Genetics of psycho-emotional well-being: genome-wide association study and polygenic risk score analysis

BackgroundPsycho-emotional well-being is essential for living a life of satisfaction and fulfillment. However, depression and anxiety have become the leading mental health issues worldwide, according to the World Health Organization. Both disorders have been linked to stress and other psychological factors. Their genetic basis remains understudied.MethodsIn 2020–2021, the psycho-emotional well-being of 30,063 Russians with no known psychiatric history was assessed using the Hospital Anxiety and Depression Scale (HADS) for general mental health and the HADS subscale A (anxiety) for anxiety. Following the original instructions, an anxiety score of ≥11 points was used as the anxiety threshold. A genome-wide association study was performed to find associations between anxiety and HADS/HADS-A scores using linear and logistic regressions based on HADS/HADS-A scores as binary and continuous variables, respectively. In addition, the links between anxiety, sociodemographic factors (such as age, sex, and employment), lifestyle (such as physical activity, sleep duration, and smoking), and markers of caffeine and alcohol metabolism were analyzed. To assess the risk of anxiety, polygenic risk score modeling was carried out using open-access software and principal component analysis (PCA) to simplify the calculations (ROC AUC = 89.4 ± 2.2% on the test set).ResultsThere was a strong positive association between HADS/HADS-A scores and sociodemographic factors and lifestyle. New single-nucleotide polymorphisms (SNPs) with genome-wide significance were discovered, which had not been associated with anxiety or other stress-related conditions but were located in genes previously associated with bipolar disorder, schizophrenia, or emotional instability. The CACNA1C variant rs1205787230 was associated with clinical anxiety (a HADS-A score of ≥11 points). There was an association between anxiety levels (HADS-A scores) and genes involved in the activity of excitatory neurotransmitters: PTPRN2 (rs3857647), DLGAP4 (rs8114927), and STK24 (rs9517326).ConclusionOur results suggest that calcium channels and monoamine neurotransmitters, as well as SNPs in genes directly or indirectly affecting neurogenesis and synaptic functions, may be involved in the development of increased anxiety. The role of some non-genetic factors and the clinical significance of physiological markers such as lifestyle were also demonstrated

Energy Metabolites and Indicative Significance of α-Ketoglutarate and α-Ketoglutaramate in Assessing the Progression of Chronic Hepatoencephalopathy

In the example of a rat model with chronic hepatoencephalopathy (HE), changes in the organ morphology of rats affect the balance of metabolites of the tricarboxylic acid (TCA) cycle and metabolites of the glutamine–glutamate (Gln-Glu) cycle, namely α-ketoglutarate (αKG) and α-ketoglutaramate (αKGM), as well as the enzymes associated with them, ω-amidase (ωA) and glutamine transaminase (GTK). This model of rats was obtained as a result of 2–22 weeks of consumption by animals of hepatotoxin thioacetamide (TAA) added to drinking water at a concentration of 0.4 g/L. The control (n = 26) and TAA-induced (n = 55) groups of rats consisted of 11 cohorts each. The control cohorts consisted of 2–4 rats, and the TAA-induced cohorts consisted of 4–7 individuals. Every two weeks, samples of blood plasma, liver, kidney, and brain tissues were taken from the next cohort of rats (a total of 320 samples). By the end of the experiment, irreversible morphological changes were observed in the organs of rats: the weight of the animals was reduced up to ~45%, the weight of the kidneys up to 5%, the brain up to ~20%, and the weight of the liver increased up to ~20%. The analysis revealed: (i) a decrease in the activity of ωA and GTK in the tissues of the brain, kidneys, and liver of rats with chronic HE (by ~3, 40, and 65% and ~10, 60, and 70%, respectively); and (ii) the appearance of a significant imbalance in the content of metabolites of the Gln-Glu cycle, αKG, and αKGM. It is indicative that a ~1.5–12-fold increase in the level of αKG in the blood plasma and tissues of the organs of rats with chronic HE was accompanied by a synchronous, ~1.2–2.5-fold decrease in the level of αKGM. The data obtained indicate an essential involvement of the Gln-Glu cycle in the regulation of energy metabolism in rats under conditions of chronic HE. Attention is focused on the significance of the αKG/αKGM ratio, which can act as a potential marker for diagnosing the degree of HE development

B16 cells stimulated the growth of DRG neurons <i>in vitro</i>.

<p>DRG cultures were treated with B16-conditioned medium (10% v/v, 72 h), stained for Neuronal class III ß-tubulin (A, upper panels) and subjected to 3D neuron and dendrite reconstruction (A, lower panels).Quantitative analysis was performed to determine DRGdendritic length, area, volume, and the number of segments and t branches per slide using the FilamentTracer module of Imaris (Bitplane) software package as described in Materials and Methods (B). Bars represent morphometric parameters of neurons treated with B16 conditioned medium as the percentage of control non-treated neurons. Representative images and automated data from one experiment are shown. Data from four independent cultures were combined to determine means±SEM.</p

Pre-existence of DRG neurons within the Matrigel increased B16 melanoma growth in the Matrigel in mice.

<p>C57BL/6 mice (5 mice/group) received s.c. injection of control Matrigel (500μl ECM gel diluted 1:1 in RPMI 1640) and Matrigel with cultured DRG neurons (1x10⁴ cells). B16 cells (5x10⁴/300μl PBS) were administered into the Matrigel plaques two weeks later. Animals were sacrificed two weeks post tumor inoculation, and Matrigel plaques were weighted to characterize tumor growth (A). 50x10³ tumor cells alone or mixed with cultured DRG neurons (1:5 cell:cell ratio). (A). The presence of live DRG neurons in the Matrigel harvested two weeks after administration, i.e., right before the tumor cell injection, was determined by immunohistochemistry with anti-Neurofilament H antibody as described in Materials and Methods (B). Left panel show control Matrigel, right panel show Matrigel with added DRG neurons two weeks after injections. Matrigel weight is expressed as the mean ± SEM. *, p<0.05 (ANOVA, n = 3).</p

DRG neurons do not affect proliferation of B16 cells in vitro.

<p>B16 cells were cultured in the presence of DRG culture medium (10% v/v), and DRG conditioned medium (10% v/v) and cell proliferation were determined by the ³H-thymidine incorporation assay as described in Materials and Methods (A). The results are expressed as counts per minute (cpm) and shown as the mean±SEM (n = 3). Analysis of cell cycle was done by flow cytometry using propidium iodide (PI) to label DNA content in B16 cells cultured with and w/o DRG conditioned medium (B). The results of a representative experiment are shown (n = 2).</p

Co-administration of DRG neurons with B16 melanoma cells up-regulated tumor growth in mice.

<p>C57BL/6 mice (5 mice/group) received s.c. injection of 50x10³ tumor cells alone or mixed with cultured DRG neurons (1:5 cell:cell ratio). Tumor size was assessed using a caliper and expressed in mm² (A). Administration of DRG cells alone, as expected, did not induce any tumor growth. Tumor tissues were harvested two weeks later, and the presence of live DRG neurons in the tumor was determined by DAB staining after 14 days using an antibody against the anti-Neurofilament H epitope (B). Left panels show control tumors (administration of B16 cell alone), right panels show tumors growing in mice receiving B16+DRG neurons injections. Tumor size is expressed as the mean ± SEM. *, p<0.05 (ANOVA, n = 3).</p

Accelerated growth of melanoma in the presence of DRG neurons was accompanied by an increased tumor infiltration by MDSC <i>in vivo</i>.

<p>C57BL/6 mice received s.c. injection of control Matrigel and Matrigel with DRG neurons as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0156095#pone.0156095.g002" target="_blank">Fig 2</a> legend. B16 cells were administered into the Matrigel plaques two weeks later. Animals were sacrificed two weeks post tumor inoculation, and Matrigel plaques were harvested, dissolved and subject for the presence of granulocytic CD11b⁺Ly6G⁺ and monocytic CD11b⁺Ly6C⁺ MDSC among CD45⁺ leukocytes by flow cytometry. The results of a representative experiment from six mice analyzed in two independent studies are shown.</p

Functional Characteristics of Serum Anti-SARS-CoV-2 Antibodies against Delta and Omicron Variants after Vaccination with Sputnik V

Anti-SARS-CoV-2 vaccination leads to the production of neutralizing as well as non-neutralizing antibodies. In the current study, we investigated the temporal dynamics of both sides of immunity after vaccination with two doses of Sputnik V against SARS-CoV-2 variants Wuhan-Hu-1 SARS-CoV-2 G614-variant (D614G), B.1.617.2 (Delta), and BA.1 (Omicron). First, we constructed a SARS-CoV-2 pseudovirus assay to assess the neutralization activity of vaccine sera. We show that serum neutralization activity against BA.1 compared to D614G is decreased by 8.16-, 11.05-, and 11.16- fold in 1, 4, and 6 months after vaccination, respectively. Moreover, previous vaccination did not increase serum neutralization activity against BA.1 in recovered patients. Next, we used the ADMP assay to evaluate the Fc-mediated function of vaccine-induced serum antibodies. Our results show that the antibody-dependent phagocytosis triggered by S-proteins of the D614G, B.1.617.2 and BA.1 variants did not differ significantly in vaccinated individuals. Moreover, the ADMP efficacy was retained over up to 6 months in vaccine sera. Our results demonstrate differences in the temporal dynamics of neutralizing and non-neutralizing antibody functions after vaccination with Sputnik V