as verbal fluency, working memory, attention set shifting, and response inhibition were evaluated. A total of ...401 healthy volunteers were genotyped. The effect of polymorphism on working memory during the counting test was detected. The test performance in heterozygotic carriers was much worse than in homozygotic ones. Individuals with the
MetMet
genotype demonstrated the best results, presumably due to molecular mechanisms compensating for the neuropeptide secretion deficiency.
To study the association between proinflammatory cytokine genes and depression.
IL-1B С-511T and TNF-a G-308A gene polymorphisms were studied in patients diagnosed with depression and age and ...sex-matched healthy controls.
The IL-1B С-511T and TNF-a G-308A polymorphisms were associated with depression; CC genotype (р=0,001, OR=1.9 CI 1,3-2,7) and GG genotype (р=0,001, OR=3,0 CI 1,8-4,9) were the risk factors. The results suggest that immune factors may play a role in the development of depression. The authors highlight the role of clinical polymorphism of depression that makes it difficult to form homogenous groups of patients and to select phenotypes for biological studies.
Associations of genes for the serotonin transporter (the 5-HTTLPR polymorphism) and the brain-derived neurotrophic factor (the BDNF Val66Met polymorphism) with the neurophysiological characteristics ...at the initial stage of processing lexical information in patients with schizophrenia spectrum disorder and human mental health were studied. Neurophysiological characteristics at the initial stage of processing meaningful verbal information were found to differ in carriers of different variants of the Val66Met and 5-HTTLPR polymorphisms. Word recognition efficiency in implicit conditions was greater in carriers of the ValVal (BDNF Val66Met) or SS (5-HTTLPR) polymorphisms than in carriers of the Met or L variants. Genetic variants were found to have significant effects in mentally healthy people but not in patients with schizophrenia disorders.
Disorders of social functioning are the most persistent consequences of schizophrenia and are an important factor influencing the prognosis of mental disorders. Considering the role of
HLA-G
in ...modulating the immunological relationship between the mother and the fetus and, as a consequence, its role in the development of the embryonic brain, we studied the influence of the INDEL polymorphism of the
HLA-G
gene on the social functioning of patients with schizophrenia. The study included 812 people with schizophrenia and schizophrenia spectrum disorders. It was found that, in carriers of the
D
/
D
genotype, there is a decrease in the level of social functioning in all areas, which increases the risk of an unfavorable functional outcome.
Research suggests that, in contrast to circulating C-reactive protein (CRP), genetic variants conferring higher CRP levels have protective effects against schizophrenia and moderate influences of ...season of birth on the development of the disease. This study aimed to explore whether the
CRP
gene also moderates the relations between childhood adversity and clinical characteristics of schizophrenia. The relations between childhood adversity, genotypes at rs2794521 within the
CRP
locus, syndromes measured as five factors and two negative subfactors of the Positive and Negative Syndrome Scale, and history of suicide attempts were analyzed in 921 schizophrenia patients. A significant effect of genotype on suicide attempts in patients exposed to childhood adversity was found. The result suggests a moderating role of genetic determinants of inflammation in translating early life psychological stress effects into risk of suicide attempts in schizophrenia.
To evaluate the association of the DRD2 gene and DRD2 x HTR2C interaction with hedonic and activational aspects of approach motivation in schizophrenia.
Genotypes at polymorphic loci DRD2 rs1800497 ...and HTR2C rs6318 (Cys23Ser) were identified in a sample that included 174 patients with schizophrenic spectrum disorders and 268 healthy subjects without a family history of psychoses. The participants completed the BIS/BAS and Temporal Experience of Pleasure Scale (TEPS).
A MANCOVA with sex and age as covariates revealed the effect of the 'DRD2 x HTR2C x diagnosis' interaction on the BAS scores (p=0.033). The effect was significant for the Fun-Seeking and Drive scales. Among patients, the carriers of the DRD2 TT/CT x HTR2C GG/G genotype showed the highest scores on the both scales, and those with the minor alleles in the two loci had the lowest ones. Differences between these groups were nominally significant for both the Fun-Seeking and Drive, but did not survive the correction for multiple comparisons. Among controls, subjects without minor alleles demonstrated the highest scores on these two scales. They differed significantly from the carriers of the DRD2 TT/CT+HTR2C GG/G genotype on the Fun-Seeking (p=0.008). No effects of DRD2 and HTR2C on TEPS scores were found. In general, the results of the study can be interpreted in favor of the hypothesis about the role of the HTR2C and DRD2 genes interaction in the variability of the activational aspects of approach motivation in schizophrenia and healthy subjects. However, the lack of differences survived correction for multiple comparisons makes it difficult to interpret the revealed effects.
The need to use large samples to identify the genetic risk loci of mental disorders has led us to the dilemma of phenotyping quality. Especially this problem relates to such common mental disorders ...as depression (lifetime prevalence 16.2%). On the one hand, there is a very resource-intensive method of capturing patient data by physicians using diagnostic criteria of mental disorders (DSM-V/ICD-10). On the other, there is a popular method of minimal phenotyping using hospital registers, self-reports of respondents on symptoms, diagnosis and treatment of depression. To date, there is no ideal method for phenotyping depression because all of them focus only on its clinical symptoms. The active usage of minimal phenotyping in Genome-Wide Association Study (GWAS) has led to a significant increase in both clinical and genetic heterogeneity of depression. However, an important limitation of using DSM-V/ICD-10 is the high cost of phenotyping due to the involvement of medical specialists. Thus, the most rational is to use electronic diagnostic questionnaires based on DSM-V/ICD-10 criteria. Such an approach will accelerate the increase in research capacity, but will preserve all internal contradictions inherent in official diagnostic classifications (heterogeneity of phenotypes, absence of objective diagnostic criteria, categorical approach, etc.). In this regard, the critical role of psychiatric epidemiology is growing both in the development of standardized tools for operationalized diagnostic criteria and in future GWAS by introducing new phenotypic subtypes of depression and its dimensions.
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