Enhanced polygenic risk score incorporating gene-environment interaction suggests the association of major depressive disorder with cardiac and lung function.

BACKGROUND: Depression has been linked to an increased risk of cardiovascular and respiratory diseases; however, its impact on cardiac and lung function remains unclear, especially when accounting for potential gene-environment interactions. METHODS: We developed a novel polygenic and gene-environment interaction risk score (PGIRS) integrating the major genetic effect and gene-environment interaction effect of depression-associated loci. The single nucleotide polymorphisms (SNPs) demonstrating major genetic effect or environmental interaction effect were obtained from genome-wide SNP association and SNP-environment interaction analyses of depression. We then calculated the depression PGIRS for non-depressed individuals, using smoking and alcohol consumption as environmental factors. Using linear regression analysis, we assessed the associations of PGIRS and conventional polygenic risk score (PRS) with lung function (N = 42 886) and cardiac function (N = 1791) in the subjects with or without exposing to smoking and alcohol drinking. RESULTS: We detected significant associations of depression PGIRS with cardiac and lung function, contrary to conventional depression PRS. Among smokers, forced vital capacity exhibited a negative association with PGIRS (ß = -0.037, FDR = 1.00 × 10-8), contrasting with no significant association with PRS (ß = -0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (ß = 0.088, FDR = 0.010), whereas no such association was found with PRS (ß = 0.040, FDR = 0.265). Notably, in individuals who both smoked and drank, forced expiratory volume in 1-second demonstrated a negative association with PGIRS (ß = -0.042, FDR = 6.30 × 10-9), but not with PRS (ß = -0.003, FDR = 0.857). CONCLUSIONS: Our findings underscore the profound impact of depression on cardiac and lung function, highlighting the enhanced efficacy of considering gene-environment interactions in PRS-based studies.

A genome-wide association study identifies candidate genes for sleep disturbances in depressed individuals.

OBJECTIVE: This study aimed to identify candidate loci and genes related to sleep disturbances in depressed individuals and clarify the co-occurrence of sleep disturbances and depression from the genetic perspective. METHODS: The study subjects (including 58,256 self-reported depressed individuals and 6,576 participants with PHQ-9 score ≥ 10, respectively) were collected from the UK Biobank, which were determined based on the Patient Health Questionnaire (PHQ-9) and self-reported depression status, respectively. Sleep related traits included chronotype, insomnia, snoring and daytime dozing. Genome-wide association studies (GWASs) of sleep related traits in depressed individuals were conducted by PLINK 2.0 adjusting age, sex, Townsend deprivation index and 10 principal components as covariates. The CAUSALdb database was used to explore the mental traits associated with the candidate genes identified by the GWAS. RESULTS: GWAS detected 15 loci significantly associated with chronotype in the subjects with self-reported depression, such as rs12736689 at RNASEL (P = 1.00 × 10- 09), rs509476 at RGS16 (P = 1.58 × 10- 09) and rs1006751 at RFX4 (P = 1.54 × 10- 08). 9 candidate loci were identified in the subjects with PHQ-9 ≥ 10, of which 2 loci were associated with insomnia such as rs115379847 at EVC2 (P = 3.50 × 10- 08), and 7 loci were associated with daytime dozing, such as rs140876133 at SMYD3 (P = 3.88 × 10- 08) and rs139156969 at ROBO2 (P = 3.58 × 10- 08). Multiple identified genes, such as RNASEL, RGS16, RFX4 and ROBO2 were reported to be associated with chronotype, depression or cognition in previous studies. CONCLUSION: Our study identified several candidate genes related to sleep disturbances in depressed individuals, which provided new clues for understanding the biological mechanism underlying the co-occurrence of depression and sleep disorders.

Epigenetic analysis suggests aberrant cerebellum brain aging in old-aged adults with autism spectrum disorder and schizophrenia.

The aberrant aging hypothesis of schizophrenia (SCZ) and autism spectrum disorder (ASD) has been proposed, and the DNA methylation (DNAm) clock, which is a cumulative evaluation of DNAm levels at age-related CpGs, could serve as a biological aging indicator. This study evaluated epigenetic brain aging of ASD and SCZ using Horvath's epigenetic clock, based on two public genome-wide DNA methylation datasets of post-mortem brain samples (NASD = 222; NSCZ = 142). Total subjects were further divided into subgroups by gender and age. The epigenetic age acceleration (AgeAccel) for each sample was calculated as the residual value resulting from the regression model and compared between groups. Results showed DNAm age has a strong correlation with chronological age in both datasets across multiple brain regions (P < 0.05). When divided into equally sized age groups, the AgeAccel of the cerebellum (CB) region from people over 45 years of age was greater compared to the control sample (AgeAccel of ASD vs control: 5.069 vs -6.249; P < 0.001). And a decelerated epigenetic aging process was observed in the CB region of individuals with SCZ aged 50-70 years (AgeAccel of SCZ vs control: -3.171 vs 2.418; P < 0.05). However, our results showed no significant difference in AgeAccel between ASD and control groups, and between SCZ and control groups in the total and gender-specific groups (P > 0.05). This study's results revealed some evidence for aberrant epigenetic CB brain aging in old-aged patients with ASD and SCZ, indicating a different pattern of CB aging in older adults with these two diseases. However, further studies of larger ASD and SCZ cohorts are necessary to make definitive conclusions on this observation.

An atlas of causal association between micronutrients and osteoarthritis.

OBJECTIVE: This study examines the causal relationships between serum micronutrients and site-specific osteoarthritis (OA) using Mendelian Randomization (MR). METHODS: This study performed a two-sample MR analysis to explore causal links between 21 micronutrients and 11 OA outcomes. These outcomes encompass overall OA, seven site-specific manifestations, and three joint replacement subtypes. Sensitivity analyses using MR methods, such as the weighted median, MR-Egger, and MR-PRESSO, assessed potential horizontal pleiotropy and heterogeneity. Genome-wide association summary statistical data were utilized for both exposure and outcome data, including up to 826,690 participants with 177,517 OA cases. All data was sourced from Genome-wide association studies datasets from 2009 to 2023. RESULTS: In the analysis of associations between 21 micronutrients and 11 OA outcomes, 15 showed Bonferroni-corrected significance (P < 0.000216), without significant heterogeneity or horizontal pleiotropy. Key findings include strong links between gamma-tocopherol and spine OA (OR = 1.70), and folate with hand OA in finger joints (OR = 1.15). For joint replacements, calcium showed a notable association with a reduced likelihood of total knee replacement (TKR) (OR = 0.52) and total joint replacement (TJR) (OR = 0.56). Serum iron was significantly associated with an increased risk of total hip replacement (THR) (OR = 1.23), while folate indicated a protective effect (OR = 0.95). Various sex-specific associations were also uncovered. CONCLUSION: These findings underscore the critical role of micronutrients in osteoarthritis, providing valuable insights for preventive care and potential enhancement of treatment outcomes.

Assessing the effect of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes.

Longitudinal changes in brain structure and lifestyle can affect sleep phenotypes. However, the influence of the interaction between longitudinal changes in brain structure and lifestyle on sleep phenotypes remains unclear. Genome-wide association study dataset of longitudinal changes in brain structure was obtained from published study. Phenotypic data of lifestyles and sleep phenotypes were obtained from UK Biobank cohort. Using genotype data from UK Biobank, we calculated polygenetic risk scores of longitudinal changes in brain structure phenotypes. Linear/logistic regression analysis was conducted to evaluate interactions between longitudinal changes in brain structure and lifestyles on sleep duration, chronotype, insomnia, snoring and daytime dozing. Multiple lifestyle × longitudinal changes in brain structure interactions were detected for 5 sleep phenotypes, such as physical activity×caudate_age2 for daytime dozing (OR = 1.0389, P = 8.84 × 10-3) in total samples, coffee intake×cerebellar white matter volume_age2 for daytime dozing (OR = 0.9652, P = 1.13 × 10-4) in females. Besides, we found 4 overlapping interactions in different sleep phenotypes. We conducted sex stratification analysis and identified one overlapping interaction between female and male. Our results support the moderate effects of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes, and deepen our understanding of the pathogenesis of sleep disorders.

Involvement of Yes-Associated Protein 1 Activation in the Matrix Degradation of Human-Induced-Pluripotent-Stem-Cell-Derived Chondrocytes Induced by T-2 Toxin and Deoxynivalenol Alone and in Combination.

T-2 toxin and deoxynivalenol (DON) are two prevalent mycotoxins that cause cartilage damage in Kashin-Beck disease (KBD). Cartilage extracellular matrix (ECM) degradation in chondrocytes is a significant pathological feature of KBD. It has been shown that the Hippo pathway is involved in cartilage ECM degradation. This study aimed to examine the effect of YAP, a major regulator of the Hippo pathway, on the ECM degradation in the hiPS-derived chondrocytes (hiPS-Ch) model of KBD. The hiPS-Ch injury models were established via treatment with T-2 toxin/DON alone or in combination. We found that T-2 toxin and DON inhibited the proliferation of hiPS-Ch in a dose-dependent manner; significantly increased the levels of YAP, SOX9, and MMP13; and decreased the levels of COL2A1 and ACAN (all p values < 0.05). Immunofluorescence revealed that YAP was primarily located in the nuclei of hiPS-Ch, and its expression level increased with toxin concentrations. The inhibition of YAP resulted in the dysregulated expression of chondrogenic markers (all p values < 0.05). These findings suggest that T-2 toxin and DON may inhibit the proliferation of, and induce the ECM degradation, of hiPS-Ch mediated by YAP, providing further insight into the cellular and molecular mechanisms contributing to cartilage damage caused by toxins.

Assessing the interaction effects of brain structure longitudinal changes and life environmental factors on depression and anxiety.

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = -.003, p = .018 for depression; beta = -003, p = .008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta = .088, p = .002 for depression; beta = .070, p = .008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = -.004, p = .020 for depression; beta = -.005, p = .002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety.

Exome-wide screening identifies novel rare risk variants for major depression disorder.

Despite thousands of common genetic loci of major depression disorders (MDD) have been identified by GWAS to date, a large proportion of genetic variation predisposing to MDD remains unaccounted for. By utilizing the newly released UK Biobank 200,643 exome dataset, we conducted an exome-wide association study to identify rare risk variants contributing to MDD. After quality control, 120,033 participants with MDD polygenic risk scores (PRS) values were included. The individuals with lower 30% quantile of the PRS value were filtered for case and control selecting. Then the cases were set as the individuals with upper 10% quantile of the PHQ depression score and lower 10% quantile were set as controls. Finally, 1612 cases and 1612 controls were included in this study. The variants were annotated by ANNOVRA software. After exclusions, 34,761 qualifying variants, including 148 frameshift variant, 335 non-frameshift variant, 33,758 nonsynonymous, 91 start-loss, 393 stop-gain, 36 stop-loss variants were imported into the SKAT R-package to perform single variants, gene-based burden and robust burden tests with minor allele frequency (MAF) < 0.01. Single variant association testing identified one variant, rs4057749 (P = 5.39 × 10-9), within OR8B4 gene at an exome-wide significance level. The gene-based burden test of the exonic variants identified genome-wide significant associations in OR8B4 (PSKAT = 6.23 × 10-5, PSKAT Robust = 4.49 × 10-5), TRAPPC11 (PSKAT = 0.014, PSKAT Robust = 0.015), SBK3 (PSKAT = 0.020, PSKAT Robust = 0.025) and TNRC6B (PSKAT = 0.026, PSKAT Robust = 0.036). We identified multiple novel rare risk variants contributing to MDD in the individuals with lower PRS of MDD. The findings can help to broaden the genetic insights of the MDD pathogenesis.

Treatment Resistance in Schizophrenia Is Associated with Attention Deficit/Hyperactivity Disorder and Gut Microbiota: A Genetic Correlation and Mendelian Randomization Study.

INTRODUCTION: Observational studies highlight associations of common diseases with individual schizophrenia symptoms. However, it is unclear whether these diseases are associated with individual treatment-resistant schizophrenia (TRS). We aimed to explore the genetic associations between common immune diseases, metabolic diseases, psychiatric disorders, gut microbiota and TRS. METHODS: Genome-wide association study (GWAS) summary data of European participants (n = ∼456,327) included TRS, 11 psychiatric disorders, 23 immune and metabolic diseases, body mass index, height, and 211 gut microbiota. In this genetic correlation and two-sample Mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with common immune diseases, metabolic diseases, psychiatric disorders, and gut microbiota with TRS. RESULTS: LDSC revealed candidate associations between attention deficit/hyperactivity disorder (ADHD), schizophrenia, intestinal infectious diseases, obesity and TRS (genetic correlation range, 0.230-0.702; p < 0.05). Two-sample MR analyses suggested that ADHD was positively associated with TRS (estimate [SE] = 0.204 [0.073], p = 0.005), a finding that remained stable across statistical models. Besides, schizophrenia and genus Barnesiella levels were causally associated with TRS but not consistent across MR approaches. CONCLUSION: This study reports genetic correlations between ADHD, schizophrenia, intestinal infectious diseases, obesity and TRS. The study also found that genus Barnesiella was associated with TRS. These findings may have clinical implications, highlighting the possible strategy for TRS prevention.

Maternal smoking around birth may lower the protective effects of breastfeeding on anxiety, depression and neuroticism in adult offspring: a UK biobank study.

We aim to explore the combined effects of the smoking and breastfeeding on offspring mental health outcomes. We used data from UK biobank (N = 342,846) to evaluate joint effect of breastfeeding and maternal smoke during pregnancy (MSDP) on seven adult offspring mental health outcomes (self-reported depression, depression score, self-reported anxiety, anxiety score, neuroticism score, self-harm, suicide). We stratified individuals to MSDP group and non-MSDP group as well as breastfeeding group and non-breastfeeding group. Multiple linear regression and logistic regressions analysis were performed between independent variables (MSDP or breastfeeding) and dependent variables separately (seven mental health outcomes) in each stratum. Effect estimates were expressed as ß values and OR values. Sex, age, 10 principle components of population structure, smoking, alcohol use, and Townsend deprivation index were examined as covariates. At MSDP grouping level, coefficients (odds ratio [OR]) for association of breastfed as a baby with self-reported anxiety (category variable) were 0.87 (95%CI, (0.82-0.93), P = 1.74 × 10-5) in the MSDP group and 0.83 (95%CI, (0.79-0.87), P = 2.76 × 10-17) in the non-MSDP group. At breastfeeding grouping level, OR for association of MSDP and self-reported anxiety were 1.15 (95%CI, (1.10-1.20), P = 5.36 × 10-11) in breastfeeding group and 1.12(95%CI, (1.06-1.20), P = 2.02 × 10-4) in non-breastfeeding group. At MSDP grouping level, negatively associations were found for breastfeeding and anxiety score (continuable variable) in MSDP group (-0.04 SD change per SD change in MSDP, 95% CI, (- 0.06, - 0.02), P = 2.42 × 10-3) and non-MSDP group (-0.06 SD change per SD change in MSDP, 95%CI, (- 0.07, - 0.04), P = 1.70 × 10-11). At breastfeeding grouping level, positive association was found for MSDP and anxiety score in the breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.06-0.09), P = 1.49 × 10-20) and non-breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.05-0.09), P = 7.19 × 10-8). Compared with non-MSDP group, the protective effect (reflected by coefficients) of breastfeeding on anxiety in the MSDP decreased. Our preliminary study found MSDP may lower the protective effect of breastfeeding on the adult offspring anxiety, depression and neuroticism, providing useful recommendations for health care service via quitting smoking during pregnancy and encouraging prolonged breastfeeding.

Association between gut microbiota and longevity: a genetic correlation and mendelian randomization study.

BACKGROUND: Longevity is one of the most complex phenotypes, and its genetic basis remains unclear. This study aimed to explore the genetic correlation and potential causal association between gut microbiota and longevity. RESULTS: Linkage disequilibrium score (LDSC) regression analysis and a bi-directional two-sample Mendelian Randomization (MR) analysis were performed to analyze gut microbiota and longevity-related traits. LDSC analysis detected four candidate genetic correlations, including Veillonella (genetic correlation = 0.5578, P = 4.67 × 10- 2) and Roseburia (genetic correlation = 0.4491, P = 2.67 × 10- 2) for longevity, Collinsella (genetic correlation = 0.3144, P = 4.07 × 10- 2) for parental lifespan and Sporobacter (genetic correlation = 0.2092, P = 3.53 × 10- 2) for healthspan. Further MR analysis observed suggestive causation between Collinsella and parental longevity (father's age at death) (weighted median: b = 1.79 × 10- 3, P = 3.52 × 10- 2). Reverse MR analysis also detected several causal effects of longevity-related traits on gut microbiota, such as longevity and Sporobacter (IVW: b = 7.02 × 10- 1, P = 4.21 × 10- 25). Statistical insignificance of the heterogeneity test and pleiotropy test supported the validity of the MR study. CONCLUSION: Our study found evidence that gut microbiota is causally associated with longevity, or vice versa, providing novel clues for understanding the roles of gut microbiota in aging development.

Dissecting the association between psychiatric disorders and neurological proteins: a genetic correlation and two-sample bidirectional Mendelian randomization study.

OBJECTIVES: The role of neurological proteins in the development of bipolar disorder (BD) and schizophrenia (SCZ) remains elusive now. The current study aims to explore the potential genetic correlations of plasma neurological proteins with BD and SCZ. METHODS: By using the latest genome-wide association study (GWAS) summary data of BD and SCZ (including 41,917 BD cases, 11,260 SCZ cases, and 396,091 controls) derived from the Psychiatric GWAS Consortium website (PGC) and a recently released GWAS of neurological proteins (including 750 individuals), we performed a linkage disequilibrium score regression (LDSC) analysis to detect the potential genetic correlations between the two common psychiatric disorders and each of the 92 neurological proteins. Two-sample Mendelian randomisation (MR) analysis was then applied to assess the bidirectional causal relationship between the neurological proteins identified by LDSC, BD and SCZ. RESULTS: LDSC analysis identified one neurological protein, NEP, which shows suggestive genetic correlation signals for both BD (coefficient = -0.165, p value = 0.035) and SCZ (coefficient = -0.235, p value = 0.020). However, those association did not remain significant after strict Bonferroni correction. Two sample MR analysis found that there was an association between genetically predicted level of NEP protein, BD (odd ratio [OR] = 0.87, p value = 1.61 × 10-6) and SCZ (OR = 0.90, p value = 4.04 × 10-6). However, in the opposite direction, there is no genetically predicted association between BD, SCZ, and NEP protein level. CONCLUSION: This study provided novel clues for understanding the genetic effects of neurological proteins on BD and SCZ.

Identifying discriminative features for diagnosis of Kashin-Beck disease among adolescents.

INTRODUCTION: Diagnosing Kashin-Beck disease (KBD) involves damages to multiple joints and carries variable clinical symptoms, posing great challenge to the diagnosis of KBD for clinical practitioners. However, it is still unclear which clinical features of KBD are more informative for the diagnosis of Kashin-Beck disease among adolescent. METHODS: We first manually extracted 26 possible features including clinical manifestations, and pathological changes of X-ray images from 400 KBD and 400 non-KBD adolescents. With such features, we performed four classification methods, i.e., random forest algorithms (RFA), artificial neural networks (ANNs), support vector machines (SVMs) and linear regression (LR) with four feature selection methods, i.e., RFA, minimum redundancy maximum relevance (mRMR), support vector machine recursive feature elimination (SVM-RFE) and Relief. The performance of diagnosis of KBD with respect to different classification models were evaluated by sensitivity, specificity, accuracy, and the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Our results demonstrated that the 10 out of 26 discriminative features were displayed more powerful performance, regardless of the chosen of classification models and feature selection methods. These ten discriminative features were distal end of phalanges alterations, metaphysis alterations and carpals alterations and clinical manifestations of ankle joint movement limitation, enlarged finger joints, flexion of the distal part of fingers, elbow joint movement limitation, squatting limitation, deformed finger joints, wrist joint movement limitation. CONCLUSIONS: The selected ten discriminative features could provide a fast, effective diagnostic standard for KBD adolescents.

Roles of glycoprotein glycosylation in the pathogenesis of an endemic osteoarthritis, Kashin­Beck disease, and effectiveness evaluation of sodium hyaluronate treatment

Background/aim: We aimed to explore the roles of glycoprotein glycosylation in the pathogenesis of Kashin­Beck disease (KBD), and evaluated the effectiveness of sodium hyaluronate treatment. Materials and methods: Blood and saliva were collected from KBD patients before and after the injection of sodium hyaluronate. Normal healthy subjects were included as controls. Saliva and serum lectin microarrays and saliva and serum microarray verifications were used to screen and confirm the differences in lectin levels among the three groups. Results: In saliva lectin microarray, bindings to Sophora japonica agglutinin (SJA), Griffonia (Bandeiraea) simplicifolia lectin I (GSL-I), Euonymus europaeus lectin (EEL), Maackia amurensis lectin II (MAL-II), Sambucus nigra lectin (SNA), Hippeastrum hybrid lectin (HHL), and Aleuria aurantia lectin (AAL) were higher in the untreated KBD patients than in the control group. Increased levels of HHL, MAL-II, and GSL-I in the untreated KBD patients discriminated them in particular from the treated ones. Jacalin was lower in the untreated KBD patients compared to the treated KBD and control groups. In serum lectin microarray, HHL and peanut agglutinin (PNA) were increased in the untreated KBD group in comparison to the control one. AAL, Phaseolus vulgaris agglutinin (E+L) (PHA-E+L), and Psophocarpus tetragonolobus lectin I (PTL-I) were lower in the untreated KBD patients compared to the treated KBD and control groups. Hyaluronate treatment appeared to normalize SNA, AAL, and MAL-II levels in saliva, and HHL, PNA, AAL, PTL-I, and PHA-E+L levels in serum. Saliva reversed microarray verification confirmed significant differences between the groups in SNA and Jacalin, in particular for GSL-I levels, while serum reversed microarray verification indicated that HHL, PNA, and AAL levels returned to normal levels after the hyaluronate treatment. Lectin blot confirmed significant differences in HHL, AAL, and Jacalin in saliva, and HHL, PNA, PHA-E+L, and AAL in serum. Conclusion: HHL in saliva and serum may be a valuable diagnostic biomarker of KBD, and it may be used as follow-up for the hyaluronate treatment.

Modulatory interactions of T-2 and deoxynivalenol mycotoxins on murine femoral development and osteological integrity.

In this study, we conducted a systematic assessment of the effectsof deoxynivalenol (DON) and T-2 mycotoxins (T-2) on the developmental processes and structural integrity of murine femurs, considering both the isolated and synergistic effects of these toxins. To this end, we divided 72 male mice into nine groups, each subjected to varying dosages of T-2, DON, or their combinations. Over a four-week experimental period, meticulous monitoring was undertaken regarding the mice's body weight, biochemical markers of bone formation and resorption, and the activity of relevant cells. To comprehensively evaluate alterations in bone structure, we employed biomechanical analysis, micro-computed tomography (micro-CT), and transmission electron microscopy.Our findings unveiled a significant revelation: the mice exhibited a dose-dependent decrease in body weight upon exposure to individual mycotoxins, while the combined use of these toxins manifested an atypical antagonistic effect. Furthermore, we observed variations in the levels of calcium, phosphorus, and vitamin D, as well as adjustments in the activities of osteoblasts and osteoclasts, all intricately linked to the dosage and ratio of the toxins. Alterations in biomechanical properties were also noted to correlate with the dosage and combination of toxins. Analyses via micro-CT and transmission electron microscopy further corroborated the substantial impact of toxin dosage and combinations on both cortical and trabecular bone structures.In summation, our research unequivocally demonstrates the dose- and ratio-dependent detrimental effects of DON and T-2 mycotoxins on the growth and structural integrity of murine femurs. These insights accentuate the importance of a profound understanding of the potential risks these toxins pose to bone health, offering pivotal guidance for future toxicological research and public health preventative strategies.

HT-2 mycotoxin and selenium deficiency: Effects on Femur development and integrity in Young mice.

Kashin-Beck Disease (KBD), an osteoarticular disorder, is potentially influenced by several factors, among which selenium deficiency and HT-2 mycotoxin exposure are considered significant. However, the combined effect of these factors on femoral development remains unclear, Conducted over eight weeks on forty-eight male mice categorized into control, selenium-deficient, and HT-2 toxin-exposed groups, including dual-exposure sets, this study comprehensively monitored body weight, bone metabolism markers, and cellular health. Employing biomechanical analysis, micro-computed tomography (micro-CT), and transmission electron microscopy (TEM), we unearthed a reduction in body weight due to HT-2 toxin alone, with selenium deficiency exacerbating these effects synergistically. Our results unveil that both factors independently affect bone metabolism, yet their confluence leads to a pronounced degradation of bone health parameters, including alterations in calcium, phosphorus, and vitamin D levels, alongside marked changes in osteoblast and osteoclast activity and bone cell structures. The notable damage to femoral cortical and trabecular architectures underscores the perilous interplay between dietary selenium absence and HT-2 toxin presence, necessitating a deeper understanding of their separate and joint effects on bone integrity. These discoveries underscore the imperative for a nuanced approach to toxicology research and public health policy, highlighting the pivotal influence of environmental and nutritional factors on skeletal well-being.

Associations of classical HLA alleles with depression and anxiety.

Immune dysregulation has been widely observed in patients with psychiatric disorders. This study aims to examine the association between HLA alleles and depression and anxiety. Using data from the UK Biobank, we performed regression analyses to assess the association of 359 HLA alleles with depression and anxiety, as determined by Patient Health Questionnaire (PHQ) score (n = 120,033), self-reported depression (n = 121,685), general anxiety disorder (GAD-7) score (n = 120,590), and self-reported anxiety (n = 108,310). Subsequently, we conducted gene environmental interaction study (GEIS) to evaluate the potential effects of interactions between HLA alleles and environmental factors on the risk of depression and anxiety. Sex stratification was implemented in all analysis. Our study identified two significant HLA alleles associated with self-reported depression, including HLA-C*07:01 (ß = -0.015, p = 5.54 × 10-5 ) and HLA-B*08:01 (ß = -0.015, p = 7.78 × 10-5 ). Additionally, we identified four significant HLA alleles associated with anxiety score, such as HLA-DRB1*07:01 (ß = 0.084, p = 9.28 × 10-5 ) and HLA-B*57:01 (ß = 0.139, p = 1.22 × 10-4 ). GEIS revealed that certain HLA alleles interacted with environmental factors to influence mental health outcomes. For instance, HLA-A*02:07 × cigarette smoking was associated with depression score (ß = 0.976, p = 1.88 × 10-6 ). Moreover, sex stratification analysis revealed significant sex-based differences in the interaction effects of certain HLA alleles with environmental factors. Our findings indicate the considerable impact of HLA alleles on the risks of depression and anxiety, providing valuable insights into the functional relevance of immune dysfunction in these conditions.

Mendelian randomization study of the relationship between blood and urine biomarkers and schizophrenia in the UK Biobank cohort.

BACKGROUND: The identification of suitable biomarkers is of crucial clinical importance for the early diagnosis of treatment-resistant schizophrenia (TRS). This study aims to comprehensively analyze the association between TRS and blood and urine biomarkers. METHODS: Candidate TRS-related single nucleotide polymorphisms (SNPs) were obtained from a recent genome-wide association study. The UK Biobank cohort, comprising 376,807 subjects with blood and urine biomarker testing data, was used to calculate the polygenic risk score (PRS) for TRS. Pearson correlation analyses were performed to evaluate the correlation between TRS PRS and each of the biomarkers, using calculated TRS PRS as the instrumental variables. Bidirectional two-sample Mendelian randomization (MR) was used to assess potential causal associations between candidate biomarkers with TRS. RESULTS: Here we identify a significant association between TRS PRS and phosphate (r = 0.007, P = 1.96 × 10-4). Sex subgroup analyses identify seven and three candidate biomarkers associated with TRS PRS in male and female participants, respectively. For example, total protein and phosphate for males, creatinine and phosphate for females. Bidirectional two-sample MR analyses indicate that TRS is negatively associated with cholesterol (estimate = -0.363, P = 0.008). Conversely, TRS is positively associated with total protein (estimate = 0.137, P = 0.027), mean corpuscular volume (estimate = 0.032, P = 2.25 × 10-5), and mean corpuscular hemoglobin (estimate = 0.018, P = 0.007). CONCLUSIONS: Our findings provide insights into the roles of blood and urine biomarkers in the early detection and treatment of TRS.

People with schizophrenia experience periods of time during which they misperceive reality. Some people with schizophrenia do not respond well to the usual drugs that are used to relieve their symptoms. This type of schizophrenia is known as treatment-resistant schizophrenia (TRS). We looked at differences in the genes (inherited characteristics), blood and urine of a group of people in the UK with schizophrenia to see if people with TRS have particular characteristics that would enable them to be distinguished from patients with schizophrenia who tend to respond to usual treatment. We found several differences in the blood that could be used to predict which people might get TRS, including some that were specific to men or women. These discoveries are important because they can help doctors identify people who are more likely to develop TRS earlier, enabling them to avoid using treatments that might not work well for them.

Activation of Notch Signaling Pathway is involved in Extracellular Matrix Degradation in human induced pluripotent stem cells chondrocytes induced by HT-2 toxin.

Notch signaling regulates cartilage formation and homeostasis. Kashin-Beck Disease (KBD), an endemic osteochondropathy, is characterized by severe cartilage degradation. The etiology of KBD is related to the exposure of HT-2 toxin, a mycotoxin and primary metabolite of T-2 toxin. This study aims to explore the role of HT-2 toxin in the Notch signaling regulation and extracellular matrix (ECM) metabolism of hiPSCs-Chondrocytes. Immunohistochemistry and qRT-PCR were employed to investigate the expression of Notch pathway molecules in KBD articular cartilage and primary chondrocytes. hiPSCs-Chondrocytes, derived from hiPSCs, were treated with 100 ng/mL HT-2 toxin and the γ-secretase inhibitor (DAPT) for 48h, respectively. The markers related to the Notch signaling pathway and ECM were assessed using qRT-PCR and Western blot. Notch pathway dysregulation was prominent in KBD cartilage. HT-2 toxin exposure caused cytotoxicity in hiPSCs-Chondrocytes, and activated Notch signaling by increasing the mRNA and protein levels of NOTCH1 and HES1. HT-2 toxin also upregulated ECM catabolic enzymes and downregulated ECM components (COL2A1 and ACAN), indicating ECM degradation. DAPT-mediated Notch signaling inhibition suppressed the mRNA and protein level of ADAMTS5 expression while enhancing ECM component expression in hiPSCs-Chondrocytes. This study suggests that HT-2 toxin may induce ECM degradation in hiPSCs-Chondrocytes through activating Notch signaling.

Long-term ambient air pollution and the risk of musculoskeletal diseases: A prospective cohort study.

Evidence of the associations of air pollution and musculoskeletal diseases is inconsistent. This study aimed to examine the associations between air pollutants and the risk of incident musculoskeletal diseases, such as degenerative joint diseases (n = 38,850) and inflammatory arthropathies (n = 20,108). An air pollution score was constructed to assess the combined effect of PM2.5, PM2.5-10, NO2, and NOX. Cox proportional hazard model was applied to assess the relationships between air pollutants and the incidence of each musculoskeletal disease. The air pollution scores exhibited the modest association with an increased risk of osteoporosis (HR = 1.006, 95% CI: 1.002-1.011). Among the individual air pollutants, PM2.5 and PM2.5-10 exhibited the most significant effect on elevated risk of musculoskeletal diseases, such as PM2.5 on osteoporosis (HR = 1.064, 95% CI: 1.020-1.110), PM2.5-10 on inflammatory arthropathies (HR = 1.059, 95% CI: 1.037-1.081). Females were found to have a higher risk of incident musculoskeletal diseases when exposed to air pollutants. Individuals with extreme BMI or lower socioeconomic status had a higher risk of developing musculoskeletal diseases. Our findings reveal that long-term exposure to ambient air pollutants may contribute to an increased risk of musculoskeletal diseases.