Causal Connection Research Articles

Association of Walking Pace and Risk of Stroke: A Two- Sample Mendelian Randomization Study in a European Ancestry Cohort.

Walking pace (WP), a simple physiological indicator, has been found to be strongly associated with a variety of health outcomes in recent years. Among them, the relationship between walking pace and stroke is of particular interest. Given the high morbidity, disability and mortality associated with stroke, identifying modifiable indicators of health, such as walking pace, could help in stroke prevention strategies. However, the causal relationship between WP and stroke risk remains unclear. This study aims to determine the causal relationship between walking pace and risk of stroke using a two-sample Mendelian randomization approach in a European-ancestry population. In order to evaluate the potential for a causal relationship between WP and stroke in people of European heritage, a two-sample Mendelian randomization (MR) study was carried out. Statistics about the association of single nucleotide polymorphisms (SNPs) with stroke were taken from FinnGen (R8) (n = 284,040), while the UK Biobank genome-wide association studies (GWAS) provided the summary data on the association of SNPs with WP (n = 459,915). The inverse-variance weighted (IVW) method was utilised as the primary strategy to examine the causal connection between WP and stroke. Additionally, complementary analyses were conducted using the MR-Egger and weighted median. In order to identify the potential directional pleiotropy and heterogeneity, the MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were all carried out. This connection was evaluated using OR with 95% confidence intervals (CIs). A total of 48 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The result showed that a slower walking pace is associated with a higher risk of stroke (OR = 0.573; 95% CI, 0.383-0.858, P = 0.007). The "leave-one-out" analysis demonstrated that the absence of a single SNP did not affect the robustness of our results. The MR-Egger intercept test indicated that genetic pleiotropy did not introduce bias into the results [intercept = -2.9E-03, SE = 0.008, P = 0.719] and Cochran's Q test revealed no heterogeneity. Therefore, the sensitivity analyses yielded comparable results. Consequently, the results of the sensitivity analyses were consistent. Our MR study revealed that WP is inversely associated with risk of stroke. These results provided evidence that slower WP causally increased the risk of stroke, recommending that patients with lower WP should have a prompt physical examination and targeted interventions to reduce their risk of stroke and enhance their quality of life.

Agency at a distance: learning causal connections

AbstractIn a series of papers, we have argued that causal cognition has coevolved with the use of various tools. Animals use tools, but only as extensions of their own bodies, while humans use tools that act at a distance in space and time. This means that we must learn new types of causal mappings between causes and effects. The aim of this article is to account for what is required for such learning of causal relations. Following a proposal by Grush and Springle, we argue that learning of inverse mappings from effects to causes is central. Learning such mappings also involves constraints based on monotonicity, continuity and convexity. In order for causal thinking to extend beyond space and time, mental simulations are required that predict the effects of actions. More advanced forms of causal reasoning involve more complicated forms of simulations.

The association of ultra-processed food intake with adolescent metabolic dysfunction-associated steatotic liver disease in the NHANES.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major public health concern. A thorough analysis of the link between ultra-processed food (UPF) intake and MASLD in the adolescent population is lacking. Adolescent participants of the National Health and Nutrition Examination Survey (NHANES) pre-pandemic cohort were included. Different controlled attenuation parameter (CAP) cut-offs were used to assess MASLD. The percentage energy intake of UPF, categorized according to the NOVA classification, to total energy intake was taken as the main outcome marker. Structural equation modelling (SEM) was used to better quantify the causal connection between UPF and liver steatosis. UPF consumption constituted a median 75% (62-86) of total energy intake. There was no significant correlation between UPF intake and CAP (ρ = 0.061, p = 0.091). The median proportion UPF intake was not associated with steatosis severity. SEM similarly yielded a weak and non-significant correlation of 0.078. In participants with MASLD, total energy intake was significantly higher (p < 0.001) and sugar-containing beverage (SCB) consumption showed a non-significant trend towards higher consumption. No clinically relevant association between UPF intake and MASLD in adolescents could be demonstrated. Our results nonetheless suggest that total energy intake and consumption of SCBs are important contributors to paediatric obesity and MASLD.

Investigating causal links between gallstones, cholecystectomy, and 33 site-specific cancers: a Mendelian randomization post-meta-analysis study

Background and aimThe association between gallstones/cholecystectomy and cancer remains inconclusive in the current literature. This study aimed to explore the causal connections between gallstones/cholecystectomy and cancer risk by utilizing a bidirectional two-sample multivariable Mendelian randomization approach with Genome-Wide Association Studies data.MethodsUtilizing Genome-Wide Association Studies data from the UK Biobank and FinnGen, this research employed multivariable Mendelian randomization analyses to explore the impact of gallstones and cholecystectomy on the risk of 33 distinct cancer types. Instrumental variables for gallstones and cholecystectomy were carefully selected to ensure robust analyses, and sensitivity and heterogeneity tests were conducted to verify the findings’ validity.ResultsMultivariable Mendelian randomization analysis, incorporating data from more than 450,000 individuals for gallstones and cholecystectomy, revealed nuanced associations with cancer risk. Cholecystectomy was associated with a significantly increased risk of nonmelanoma skin cancer (OR = 1.59, 95% CI: 1.21 to 2.10, P = 0.001), while gallstones were linked to a decreased risk of the same cancer type (OR = 0.63, 95% CI: 0.47 to 0.84, P = 0.002). Interestingly, the analysis also suggested that cholecystectomy may lower the risk of small intestine tumors (OR = 0.18, 95% CI: 0.043 to 0.71, P = 0.015), with gallstones showing an inverse relationship, indicating an increased risk (OR = 6.41, 95% CI: 1.48 to 27.80, P = 0.013).ConclusionsThe multivariable Mendelian randomization analysis highlights the differential impact of gallstones and cholecystectomy on cancer risk, specifically for nonmelanoma skin cancer and small intestine tumors. These results underscore the importance of nuanced clinical management strategies and further research to understand the underlying mechanisms and potential clinical implications of gallstone disease and cholecystectomy on cancer risk.

Causal relationships between immunophenotypes, plasma metabolites, and temporomandibular disorders based on Mendelian randomization

While numerous studies have underscored the implication of immune cells and metabolites in temporomandibular disorders (TMD), conclusive evidence for causality remains elusive. Consequently, our aim is to explore the causal connections between immunophenotypes and plasma metabolites in relation to TMD employing a bidirectional Mendelian randomization (MR) approach. Summary statistics data on 731 immunophenotypes (n = 3757) and 1091 plasma metabolites (n = 8299) were obtained from comprehensive genome-wide association studies (GWAS), while TMD data (5668 cases and 205,355 controls) were acquired from the FinnGen Consortium. Bidirectional MR analyses and a two-step MR approach assessed causal relationships and potential intermediaries. Various corrections and sensitivity analyses were utilized to assess the robustness of the findings. Two immunophenotypes and seven metabolites were significantly associated with TMD risk. Specifically, Alpha-hydroxyisovalerate mediated the link between CD33 on CD33dim HLA DR + CD11b + and TMD (β = 0.034, P = 5.95 × 10–5), while CD8 on NKT cells mediated the causal relationship between 5-acetylamino-6-formylamino-3-methyluracil levels and TMD (β = 0.069, P = 5.11 × 10–5). Our findings revealed the causal relationships between immunophenotypes and plasma metabolites on TMD from a genetic perspective, potentially aiding in TMD prevention.

Causal effect of air pollution on the risk of brain health and potential mediation by gut microbiota

ObjectiveEpidemiologic investigations have examined the correlation between air pollution and neurologic disorders and neuroanatomic structures. Increasing evidence underscores the profound influence of the gut microbiota on brain health. However, the existing evidence is equivocal, and a causal link remains uncertain. This study aimed: to determine if there is a causal connection between four key air pollutants, and 42 neurologic diseases, and 1325 distinct brain structures; and to explore the potential role of the gut microbiota in mediating these associations. MethodsUnivariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) models were deployed to estimate the causal impact of air pollutants (including particulate matter [PM] with aerodynamic diameters <2.5 μm [PM2.5], and <10 μm [PM10]; PM2.5 absorbance; and nitrogen oxides [NOx]) on brain health through various Mendelian randomization methodologies. Lastly, the mediating role of the gut microbiome in the connections between the identified pollutants and neurologic diseases and brain structures was systematically examined. ResultsThe potential causal associations of PM2.5, PM2.5 absorbance, PM10, and exposure to NOx, with the risks of intracerebral hemorrhage, hippocampal perivascular spaces, large artery strokes, generalized epilepsy with tonic-clonic seizures, Alzheimer’s disease, multiple sclerosis, anorexia nervosa, post-traumatic stress disorder (PTSD), and 420 brain structures, were investigated by UVMR analysis. Following adjustment for air pollutants by MVMR analysis, the genetic correlations between PM10 exposure and PTSD and multiple sclerosis remained significant and robust. Importantly, we observed that phylum Lentisphaerae may mediate the association between PM10 and multiple sclerosis. Additionally, PM2.5 absorbance with a greater risk of reduced thickness in the left anterior transverse temporal gyrus of Heschl and a decreased area in the right sulcus intermedius primus of Jensen, mediated by genus Senegalimassilia and genus Lachnospiraceae UCG010, respectively. Finally, we provided evidence that Clostridium innocuum and genus Ruminococcus2 may partly mediate the causal effect of NOx on altered thickness in the left transverse temporal cortex and area in the right sulcus intermedius primus of Jensen, respectively. ConclusionThis study established a genetic connection between air pollution and brain health, implicating the gut microbiota as a potential mediator in the relationship between air pollution, neurologic disorders, and altered brain structures.

Exploring the Causal Association between Morning Diurnal Preference and Psychiatric Disorders: A Bidirectional Two-Sample Mendelian Randomization Analysis.

The causal connection between morning diurnal preference and psychiatric disorders remains enigmatic. Using bidirectional two-sample Mendelian randomization (MR), we aim to explore the potential causal associations between morning diurnal preference and seven prominent psychiatric disorders. MR is a genetic epidemiological method that leverages genetic variants as instrumental variables to infer causal associations between exposures and outcomes. We obtained morning diurnal preference data from genome-wide association study (GWAS) datasets and identified 252,287 individuals as morning people. Psychiatric disorder data were sourced from the FinnGen consortium R9 dataset. Our primary analysis used the inverse-variance weighted (IVW) approach to evaluate the overall causal effect by combining the estimates from each genetic variant. Addition analyses, including weighted median, MR-Egger regression, weighted mode, and simple mode techniques were conducted to ensure robustness. Being a morning person is related to reduced odds of multiple psychiatric disorders, including depression or dysthymia (OR: 0.93, 95% CI: 0.88, 0.999), anxiety disorders (OR: 0.90, 95% CI: 0.84, 0.96), self-harming behaviors (OR: 0.87, 95% CI: 0.76, 0.99), substance-use disorders (OR: 0.81, 95% CI: 0.71, 0.93), alcohol dependence (OR: 0.82, 95% CI: 0.73, 0.92), alcohol use disorders (OR: 0.85, 95% CI: 0.76, 0.94), acute alcohol intoxication (OR: 0.86, 95% CI: 0.76, 0.96), schizophrenia (OR: 0.77, 95% CI: 0.65, 0.92), and schizophrenia or delusion (OR: 0.80, 95% CI: 0.70, 0.92). Alcohol dependence (OR: 0.97, 95% CI: 0.94, 0.999) and alcohol use disorders (OR: 0.96, 95% CI: 0.94, 0.99) were also related to a lower morning diurnal preference. Our study provides evidence that being a morning person is a protective factor for various psychiatric disorders from a genetic perspective. The results provide insights for potential targeted interventions to improve mental wellbeing.

Quasi-Experimental Evaluations of Border-Enforcement Measures

Abstract In this article, we seek to establish a causal connection between border-enforcement actions or policies and metrics that might be used to measure relevant outcomes at the border. Applying quasi-experimental methods, we investigate the impact of surveillance technology on levels of U.S. Border Patrol apprehensions of unlawful border-crossers between ports of entry along the southwest border. Our analysis offers insights into some of the effects of surveillance technology and serves as a demonstration of concept for the usefulness of such statistical methods. The most robust finding is that deploying one type of technology – integrated fixed towers (IFTs) – is associated with decreased apprehension levels in the zones of deployment. Although we emphasize ambiguity in the meaning of the results and the uncertainty in statistical inference with relatively small numbers of deployments, we conclude that there is strong evidence that some migrants were deterred from crossing surveilled areas of the border. The results are more inconclusive for other surveillance assets, but there are suggestions that some may elevate apprehension levels, pointing to a boost to the U.S. Border Patrol’s situational awareness. Statistical methods both hold promise and have limitations for the study of the impact of border-enforcement measures beyond the analysis in this study. Although these methods cannot, on their own, yield clear answers in every case, they do have the potential to help policymakers understand and anticipate the impact and effectiveness of different border-enforcement measures.

Causal role of peripheral immune cells in epilepsy: A large-scale genetic correlation study

BackgroundWhile an increasing number of researchers have focused on the correlation between the immune system and epilepsy, the precise causal role of immune cells in epilepsy continues to elude scientific understanding. The aim of the study was to examine the causal relationship between peripheral immune phenotypes and epilepsy. MethodsMendelian randomization (MR) analysis and linkage disequilibrium score regression (LDSC) were utilized to determine the causal relationship between 731 immune cell traits and various types of epilepsy in this study. ResultsLDSC revealed that 80 immunophenotypes showed genetic correlation with epilepsy, including 58 immunophenotypes associated with a single type of epilepsy (72.5 %),14 immunophenotypes associated with two types of epilepsy (17.5 %),7 immunophenotypes with 3 types of epilepsy (8.75 %) and 1 immunophenotype with 5 types of epilepsy (1.25 %). Although none of the types of epilepsy had a statistically significant effect on immunophenotypes, it is noteworthy that the MR revealed the protective effects of five immunophenotypes on epilepsy: CD45RA+CD8br AC (OR:0.86, 95 %CI:0.80–0.93), FSC-A on myeloid DC (OR:0.95, 95 %CI:0.91–0.98）, CM CD8br AC (OR:0.69, 95 %CI:0.59––0.82), CD33 on CD66b++ Myeloid cell (OR:0.88, 95 %CI:0.83–0.93) and CD127 on CD28- CD8br (OR:0.97, 95 %CI:0.95–0.98). Additionally, harmful effects were observed for two immunophenotypes on epilepsy:CD4 Treg %CD4 (OR:1.04, 95 %CI:1.02–1.06) and SSC-A on plasmacytoid DC (OR:1.01, 95 %CI:1.00–1.02). ConclusionOur research has demonstrated the causal connections between immune cells and epilepsy, potentially providing valuable insights for future clinical studies.

Whole brain causal functional connectivity analysis of noise-induced deafness based on resting state-functional magnetic resonance imaging

Objective: To investigate the changes of directional connections of auditory and non-auditory in patients with noise-induced deafness (NID) by degree centrality (DC) and Granger causality analysis (GCA), and to explore the mode of brain function remodeling after NID. Methods: In October 2023, a total of 58 patients diagnosed with NID by the Occupational Diseases Department of Yantaishan Hospital of Yantai from 2014 to 2022 were collected as case group (NID group), and 42 healthy volunteers matched by gender, age and education level were selected as the control group (HC group). Resting state-functional magnetic resonance imaging (Rs-fMRI) was perfomed and PC analysis was performed. The brain regions with statistically significant differences in DC values between groups and the bilateral Heschl regions were extracted as regions of interest (ROI) for voxel-based whole brain GCA and correlation analysis. Results: Compared with HC group, the SOG.L DC value of NID group was lower, the connectivity values of SFGdor.L to SOG.L was increased, the connectivity value of PCL.L to SOG.L was decreased, the connectivity values of ORBmid.L, PCG.R and CUN. L/R to HES.L were increased, the connectivity value of SFGdor.L to HES.L was decreased, the connectivity value of HES.L to PCUN.L was decreased, the connectivity values of ORBsup.L and PCG.R to HES.R were increased, the connectivity value of HES.R to CUN.L was decreased (P voxel level<0.01, P cluster level<0.05). The connectivity value of PCL.L to SOG.L was negatively correlated with the weighted value of the better whisper frequency (P<0.05) . Conclusion: The NID patients have abnormal directional connectivity activity in multiple brain regions, such as auditory vision, executive control, somatosensory movement, and default mode network. It is suggested that hearing loss may cause complex neural remodeling between auditory and non-auditory centers.

Genetically predicted blood metabolites mediate relationships between gut microbiota and ovarian cancer: a Mendelian randomization study.

While there is evidence that gut microbiota (GM) and blood metabolites are associated with ovarian cancer (OC), the precise mechanisms underlying this relationship are still unclear. This study used Mendelian randomization (MR) to elucidate the causal connections between GM, blood metabolite biomarkers, and OC. In this study, we leveraged summary data for GM (5,959 individuals with genotype-matched GM), blood metabolites (233 circulating metabolic traits with 136,016 participants), and OC (63,702 participants with 23,564 cases and 40,138 controls) from genome-wide association studies (GWASs). We performed MR analysis to explore the causal relationship between GM and OC. Further, we harnessed univariable MR (UVMR) analysis to evaluate the causal associations between GM and circulating metabolites. Finally, we employed a two-step approach based on multivariable MR (MVMR) to evaluate the total genetic prediction effect of metabolites mediating the GM on the risk of OC to discover a potential causal relationship. In the MR analysis, 24 gut bacteria were causally associated with the pathogenesis of OC, including 10 gut bacteria (Dorea phocaeense, Succinivibrionaceae, Raoultella, Phascolarctobacterium sp003150755, Paenibacillus J, NK4A144, K10, UCG-010 sp003150215, Pseudomonas aeruginosa, and Planococcaceae) that were risk factors, and 14 gut bacteria (CAG-177 sp002438685, GCA-900066135 sp900066135, Enorma massiliensis, Odoribacter laneus, Ruminococcus E sp003521625, Streptococcus sanguinis, Turicibacter sp001543345, Bacillus velezensis, CAG-977, CyanobacteriaStaphylococcus A fleurettii, Caloranaerobacteraceae, RUG472 sp900319345, and CAG-269 sp001915995) that were protective factors. The UVMR analysis showed that these 24 positive gut bacteria were causally related to lipoproteins, lipids, and amino acids. According to the MVMR analysis, Enorma massiliensis could reduce the risk of OC by raising the total cholesterol to total lipids ratio in large low-density lipoprotein (LDL) and cholesteryl esters to total lipids ratio in intermediate-density lipoprotein (IDL). Turicibacter sp001543345, however, could reduce the risk of OC by lowering free cholesterol in small high-density lipoprotein (HDL) and increasing the ratios of saturated fatty acids to total fatty acids, total cholesterol to total lipids ratio in very small very-low-density lipoprotein (VLDL), and cholesteryl esters to total lipids ratio in very small VLDL. The current MR study provides evidence that genetically predicted blood metabolites can mediate relationships between GM and OC.

Association of Obstructive Sleep Apnea on Heart Failure and Its Risk Factors: A Two-Step Mendelian Randomization Study

Introduction: Recent studies have indicated that obstructive sleep apnea (OSA) is linked to a higher likelihood of heart failure (HF). However, the causal connection between the two conditions is uncertain. We aimed to investigate the causal association of OSA with HF and its risk factors. Methods: The OSA summary statistics are derived from the FinnGen database, including 38,998 cases and 336,659 controls. HF summary statistics come from HERMES, the UK Biobank, and the FinnGen database. A two-sample mendelian randomization (MR) analysis was conducted to examine the causality of OSA on HF risk. Furthermore, the mediator effect of potential risk factors was assessed by a two-step MR. Results: The results of MR analysis demonstrated that genetically determined OSA is causal associated with the higher likelihood of HF (HERME: odds ratio [OR] = 1.222; 95% confidence interval [CI]: 1.091, 1.369; p = 5.19 × 10−4) (FinnGen: OR = 1.233; 95% CI: 1.129, 1.346; p = 3.32 × 10−6) (UK Biobank: OR = 1.002; 95% CI: 1.000, 1.003; p = 0.014). Two-step MR analysis indicated that obesity, blood glucose, depression, and other CVDs have significant mediating effects on the causal effect between OSA and HF. Conclusion: This MR study emphasizes the causal effect of OSA on HF risk. Adiposity traits play a major role in the process of OSA leading to HF. Considering the detrimental impact of OSA on HF, it becomes imperative to prioritize the prevention and management of HF in individuals afflicted with OSA. The foremost intervention strategy should revolve around effective obesity management.

Assessing the causal effect of inflammation-related genes on myocarditis: A Mendelian randomization study.

Prior evidence has shown a significant link between inflammation and the development of myocarditis. This study aimed to investigate the causal relationship between inflammation-related genes (IRGs) and myocarditis. In this study, the causal relationship between 167 IRGs and myocarditis were investigated using datasets from the Gene Set Enrichment Analysis and Integrative Epidemiology Unit open genome-wide association study (IEU OpenGWAS) databases. The GWAS data (finn-b-I9 MYOCARD) contained single nucleotide polymorphisms (SNPs) data from 117755 myocarditis samples (16379455 SNPs, 829 cases vs. 116926 controls). Five algorithms [MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode regression] were employed for the MR analysis, with IVW as the primary method, and sensitivity analysis was conducted. Subcellular localization and protein-protein interaction (PPI) network analyses were performed for selected biomarkers. Results were verified in ebi-a-GCST90018882 (24180570 SNPs, 633 cases vs. 427278 controls) and finn-b-I9 MYOCARD EXNONE (16380466 SNPs, 829 cases vs. 217963 controls) to enhance reliability. IRF7 and ADORA2B were shown to be two exposure factors after screening. Univariable MR (UVMR) analysis revealed that IRF7 was a risk factor for myocarditis [IVW: odd ratio (OR)=1.041, 95% confidence interval (CI)=1.018-1.955, P=0.039], while ADORA2B was a protective factors for myocarditis (IVW: OR=0.799, 95% CI=0.640-0.997, P=0.047). Sensitivity analysis confirmed the robustness of these findings. Multivariable MR (MVMR) analysis further demonstrated a direct causal role of ADORA2B in preventing myocarditis. Subcellular localization analysis indicated predominant cytoplasmic expression and limited mitochondrial expression for both genes. The results of PPI analysis showed that 20 genes were predicted to be associated with IRF7 function, such as response to type I interferon, pattern recognition receptor signalling pathway, and toll-like receptor signalling pathway. The results in finn-b-I9 MYOCARD EXNONE were consistent with MR analysis. The findings indicated there was a causal connection between IRGs (IRF7 and ADORA2B) and myocarditis, which offered a crucial point of reference and guidance for future studies and myocarditis treatment.

The weather today rocks or sucks for my tree: exploring the understanding of climate impacts on forests at high school level through tweets

Abstract. With the progression of global warming, impacts on the human sphere will undoubtedly increase. One prominent example at mid-latitudes is the stress on forests caused by climate change, which the BayTreeNet project (https://baytreenet.de/, last access: 30 July 2024) addresses from an interdisciplinary viewpoint. Scientists from physical climatology, dendroecology, and educational research collaborate to examine how long-term changes in weather patterns affect the state of trees, and how the atmosphere–tree relation can be used to the advantage of improving the communication of climate change effects to, in particular, high school students. This article presents a 1-week case study for the summer of 2021, when a distinct variability in weather patterns induced significant tree responses. The students of seven selected partner schools commented on the measured tree and weather data, which were available in real time, in the form of tweets and in conjunction with their educational geography program. The analyses of the tweets reveal that the students succeed in verbalizing the measured weather and, furthermore, manage to draw links between the stem diameter changes in trees and the weather variability. Problems arise with the use of less perceivable variables like the sap flow in the trees; also, the student posts exhibit shortcomings in establishing causal connections. Hence, the case study points to a discrepancy between describing basic environmental information and appreciating or understanding the underlying mechanistic links. This point will serve to refine future classroom concepts and, moreover, to enhance the communication of climate change effects on forests to the general public.

The 1400 metabolite-mediated relationship between 91 inflammatory cytokines and migraine: An exploratory two-step Mendelian randomization study.

Inflammatory cytokines and migraines have been associated in previous research, but the underlying mechanisms of action are still elusive. The biological functions of metabolites are crucial in the onset of migraine. Our goals were to clarify the cause-and-effect connection between inflammatory cytokines and migraines and explore the potential mediating function of metabolites. Utilizing summary-level data from genome-wide association studies (GWAS), we conducted two-sample Mendelian randomization (MR) analyses to evaluate the possible causal connection between inflammatory cytokines and migraines. A two-step MR analysis was employed to further investigate the potential mediating pathways of metabolites. MR analysis identified a total of 9 inflammatory cytokines that were genetically associated with migraines, and we subsequently identified 21 mediated relationships, with 20 metabolites (13 metabolites, 7 ratios) acting as potential mediators between 8 inflammatory cytokines and migraine. The 9 inflammatory cytokines were beta-nerve growth factor levels (β-NGF), T-cell surface glycoprotein CD5 levels (CD5), T-cell surface glycoprotein CD6 isoform levels (CD6), C-X-C motif chemokine 11 levels (CXCL11), interleukin-4 levels (IL-4), oncostatin-M levels (OSM), signalling lymphocytic activation molecule levels (SLAM), C-C motif chemokine 25 levels (CCL25) and monocyte chemoattractant protein-1 levels (MCP-1). Our research findings provide evidence for both a causal connection between inflammatory cytokines and migraines, as well as a metabolite-mediated pathway. These biomarkers facilitate the detection, diagnosis and treatment of migraines while offering fresh perspectives on their underlying mechanisms.

Causal influence of plasma metabolites on age-related macular degeneration: A Mendelian randomization study.

Using genome-wide association study data from European populations, this research clarifies the causal relationship between plasma metabolites and age-related macular degeneration (AMD) and employs Metabo Analyst 5.0 for enrichment analysis to investigate their metabolic pathways. Employing Mendelian randomization analysis, this study leveraged single nucleotide polymorphisms significantly associated with plasma metabolites as instrumental variables. This approach established a causal link between metabolites and AMD. Analytical methods such as inverse-variance weighted, Mendelian randomization-Egger, and weighted median were applied to validate causality. Mendelian Randomization Pleiotropy Residual Sum and Outlier was utilized for outlier detection and correction, and Cochran's Q test was conducted to assess heterogeneity. To delve deeper into the metabolic characteristics of AMD, metabolic enrichment analysis was performed using Metabo Analyst 5.0. These combined methods provided a robust framework for elucidating the metabolic underpinnings of AMD. The 2-sample MR analysis, after meticulous screening, identified causal relationships between 88 metabolites and AMD. Of these, 16 metabolites showed a significant causal association. Following false discovery rate correction, 3 metabolites remained significantly associated, with androstenediol (3 beta, 17 beta) disulfate (2) exhibiting the most potent protective effect against AMD. Further exploration using Metabo Analyst 5.0 highlighted 4 metabolic pathways potentially implicated in AMD pathogenesis. This pioneering MR study has unraveled the causal connections between plasma metabolites and AMD. It identified several metabolites with a causal impact on AMD, with 3 maintaining significance after FDR correction. These insights offer robust causal evidence for future clinical applications and underscore the potential of these metabolites as clinical biomarkers in AMD screening, treatment, and prevention strategies.

Causal relationship between immune cells and pulmonary arterial hypertension: Mendelian randomization analysis.

Immunity and inflammation in pulmonary arterial hypertension (PAH) has gained more attention. This research aimed to investigate the potential causal connections between 731 immunophenotypes and the likelihood of developing PAH. We obtained immunocyte data and PAH from openly accessible database and used Mendelian randomization (MR) analysis to evaluate the causal association between each immunophenotype and PAH. Various statistical methods were employed: the MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode. In the study of 731 different types of immune cells, it was found that 9 showed a potential positive connection (IVW P < .05) with increased risk of PAH, while 19 had a possible negative link to decreased risk. Following false discovery rate (FDR) adjustment, the analysis using the IVW method demonstrated that 5 immune phenotypes were significantly associated with PAH (FDR < 0.05, OR > 1). Conversely, there was a negative correlation between PAH and 4 immune cell types (FDR < 0.05, OR < 1). Sensitivity analyses suggested the robustness of all MR findings. This research, for the first time, has revealed indicative evidence of a causal link between circulating immune cell phenotypes and PAH through genetic mechanisms. These results underscore the importance of immune cells in the pathogenesis of PAH.

The Impact of Ethnic Identity on Language Attitudes

ABSTRACT Few studies have explored the relationship between ethnic identity and language attitudes in heritage language speakers. Via self-reported questionnaire data, the present study examined correlational and causal connections between ethnic identity and language attitudes in three generations of Israeli and American Mountain Jews. Native to the eastern Caucasus, Mountain Jews immigrated in the 1990s to Israel and the United States, bringing with them two heritage languages, Juhuri and Russian. The effect of ethnic identity on language attitudes emerged as strong for both Juhuri and Russian, but varied across countries, generations, languages, and types of attitudes. Strong correlations between ethnic identity and language attitudes were found for both heritage languages in Israel, but in the United States the connection between Russian and Mountain Jewish identity was lost across generations. Results are discussed in terms of previous research on heritage languages, identity and attitudes, and highlight the revival of ethnic identity among second-generation immigrants.

Neuroelectrophysiology-compatible electrolytic lesioning.

Lesion studies have historically been instrumental for establishing causal connections between brain and behavior. They stand to provide additional insight if integrated with multielectrode techniques common in systems neuroscience. Here, we present and test a platform for creating electrolytic lesions through chronically implanted, intracortical multielectrode probes without compromising the ability to acquire neuroelectrophysiology. A custom-built current source provides stable current and allows for controlled, repeatable lesions in awake-behaving animals. Performance of this novel lesioning technique was validated using histology from ex vivo and in vivo testing, current and voltage traces from the device, and measurements of spiking activity before and after lesioning. This electrolytic lesioning method avoids disruptive procedures, provides millimeter precision over the extent and submillimeter precision over the location of the injury, and permits electrophysiological recording of single-unit activity from the remaining neuronal population after lesioning. This technique can be used in many areas of cortex, in several species, and theoretically with any multielectrode probe. The low-cost, external lesioning device can also easily be adopted into an existing electrophysiology recording setup. This technique is expected to enable future causal investigations of the recorded neuronal population's role in neuronal circuit function, while simultaneously providing new insight into local reorganization after neuron loss.

Uncovering a Causal Connection between Gut Microbiota and Six Thyroid Diseases: A Two-Sample Mendelian Randomization Study.

Recent studies have established associations between the gut microbiota (GM) and thyroid diseases (TDs). However, their causal relationships remain elusive. To investigate this causality, we conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data from MiBioGen and FinnGen, with GM as the exposure and six TDs as outcomes. We identified 32 microbial taxa linked to the risk of six TDs. The Clostridium innocuum group, Ruminiclostridium5, and Lachnoclostridium exhibited protective effects against nontoxic diffuse goiter (NDG). Conversely, an increased risk of NDG was associated with Ruminococcaceae UCG002, Alistipes, Methanobrevibacter, Marvinbryantia, and Ruminococcaceae UCG014. Bifidobacterium and Sutterella were protective against nontoxic multinodular goiter (NMG), while the Ruminococcus gauvreauii group and Rikenellaceae RC9 gut group heightened NMG risk. Protective effects against nontoxic single thyroid nodule (NSTN) were observed with Defluviitaleaceae UCG011, Ruminococcus1, and Ruminococcaceae UCG010, whereas increased risk was linked to Alistipes, the Ruminococcus gauvreauii group, and Lachnospiraceae UCG010. Ruminiclostridium9, Victivallis, and Butyricimonas offered protection against thyrotoxicosis with Graves' Disease (GD), while the Eubacterium rectale group, Desulfovibrio, Bifidobacterium, Collinsella, Oscillospira, and Catenibacterium were risk factors. For thyrotoxicosis with Plummer Disease (PD), protective taxa included Butyricimonas and Lachnospira, whereas Dorea, Eggerthella, Odoribacter, Lactobacillus, Intestinimonas, and Phascolarctobacterium increased risk. Lastly, Parasutterella was protective against thyrotoxicosis with toxic single thyroid nodule (TSTN), while increased risk was associated with Sutterella, Oscillibacter, and Clostridium sensu stricto1. Our findings support a causal relationship between specific GM and TDs at the genetic level, laying the foundation for future research into potential mechanisms and the identification of novel therapeutic targets.