The ribosome is a critical component of the translation machinery. The key component of ribosomes is ribosomal RNA (rRNA). Dysregulation of rRNA biogenesis has been implicated in some human diseases. ...One of the factors affecting rRNA biogenesis is the ribosomal RNA genes (rDNA) copy number in the genome. The aim of this study was to examine the rDNA copy number (CN) variation in the genomes of patients with schizophrenia (SZ) compared to healthy controls (HC).
We evaluated rDNA CN in leukocytes of 179 subjects with SZ (108 male/71 female) in comparison with 122 HC (60 male/62 female) using two techniques: qPCR and nonradioactive quantitative hybridization (NQH), which is based on the use of biotinylated rDNA probes.
rDNA CN (NQH) and rDNA CN (qPCR) was higher in SZ patients than in controls (median 542 vs 384, p=10−25 and median 498 vs 370, p=10−12). NQH was experimentally proved to be less sensitive to severe DNA damage than qPCR. The more DNA damage, the higher the ratio R=CN (NQH)/CN (qPCR). 15% of the SZ patients had significantly higher rDNA damage degree than the HC.
Genomes of some SZ patients contain more ribosomal genes than those of HC. The elevated ribosomal genes copy number in human genome can be one of the genetic factors of schizophrenia development. This hypothesis requires further experimental studies to be corroborated or disproved.
•rDNA content was determined in the leukocytes of 179 SZ patients and 122 healthy controls.•SZ patients contain more rDNA copies than healthy controls.•The rDNA damage in some SZ patients was significantly higher than in the HC group.
Earlier we studied the copy number variations (CNVs) of ribosomal repeat (rDNA) and the satellite III fragment (1q12) (f-SatIII) in the cells of schizophrenia patients (SZ) and healthy controls (HC). ...In the present study we pursued two main objectives: (1) to confirm the increased rDNA and decreased f-SatIII content in the genomes of enlarged SZ and HC samples and (2) to compare the rDNA and f-SatIII content in the same DNA samples of SZ and HC individuals.
We determined the rDNA CN and f-SatIII content in the genomes of leukocytes of 1770 subjects HC (N = 814) and SZ (N = 956). Non-radioactive quantitative hybridization method (NQH) was applied for analysis of the various combinations of the two repeats sizes in SZ and HC groups.
f-SatIII in human leukocytes (N = 1556) varies between 5.7 and 44.7 pg/ng DNA. RDNA CN varies between 200 and 896 (N = 1770). SZ group significantly differ from the HC group by lower f-SatIII content and by rDNA abundance. The f-SatIII and rDNA CN are not randomly combined in the genome. Higher rDNA CN values are associated with higher f-SatIII index values in SZ and HC. The f-SatIII variation interval in SZ group increases significantly in the subgroup with the high rDNA CN index values (>300 copies).
Schizophrenia patients' genomes contain low number of f-SatIII copies corresponding with a large ribosomal repeats CN. A scheme is proposed to explain the low f-SatIII content in SZ group against the background of high rDNA CN.
•The patient with an SLC6A1 mutation, typically linked to disorders like epilepsy and autism, exhibited symptoms consistent with schizophrenia and bipolar disorder.•The patient's polygenic risk score ...was aligned with both schizophrenia and bipolar disorder, despite no family history of psychiatric disorders.•The study contributed to ongoing discussion of the importance of GABAergic processes in schizophrenia's etiology.
Studies of the genomic architecture of complex phenotypes, which include common somatic and mental diseases, have shown them to be characterized by high levels of polygenicity, i.e., there are large ...numbers of genes associated with the risk of developing these diseases. There is interest in establishing the genetic similarity of these two groups of diseases. The purpose of the present review is to analyze genetic studies of the comorbidity of somatic and mental diseases from the point of view of the universality and specificity of mental disorders in somatic diseases, the reciprocal relationships of these types of pathologies, and the modulating influence of external environmental factors on comorbidity. The analysis results point to the existence of a common genetic predisposition to mental and somatic diseases. The existence of genes common to both does not exclude specificity of the development of mental disorders in relation to specific somatic pathologies. We can suggest the existence of genes unique to a particular somatic and comorbid mental illness, as well as genes common to these diseases. Common genes may have varying degrees of specificity, i.e., they are universal in nature, this being apparent, for example, in the development of major depressive disorder in a variety of somatic diseases; common genes can also be specific for only a couple of individual diseases (schizophrenia and breast cancer). Moreover, common genes can have multidirectional effects, which also contributes to the specificity of comorbidity. In addition, the search for common genes for somatic and mental diseases needs account to be taken of the modulating influences of confounding factors (treatment, unhealthy lifestyle, behavioral characteristics), which may also differ in specificity depending on the diseases in question.
This review presents data indicating that the formation of the psychopathological symptoms of schizophrenia is due to complex and diverse genetic factors associated with various functional and ...metabolic pathways at different stages of ontogenesis. Although the genetic basis of the main pathophysiological manifestations of schizophrenia – positive and negative symptoms – currently remains largely unknown, the ongoing level of research allows some associations, both common and unique to positive and negative disorders, to be identified. Literature analysis demonstrates the specificity of the association of genetic variants with negative symptoms of schizophrenia, and it is also suggested that immune system genes may be specifically associated with the negative symptoms of schizophrenia. The relevance of studying the relationship between immune system genes, in particular those for pro- and anti-inflammatory cytokines, with the dimensional characteristics of negative symptoms (the abulia-apathy and expressive deficiency factors) has good grounds. Studies of this type have not yet been conducted despite evidence indicating that heterogeneity in negative symptoms is based on different neurobiological mechanisms. It is concluded that the immunological and molecular genetic study of the subdomains of psychopathological symptoms may be promising as part of the transition to deep phenotyping, which seems to be particularly relevant for investigations of a disease with such extreme clinical heterogeneity as schizophrenia. Progress in this direction is important for solving the challenges of precision medicine, which aims to provide the most effective therapy for individual patients by stratifying the disease into subclasses, taking account of their biological bases.
The aim of the present review was to consider different approaches to establishing genotype–phenotype relationships in schizophrenia taking account of schizophrenia-specific mediating factors in the ...light of contemporary advances in human genome research. A variety of structural elements of the genome are shown to be able to contribute to formation of the phenotype. Genotype–phenotype relationships can be mediated by epigenetic effects, which can have different origins – from the currently best studied methylation of defined sites in the genome to recently developing concepts of remote regulatory genomic elements in the origination of schizophrenia. The transition to more in-depth investigations of the relationship between genotype and phenotype is relevant to the current period of molecular genetic research in schizophrenia. The concept of “phenotype” as applied to schizophrenia clearly does not reduce to a causal reflection of changes in the structure of a particular gene, but is the product of a set of the actions of environmental factors and epigenetic changes influencing gene expression, taking account of tissue specificity and the level of cell stimulation.
Schizophrenia is a severe mental disorder characterized by positive and negative symptoms. The negative symptoms are highly relevant to the disease course and outcome. Because negative symptoms show ...considerable heterogeneity, there is substantial interest in elucidating the negative symptom domains that are characteristic of patient subgroups. It has been proposed that patients with schizophrenia should be classified into deficit and non-deficit groups based on the severity of their negative symptoms. Another method suggested the assessment of the factor structure of negative symptoms to understand its mechanisms. Factor analysis of the different negative symptom rating scales reveals two distinct negative symptom subdomains: diminished expression (DE) and avolition/apathy (AA). These characteristics suggest different pathophysiological mechanisms for the development of AA and DE. We present a large dataset of negative symptom factors calculated for 3006 patients with schizophrenia in the Russian population. Sex, age, age at disease onset and data of birth, including season of birth (SOB), family history of schizophrenia are presented. Negative symptoms were assessed with the Positive and Negative Syndromes Scale (PANSS). We calculated negative symptoms factors as suggested by Liemburg et al. (2013). The data will be useful in assessing the impact of such factors as sex, season of birth (SOB) and family history on the scores of negative symptoms subdomains; such data can help us to better understand the heterogeneity of the negative symptoms of schizophrenia.
Objectives.
To assess the role of interactions between oxytocin pathway gene polymorphisms and adverse childhood experiences (ACE) in deficits of the recognition of emotion in schizophrenia.
...Materials and methods
. Patients with schizophrenia spectrum disorders (
n
= 699) underwent cognitive testing in which they performed a facial emotion recognition task. Patients were then genotyped for common polymorphisms in oxytocin pathway genes which have previously been associated with face perception:
OXTR
(rs53576, rs7632287),
CD38
(rs3796863), and
ARNT2
(rs4778599). The presence of ACE factors was assessed by review of medical records.
Results
. ACE was found in 49% of patients. Analysis of covariance with control for sex and age revealed an interaction effect between
OXTR
rs53576 and ACE on emotion recognition in patients (F = 11.51;
p
< 0.001;
η
p
2
= 0.02). This effect remained significant when controlling for cognitive functioning and negative symptoms. Carriers of the A allele without ACE were worse at recognizing emotions than GG homozygotes without ACE (
p
= 0.039) and carriers of the A allele with ACE (
p
= 0.009).
Conclusions
. The present results are consistent with the role of the A allele (rs53576) in sensitivity to the characteristics of childhood experiences able to affect psychosocial development and are of value for further studies of the use of oxytocin to improve social cognition and social adaptation of patients with schizophrenia.
The role of the VNTR polymorphism of the
AS3MT
gene in determining the clinical features of schizophrenia and schizophrenic spectrum disorders was studied. The analysis included 670 individuals. We ...found no differences in PANSS scores for positive, negative, and common psychopathological symptoms between the carriers of different genotypes. The interaction of the studied polymorphism and obstetrical complications as an environmental factor was found. The genotype-environment interactions were identified for one of the characteristics reflecting the severity of schizophrenia: the level of negative symptoms. Women with the
V2/V2
genotype, who have obstetrical complications, showed significantly higher negative symptoms scores, which was associated with a poor prognosis of the disease.
Objectives
. Working from the hypothesis that activation of the immune system is one of the mechanisms whereby early environmental factors influence the onset and course of schizophrenia, we studied ...the effects of the interaction of adverse childhood experiences (ACE) and genotypes at the polymorphic loci rs16944 of the
IL1B
gene, rs2243250 of the
IL4
gene, and rs1800629 of the
TNF
-
α
gene on the severity of different groups of schizophrenia symptoms.
Materials and methods
. The cohort consisted of 546 patients with schizophrenia spectrum disorders. ACE was detected by analysis of medical records and a questionnaire completed by the patients. A five-factor Positive and Negative Syndrome Scale (PANSS) model with a built-in two-factor model of the negative syndrome was used.
Results
. The interaction of ACE and
TNF
-
α
was found to have a significant effect on the cognitive disorganization factor after adjusting for multiple comparisons, with discrimination of carriers of different genotypes in the group without ACE (
p
FDR
< 0.018;
= 0.03). The interaction of ACE and genotype was found to have a significant effect on the cognitive disorganization syndrome (F = 5.87;
p
= 0.003;
= 0.03). Stereotyped thinking and volitional disorder identified on the PANSS showed the strongest correlations with the cognitive disorganization factor (
r
o
= 0.84 and
r
o
= 0.82, respectively) and the most significant differences depending on the interaction of genotype and ACE (Kruskal–Wallis test, H = 12.28,
p
= 0.006 and H = 12.79,
p
= 0.005, respectively).
Conclusions
. ACE modifies the relationship between the pathogenesis of schizophrenia and the rs1800629 polymorphic locus located in the
TNF-α
gene promoter, which is also an enhancer of 60 more genes located in the major histocompatibility complex.
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