A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for migraine.

BACKGROUND: Migraine is a common neurological disorder with a strong genetic component. Despite the identification of over 100 loci associated with migraine susceptibility through genome-wide association studies (GWAS), the underlying causative genes and biological mechanisms remain predominantly elusive. METHODS: The FinnGen R10 dataset, consisting of 333,711 subjects (20,908 cases and 312,803 controls), was utilized in conjunction with the Genotype-Tissue Expression Project (GTEx) v8 EQTls files to conduct cross-tissue transcriptome association studies (TWAS). Functional Summary-based Imputation (FUSION) was employed to validate these findings in single tissues. Additionally, candidate susceptibility genes were screened using Gene Analysis combined with Multi-marker Analysis of Genomic Annotation (MAGMA). Subsequent Mendelian randomization (MR) and colocalization analyses were conducted. Furthermore, GeneMANIA analysis was employed to enhance our understanding of the functional implications of these susceptibility genes. RESULTS: We identified a total of 19 susceptibility genes associated with migraine in the cross-tissue TWAS analysis. Two novel susceptibility genes, REV1 and SREBF2, were validated through both single tissue TWAS and MAGMA analysis. Mendelian randomization and colocalization analyses further confirmed these findings. REV1 may reduce the migraine risk by regulating DNA damage repair, while SREBF2 may increase the risk of migraine by regulating cholesterol metabolism. CONCLUSION: Our study identified two novel genes whose predicted expression was associated with the risk of migraine, providing new insights into the genetic framework of migraine.

Protective effects of docosahexaenoic acid supplementation on cognitive dysfunction and hippocampal synaptic plasticity impairment induced by early postnatal PM2.5 exposure in young rats.

PM2.5 exposure is a challenging environmental issue that is closely related to cognitive development impairment; however, currently, relevant means for prevention and treatment remain lacking. Herein, we determined the preventive effect of docosahexaenoic acid (DHA) supplementation on the neurodevelopmental toxicity induced by PM2.5 exposure. Neonatal rats were divided randomly into three groups: control, PM2.5, and DHA + PM2.5 groups. DHA could ameliorate PM2.5-induced learning and memory dysfunction, as well as reverse the impairment of hippocampal synaptic plasticity, evidenced by enhanced long-term potentiation, recovered synaptic ultrastructure, and increased expression of synaptic proteins. Moreover, DHA increased CREB phosphorylation and BDNF levels and attenuated neuroinflammation and oxidative stress, reflected by lower levels of IBA-1, IL-1ß, and IL-6 and increased levels of SOD1 and Nrf2. In summary, our findings demonstrated that supplementation of DHA effectively mitigated the cognitive dysfunction and synaptic plasticity impairment induced by early postnatal exposure to PM2.5. These beneficial effects may be attributed to the upregulation of the CREB/BDNF signaling pathway, as well as the reduction of neuroinflammation and oxidative stress.

Autophagy alleviates hippocampal neuroinflammation by inhibiting the NLRP3 inflammasome in a juvenile rat model exposed particulate matter.

Ambient fine particulate matter (PM) is a global public and environmental problem. PM is closely associated with several neurological diseases, which typically involve neuroinflammation. We investigated the impact of PM exposure on neuroinflammation using both in vivo (in a juvenile rat model with PM exposure concentrations of 1, 2, and 10 mg/kg for 28 days) and in vitro (in BV-2 and HT-22 cell models with PM concentrations of 50-200 µg/ml for 24 h). We observed that PM exposure induced the activation of the NLRP3 inflammasome, leading to the production of IL-1ß and IL-18 in the rat hippocampus and BV-2 cells. Furthermore, inhibition of the NLRP3 inflammasome with MCC950 effectively reduced neuroinflammation and ameliorated hippocampal damage. In addition, autophagy activation was observed in the hippocampus of PM-exposed rats, and the promotion of autophagy by rapamycin (Rapa) effectively attenuated the NLRP3-mediated neuroinflammation induced by PM exposure. However, autophagic flow was blocked in BV-2 cells exposed to PM, and Rapa failed to ameliorate NLRP3 inflammasome activation. We found that autophagy was activated in HT-22 cells exposed to PM and that treatment with Rapa reduced the release of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as cell apoptosis. In a subsequent coculture model of BV-2 and HT-22 cells, we observed the activation of the NLRP3 inflammasome in BV-2 cells when the HT-22 cells were exposed to PM, and this activation was alleviated when PM-exposed HT-22 cells were pretreated with Rapa. Overall, our study revealed that PM exposure triggered hippocampal neuroinflammation by activating the NLRP3 inflammasome. Notably, autophagy mitigated NLRP3 inflammasome activation, potentially by reducing neuronal ROS and apoptosis. This research emphasized the importance of reducing PM exposure and provided valuable insight into its neurotoxicity.

Ambient particulate matter exposure induces ferroptosis in hippocampal cells through the GSK3B/Nrf2/GPX4 pathway.

Epidemiological studies have established a robust correlation between exposure to ambient particulate matter (PM) and various neurological disorders, with dysregulation of intracellular redox processes and cell death being key mechanisms involved. Ferroptosis, a cell death form characterized by iron-dependent lipid peroxidation and disruption of antioxidant defenses, may be involved in the neurotoxic effects of PM exposure. However, the relationship between PM-induced neurotoxicity and ferroptosis in nerve cells remains to be elucidated. In this study, we utilized a rat model (exposed to PM at a dose of 10 mg/kg body weight per day for 4 weeks) and an HT-22 cell model (exposed to PM at concentrations of 50, 100, and 200 µg/mL for 24 h) to investigate the potential induction of ferroptosis by PM exposure. Furthermore, RNA sequencing analysis was employed to identify hub genes that potentially contribute to the process of ferroptosis, which was subsequently validated through in vivo and in vitro experiments. The results revealed that PM exposure increased MDA content and Fe2+ levels, and decreased SOD activity and GSH/GSSG ratio in rat hippocampal and HT-22 cells. Through RNA sequencing analysis, bioinformatics analysis, and RT-qPCR experiments, we identified GSK3B as a possible hub gene involved in ferroptosis. Subsequent investigations demonstrated that PM exposure increased GSK3B levels and decreased Nrf2, and GPX4 levels in vivo and in vitro. Furthermore, treatment with LY2090314, a specific inhibitor of GSK3B, was found to mitigate the PM-induced elevation of MDA and ROS and restore SOD activity and GSH/GSSG ratio. The LY2090314 treatment promoted the upregulation of Nrf2 and GPX4 and facilitated the nuclear translocation of Nrf2 in HT-22 cells. Moreover, treatment with LY2090314 resulted in the upregulation of Nrf2 and GPX4, along with the facilitation of nuclear translocation of Nrf2. This study suggested that PM-induced ferroptosis in hippocampal cells may be via the GSK3B/Nrf2/GPX4 pathway.

Identification of novel proteins for sleep apnea by integrating genome-wide association data and human brain proteomes.

BACKGROUND: Sleep apnea is regarded as a significant global public health issue. The relationship between sleep apnea and nervous system diseases is intricate, yet the precise mechanism remains unclear. METHODS: In this study, we conducted a comprehensive analysis integrating the human brain proteome and transcriptome with sleep apnea genome-wide association study (GWAS), employing genome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and colocalization analysis to identify brain proteins associated with sleep apnea. RESULTS: The discovery PWAS identified six genes (CNNM2, XRCC6, C3orf18, CSDC2, SQRDL, and DGUOK) whose altered protein abundances in the brain were found to be associated with sleep apnea. The independent confirmatory PWAS successfully replicated four out of these six genes (CNNM2, C3orf18, CSDC2, and SQRDL). The transcriptome level TWAS analysis further confirmed two out of the four genes (C3orf18 and CSDC2). The subsequent two-sample Mendelian randomization provided compelling causal evidence supporting the association of C3orf18, CSDC2, CNNM2, and SQRDL with sleep apnea. The co-localization analysis further supported the association between CSDC2 and sleep apnea (posterior probability of hypothesis 4 = 0.75). CONCLUSIONS: In summary, the integration of brain proteomic and transcriptomic data provided multifaceted evidence supporting causal relationships between four specific brain proteins (CSDC2, C3orf18, CNNM2, and SQRDL) and sleep apnea. Our findings provide new insights into the molecular basis of sleep apnea in the brain, promising to advance understanding of its pathogenesis in future research.

TREM2 mitigates NLRP3-mediated neuroinflammation through the NF-κB and PI3k/Akt signaling pathways in juvenile rats exposed to ambient particulate matter.

Ambient particulate matter (PM) is a global public and environmental problem. PM is closely associated with several neurological disorders that typically involve neuroinflammation. There have been few studies on the effect of PM on neuroinflammation to date. In this study, we used a juvenile rat model (PM exposure was conducted at a dose of 10 mg/kg body weight per day for 4 weeks) and a BV-2 cell model (PM exposure was conducted at concentrations of 50, 100, 150, and 200 µg/ml for 24 h) to investigate PM-induced neuroinflammation mediated by NLRP3 inflammasome activation and the role of TREM2 in this process. Our findings revealed that PM exposure reduced TREM2 protein and mRNA levels in the rat hippocampus and BV-2 cells. TREM2 overexpression attenuated PM-induced spatial learning and memory deficits in rats. Moreover, we observed that TREM2 overexpression in vivo and in vitro effectively mitigated the increase in NLRP3 and pro-Caspase1 protein expression, as well as the secretion of IL-1ß and IL-18. Exposure to PM increased the expression of NF-κB and decreased the phosphorylation of PI3k/Akt in vivo and in vitro, and this process was effectively reversed by overexpressing TREM2. Our results indicated that PM exposure could reduce TREM2 expression and induce NLRP3 inflammasome-mediated neuroinflammation and that TREM2 could mitigate NLRP3 inflammasome-mediated neuroinflammation by regulating the NF-κB and PI3k/Akt signaling pathways. These findings shed light on PM-induced neuroinflammation mechanisms and potential intervention targets.

Associations between urinary heavy metals and anxiety among adults in the National Health and Nutrition Examination Survey (NHANES), 2007-2012.

BACKGROUND: Few studies have investigated the associations between heavy metals and anxiety. The purpose of this study was to examine the associations between single and combined exposure to heavy metals and anxiety. METHODS: This study employed data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2012. Anxiety was assessed by patients self-reporting the number of anxious days per month. First, we evaluated the associations between 10 heavy metals single exposure and anxiety by multivariable logistic regression. We then selected 5 heavy metals (cadmium, antimony, cobalt, tungsten, and uranium) for further analysis by elastic net regression. Subsequently, principal component analysis (PCA), weighted quantile regression (WQS), and Bayesian kernel machine regression (BKMR) were utilized to evaluate the associations between 5 heavy metals co-exposure and anxiety. RESULTS: This study included 4512 participants, among whom 1206 participants were in an anxiety state. Urinary cadmium and antimony were separately related to an increased risk of anxiety (p for trend <0.01 and < 0.01, respectively). In PCA analysis, PC1 was associated with an increased risk of anxiety (p for trend <0.001). In WQS analysis, the positive WQS index was substantially linked with the risk of anxiety (OR (95%CI): 1.23 (1.04,1.39)). In BKMR analysis, the overall effects of co-exposure to heavy metals were positively connected with anxiety. CONCLUSION: Our study identified a positive correlation between individual exposure to cadmium and antimony and the risk of anxiety. Additionally, the co-exposure to cadmium, antimony, cobalt, tungsten, and uranium was associated with an increased risk of anxiety.

Association between the Healthy Eating Index-2015 and Developmental Disabilities in Children: A Cross-Sectional Analysis.

Few studies have examined the association between dietary quality and the risk of developmental disabilities (DDs). This study aimed to investigate the association between dietary quality and the risk of DDs in US children aged 5 to 15. We employed data from the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Multivariable logistic regression was used to evaluate the association between HEI-2015 score, HEI component score, and the likelihood of DDs. Restricted cubic splines (RCS) were utilized to investigate nonlinear links between HEI-2015 score and the likelihood of DDs. Interaction analysis was utilized to explore differences between subgroups. HEI-2015 score was negatively linked with the risk of DDs after adjusting covariates [odds ratio (OR) = 0.99; 95% confidence interval (CI) = (0.98, 1.00)]. HEI-2015 score was separated by quartile into Q1, Q2, Q3, and Q4. Q1 represents the lowest HEI scores, while Q4 represents the highest HEI scores. Children in the fourth quartile of the HEI-2015 exhibited a decreased prevalence of DDs compared to those in the first quartile [(OR = 0.69; 95% CI = (0.53, 0.89)]. The association between HEI-2015 score and the risk of DDs was modified by race/ethnicity. The higher HEI-2015 score was associated with a lower risk of DDs, suggesting that better dietary quality may reduce the risk of DDs in children.

Depression associated with dietary intake of flavonoids: An analysis of data from the National Health and Nutrition Examination Survey, 2007-2010.

BACKGROUND: Flavonoids may have a protective effect against depression. The purpose of this study was to examine whether flavonoid intake was associated with depression. METHODS: This is an observational cross-sectional study. We evaluated a sample of 8183 adults from the National Health and Nutrition Examination Survey (NHANES), 2007-2010. The participants had an average age of 46.7 years, and 48.4% of them were male. Flavonoid intake was obtained through dietary recall interviews, and it included six subclasses: isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols. Depression was identified using the Patient Health Questionnaire (PHQ-9). Logistic regression was utilized to evaluate the association between flavonoid intake and depression. Restricted cubic splines (RCS) were utilized to investigate nonlinear associations. Differences between subgroups were explored. Mediation analysis was used to explore confounding/mediating factors. These models were adjusted for age, sex, race/ethnicity, poverty status, education, smoking status, alcohol consumption, BMI, energy intake, physical activity, and chronic diseases. RESULTS: There were 765 individuals with depression (PHQ-9 score ≥ 10) in the sample. After adjusting for covariates, flavanones, flavones, and total flavonoid intake were associated with a lower likelihood of depression (OR (95% CI): 0.73(0.64,0.84); 0.36(0.21,0.63); 0.86(0.74,0.99), respectively). A significant inverse correlation was observed between flavonoid consumption and the somatic symptom score of the PHQ-9. We observed a stronger association between flavonoids and depression in non-Hispanic white groups. The relationship between the total flavonoid intake and depression was explained to some extent by sleep duration (13.8%). CONCLUSIONS: Flavonoid intake was associated with lower odds of depression.

Dietary Intake of Flavonoids Associated with Sleep Problems: An Analysis of Data from the National Health and Nutrition Examination Survey, 2007-2010.

Flavonoids possess the latent ability to protect against sleep disorders. We examined the correlation between daily flavonoid intake and sleep duration, and sleep disorders. We enrolled 8216 participants aged ≥ 20 from the National Health and Nutrition Examination Survey (NHANES, 2007-2010), carrying out a cross-sectional study. Flavonoid intake was collected by dietary intake interview recalls. Logistic regression was utilized to evaluate the association between flavonoid intake sleep duration, and sleep disorders. We used subgroup and interaction analysis to explore differences between subgroups. When adjusting covariates in model 2, anthocyanidins, flavan-3-ols, flavones, flavonols, and the sum of flavonoids were considerably related to insufficient sleep duration (odds ratio (OR) (95% confidence interval (CI)); 0.83 (0.72, 0.95); 0.91 (0.83, 0.98); 0.63 (0.41, 0.98); 0.78 (0.64, 0.94); 0.85 (0.76, 0.95), respectively); the converse association was observed between flavanones, and flavones and the risk of sleep disorders (OR (95% CI); 0.85 (0.77, 0.95); 0.61 (0.41, 0.90), respectively). In relation to insufficient sleep, there were statistically significant interactions between flavonoid consumption and race/ethnicity, and education level. In relation to insufficient sleep, there were statistically significant interactions between flavonoid consumption and working status. In this study, we found that certain flavonoids were linked to increased sleep duration and a lower risk of sleep problems. Our research indicated that flavonoids might be a preventive factor for sleep disorders.