Causal Influence Research Articles

Confounding Fuels Misinterpretation in Human Genetics.

The scientific literature has seen a resurgence of interest in genetic influences on human behavior and socioeconomic outcomes. Such studies face the central difficulty of distinguishing possible causal influences, in particular genetic and non-genetic ones. When confounding between possible influences is not rigorously addressed, it invites over- and misinterpretation of data. We illustrate the breadth of this problem through a discussion of the literature and a reanalysis of two examples. Clark (2023) suggested that patterns of similarity in social status between relatives indicate that social status is largely determined by one's DNA. We show that the paper's conclusions are based on the conflation of genetic and non-genetic transmission, such as wealth, within families. Song & Zhang (2024) posited that genetic variants underlying bisexual behavior are maintained in the population because they also affect risk-taking behavior, thereby conferring an evolutionary fitness advantage through increased sexual promiscuity. In this case, too, we show that possible explanations cannot be distinguished, but only one is chosen and presented as a conclusion. We discuss how issues of confounding apply more broadly to studies that claim to establish genetic underpinnings to human behavior and societal outcomes.

Corruption in Namibia: Examining the Nexus Between Survey-Identified Causes and Empirical Validation

This study investigates the causal relationship between the factors identified in the 2016 National Corruption Perception Survey Report and corruption levels in Namibia. By analysing data from 2000 to 2022, the Toda-Yamamoto VAR Granger causality test was employed to investigate the impact of greed, poor leadership and law enforcement, poverty (working poverty), and poor pay (compensation to employees) on corruption levels. The results revealed statistically significant causal linkages between greed, poor leadership and law enforcement, and poverty. Poor pay, however, showed no significant causal influence on corruption. These findings highlight the necessity of tackling issues such as equal income distribution, poverty, and governance inadequacies in anti-corruption initiatives. Targeted measures based on empirical evidence can effectively reduce corruption and increase transparency in governance. Additionally, conducting more recent corruption surveys in Namibia could yield up-to-date perceptions that could be adopted in similar country-specific studies elsewhere.

The etiology of the association between parental nurturance and youth antisocial behavior: Evidence from a twin differences study

AbstractBackgroundLower parental nurturance is consistently associated with higher levels of youth antisocial behavior (ASB), but the etiology of this association remains unclear. To fill this gap, we employed a twin differences approach to illuminate the environmental and genetic origins of the association between parental nurturance and children's ASB.MethodsParticipants were 2060 twins (49% female) ages 6–10 from the Michigan State University Twin Registry. Parental nurturance and youth ASB were assessed using multiple measures (e.g., questionnaires, interviews) and informant reports (e.g., twins, parents, teachers). Co‐twin difference‐score correlations were analyzed separately by zygosity using specification curve analysis, an exhaustive modeling approach that examined associations across all possible specifications of the nurturance and ASB data.ResultsParental nurturance demonstrated clear, negatively signed associations with youth ASB at the individual level. However, these associations generally did not persist within twin pairs. We observed no significant twin difference correlations within monozygotic (MZ) pairs and only a handful of significant twin difference correlations among dizygotic (DZ) pairs, in which the DZ co‐twin who experienced more nurturance exhibited less ASB. Post‐hoc analyses in these data revealed that these associations differed markedly from those with harsh parenting that suggested environmental influences on youth ASB.ConclusionsThese results strongly argue against a causal influence of low parental nurturance on youth ASB, and instead suggest that genetic influences and shared environmental confounds underlie their association. Further, findings strongly suggest that different parenting behaviors are associated with child ASB via different etiologic mechanisms.

DNA methylation-estimated phenotypes, telomere length and risk of ischemic stroke: epigenetic age acceleration of screening and a Mendelian randomization study.

Aging is a complex biological process that may be accelerated in certain pathological conditions. DNA methylation age (DNAmAge) has emerged as a biomarker for biological age, which can differ from chronological age. This research peels back the layers of the relationship between fast-forward aging and ischemic stroke, poking and prodding the potential two-way causal influences between stroke and biological aging indicators. We analyzed a cohort of ischemic stroke patients, comparing DNAmAge with chronological age to measure age acceleration. We assessed variations in age acceleration among stroke subtypes and between sexes. Using Mendelian randomization, we examined the causal links between stroke, aging biomarkers like telomere length, and age acceleration's effect on stroke risk. Our investigation reveals a pronounced association between ischemic stroke and age acceleration, most notably in patients with cardioembolic strokes, who exhibited a striking median difference of 9 years between DNAmAge and chronological age. Furthermore, age acceleration differed significantly across stroke subtypes and was higher in women than in men. In terms of causality, MR analysis indicated a modest negative effect of stroke on telomere length, but no causal effect of age phenotypes on stroke or its subtypes. However, some indication of a potential causal effect of ischemic stroke on PhenoAge acceleration was observed. The study provides insight into the relationship between DNAmAge and ischemic stroke, particularly cardioembolic stroke, and suggests possible gender differences. These insights carry profound clinical significance and set stage for future investigations into the entwined pathways of stroke and accelerated aging.

Causal link between metabolic related factors and osteoarthritis: a Mendelian randomization investigation.

Metabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification. Two-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity. The UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified. The MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.

Causal association between inflammatory bowel disease and acute pancreatitis: a two-sample bidirectional mendelian randomization study.

Acute pancreatitis (AP) is an extraintestinal manifestation of inflammatory bowel disease (IBD). Numerous observational studies have reported an increased risk of AP in patients diagnosed with IBD. However, the causal association and directionality between IBD or its subtypes and the development of AP remains unclear due to the limitations of observational research. This study aims to explore the relationship between IBD or its subtypes and AP risk using Mendelian Randomization (MR) method. A two-sample bidirectional MR study was conducted, selecting genetic variants associated with IBD and AP as instrumental variables from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) and FinnGen databases, respectively. The inverse-variance weighted (IVW) method used as the primary approach for causal inference. The Cochran Q test was employed for heterogeneity assessment. Sensitivity analyses were performed using the MR Egger intercept test, MR-Presso, and Leave-one-out method. The results revealed that IBD (OR = 1.049, 95% CI = 1.010-1.090, p = 0.013) and ulcerative colitis (UC) (OR = 1.057, 95% CI = 1.013-1.102, p = 0.011) were significantly associated with an increased risk of AP. However, Crohn's disease (CD) (OR = 1.023, 95% CI = 0.993-1.055, p = 0.134) did not show a causal association with the risk of AP. Interestingly, AP was suggestively associated with a decreased risk of CD (OR = 0.797, 95% CI = 0.637-0.997, p = 0.047). Furthermore, there was no causal association between AP and the risk of IBD (OR = 0.886, 95% CI = 0.753-1.042, p = 0.144) or UC (OR = 0.947, 95% CI = 0.773-1.159, p = 0.595). In conclusion, this study provides genetic evidence supporting the causal influence of IBD (specifically UC) on AP, while CD does not appear to have a causal impact on AP.

Causal influence of immune factors on the risk of diabetic retinopathy: a mendelian randomization study

ObjectivesDiabetic retinopathy (DR) is a prevalent microvascular complication in diabetic patients. Various mechanisms have been implicated in the pathogenesis of DR. Previous studies have observed the relationship between immune factors and DR, but the causal relationship has not been determined.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis of 731 immune cells and DR, using publicly available genome-wide association study (GWAS) summary statistics, to evaluate potential causal relationships between them. Four types of immune traits were included in the analysis through flow cytometry. GWAS statistics for DR were obtained from the Finngen database, which performed GWAS on 190,594 European individuals (Ncase = 14,584, Ncontrol = 176,010) to assess genetically predicted DR. The primary method used to perform causality analysis was inverse variance weighting (IVW).ResultsFollowing false discovery rate (FDR) correction, 11MFI-DR, 5AC-DR, 5RC-DR, and 1MP-DR reached a significant causal association level (PFDR < 0.05). Notably, all AC traits exhibited potential associations with a decreased risk of DR(OR < 1), while a majority of MFI traits, along with the singular MP trait, exhibited potential associations with an increased risk of DR (OR > 1). The highest proportion of T-cell subsets in the final results.ConclusionThis study elucidates that the progression of DR is intricately influenced by immune responses, thereby confirming the immunological susceptibility of DR. Our findings may offer new targets for diagnosing and treating DR, as well as aid in developing therapeutic strategies from an immunological standpoint.

Excess topography and outburst flood: Geomorphic imprint of October 2023 extreme flood event in the Teesta catchment of Eastern Himalayas

The 2023 South-Lohnak Lake outburst flood event across the upstream Teesta catchment triggered short-lived, high-magnitude flooding and substantial socioeconomic disruption downstream. We performed landscape analysis across the Teesta catchment using topographic metrics to understand the geomorphic response to this extreme flood event. We estimated the various topographic metrics such as ksn anomaly (normalized channel steepness index) (∼500–2500 m0.9), SL-index (stream-length gradient index) (∼5000–7000 m), and KsnQ (channel steepness-weighted discharge) along the trunk channel draining through the South-Lohnak Lake, which shows high magnitude in flooded regions and numerous spikes in their longitudinal profiles across mass-wasting regions downstream. We used the KsnQ metric as an event characteristic to investigate the changes in the channel morphology due to high-magnitude flooding. There was a sudden increase in the magnitude of the KsnQ metric when the river traversed through the Chungthang dam over the high ranges of excess topography (∼0–1700 m). This shows that the downstream channel morphology changes rapidly during this flood event, and KsnQ is a significant indicator of geomorphic change. To understand the spatial relationship between the physical drivers that trigger this outburst flood, we quantified the causal relationship between glacial-hydrological drivers over the upstream Zemu-sub catchment. Our observations suggest that precipitation intensity and surface temperature had a significant direct causal influence on snowmelt and snow depth (in terms of water equivalent) over the event duration with a 5-day and 1-day lag composite. Through the inclusion of lagged composites and causal linkages, the drivers across the glaciated landscape serve as event anomalies, which trigger the glacier hillslope failure and subsequent high-magnitude outburst flooding. Therefore, we suggest that the interaction of topographic discontinuity with hydrological extremes and their causal interdependencies influences this outburst event in the upper reaches, followed by high-magnitude flooding in the downstream reaches of the Teesta River. However, the long-term geomorphic consequences of such events on the evolution of the regional landscape remain unclear.

A mediation approach in resting-state connectivity between the medial prefrontal cortex and anterior cingulate in mild cognitive impairment

Mild cognitive impairment (MCI) is recognized as the prodromal phase of dementia, a condition that can be either maintained or reversed through timely medical interventions to prevent cognitive decline. Considerable studies using functional magnetic resonance imaging (fMRI) have indicated that altered activity in the medial prefrontal cortex (mPFC) serves as an indicator of various cognitive stages of aging. However, the impacts of intrinsic functional connectivity in the mPFC as a mediator on cognitive performance in individuals with and without MCI have not been fully understood. In this study, we recruited 42 MCI patients and 57 healthy controls, assessing their cognitive abilities and functional brain connectivity patterns through neuropsychological evaluations and resting-state fMRI, respectively. The MCI patients exhibited poorer performance on multiple neuropsychological tests compared to the healthy controls. At the neural level, functional connectivity between the mPFC and the anterior cingulate cortex (ACC) was significantly weaker in the MCI group and correlated with multiple neuropsychological test scores. The result of the mediation analysis further demonstrated that functional connectivity between the mPFC and ACC notably mediated the relationship between the MCI and semantic fluency performance. These findings suggest that altered mPFC-ACC connectivity may have a plausible causal influence on cognitive decline and provide implications for early identifications of neurodegenerative diseases and precise monitoring of disease progression.

Does Rural Labor Transfer Impact Chinese Agricultural Carbon Emission Efficiency? A Substitution Perspective of Agricultural Machinery

In this paper, referring to Kaya’s method, the ratio of gross agricultural production (GAP) and agricultural carbon emission is defined as agricultural carbon emission efficiency (ACEE). Considering rural labor transfer (RLT) increases the agricultural machinery intensity (AMI), the two are substitutes for each other and may interact with agricultural carbon emission efficiency (ACEE). We constructed a Simultaneous Equations Model (SEM) of ACEE, RLT and AMI and analyzed the interaction mechanism of these three variables using the Three-Stage Least Squares (3SLS). The following conclusions are drawn. First, RLT and AMI significantly promote the improvement of ACEE, while the improvement of ACEE and AMI further promotes RLT. Secondly, the causal relationship and influence mechanism of ACEE, RLT and AMI are interactive and multi-directional. For example, an increase in AMI promotes ACEE, but an increase in ACEE inhibits an increase in AMI. Finally, China has significant regional heterogeneity, and different regions have different interaction mechanisms. Local governments should consider the local economic base and technological level when implementing policies. This paper extends the analytical framework of ACEE, RLT, and AMI and provides a reference for governments to make policies.

The effect of coffee consumption on three main bone disorders: a Mendelian randomization trial.

Despite a large number of observational studies examining the effect of coffee consumption(CC) on bone disorders(BDs), particularly, osteoarthritis(OA), osteoportic fracture(OF), and rheumatoid arthritis(RA), the conclusions are highly controversial. Thus, it is essential to examine the causal association between CC and BDs. Mendelian randomization (MR) analysis was performed to assess the causal influence of CC on OF, RA, and OA. The main endpoint was the odds ratio (OR) of the inverse variance weighted (IVW) approach. In addition, the weighted median (WM), MR-Egger regressions, MR-pleiotropy residual sum and outlier (MR-PRESSO) and multivariable MR (MVMR) were included in sensitivity analyses. Furthermore, the function of causal SNPs was evaluated by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction networks. Primary MR analysis based on the IVW method suggested that changes in CC alter risk of OF (OR = 1.383, 95%CI 1.079-1.853, P = 0.039), RA(OR: 1.623, 95%CI 1.042-2.527, P = 0.032) and HOA (hip osteoarthritis, OR = 1.536, 95% CI 1.044-2.259, P = 0.021). However, these causal relationships were not robust in sensitivity analyses. In contrast, there is a positive causal relationship between increased CC and the risk of KOA (knee osteoarthritis, OR: 2.094, 95%CI: 1.592-2.754, P = 1.41 × 10-7), as evidenced by the IVW using random effect. A similar effect size was observed across all MR sensitivity analyses, with no evidence of horizontal pleiotropy. Based on our MR analysis, increased CC was causally linked to an increase in the risk of KOA. Genetic predictions suggested that CC reduction may have benefits for bone health.

Exploring the bidirectional causal associations between pain and circulating inflammatory proteins: A Mendelian randomization study.

Multisite chronic pain (MCP) and site-specific chronic pain (SSCP) may be influenced by circulating inflammatory proteins, but the causal relationship remains unknown. To overcome this limitation, two-sample bidirectional Mendelian randomization (MR) analysis was used to analyse data for 91 circulating inflammatory proteins, MCP and SSCP encompassing headache, back pain, shoulder pain, hip pain, knee pain, stomach abdominal pain and facial pain. The primary MR method used was inverse variance weighting, sensitivity analyses included weighted median, MR pleiotropy residual sum and outlier and the Egger intercept method. Heterogeneity was also detected using Cochrane's Q test and leave-one-out analyses. Finally, a causal relationship between 29 circulating inflammatory proteins and chronic pain was identified. Among these proteins, 14 exhibited a protective effect, including MCP (T-cell surface glycoprotein cluster of differentiation 5), headache (4E-binding protein 1 [4EBP1], cluster of differentiation 40, cluster of differentiation 6 and C-X-C motif chemokine [CXCL] 11), back pain (leukaemia inhibitory factor), shoulder pain (fibroblast growth factor [FGF]-5 and interleukin [IL]-18R1), stomach abdominal pain (tumour necrosis factor [TNF]-α), hip pain (CXCL1, IL-20 and signalling lymphocytic activation molecule 1) and knee pain (IL-7 and TNF-β). Additionally, 15 proteins were identified as risk factors for MCP and SSCP: MCP (colony-stimulating factor 1, human glial cell line-derived neurotrophic factor and IL-17C), headache (fms-related tyrosine kinase 3 ligand, IL-20 receptor subunit α [IL-20RA], neurotrophin-3 and tumour necrosis factor receptor superfamily member 9), facial pain (CXCL1), back pain (TNF), shoulder pain (IL-17C and matrix metalloproteinase-10), stomach abdominal pain (IL-20RA), hip pain (C-C motif chemokine 11/eotaxin-1 and tumour necrosis factor ligand superfamily member 12) and knee pain (4EBP1). Importantly, in the opposite direction, MCP and SSCP did not exhibit a significant causal impact on circulating inflammatory proteins. Our study identified potential causal influences of various circulating inflammatory proteins on MCP and SSCP and provided promising treatments for the clinical management of MCP and SSCP.

Causal relationship between gut microbiota and pathological scars: a two-sample Mendelian randomization study.

Pathological scars, including keloids and hypertrophic scars, represent a significant dermatological challenge, and emerging evidence suggests a potential role for the gut microbiota in this process. Utilizing a two-sample Mendelian randomization (MR) methodology, this study meticulously analyzed data from genome-wide association studies (GWASs) relevant to the gut microbiota, keloids, and hypertrophic scars. The integrity and reliability of the results were rigorously evaluated through sensitivity, heterogeneity, pleiotropy, and directionality analyses. By employing inverse variance weighted (IVW) method, our findings revealed a causal influence of five bacterial taxa on keloid formation: class Melainabacteria, class Negativicutes, order Selenomonadales, family XIII, and genus Coprococcus2. Seven gut microbiota have been identified as having causal relationships with hypertrophic scars: class Alphaproteobacteria, family Clostridiaceae1, family Desulfovibrionaceae, genus Eubacterium coprostanoligenes group, genus Eubacterium fissicatena group, genus Erysipelotrichaceae UCG003 and genus Subdoligranulum. Additional sensitivity analyses further validated the robustness of the associations above. Overall, our MR analysis supports the hypothesis that gut microbiota is causally linked to pathological scar formation, providing pivotal insights for future mechanistic and clinical research in this domain.

The puzzle of mood rationality

AbstractMoods, orthodoxy holds, exist outside the space of reasons. A depressed subject may change their thoughts and behaviors as a result of their depression. But, according to this view, their mood gives them no genuine reason to do so. Instead, moods are mere causal influences on cognition. The issue is that moods, with their diffuse phenomenology, appear to lack intentionality (Directionlessness). But intentionality appears to be a necessary condition on rationality (The Content Constraint). Together, these principles conflict with the idea that moods are rational states of mind (Mood Rationality). The inconsistency of these three principles is the Puzzle of Mood Rationality. Now to many, this puzzle is hardly vexing: we should reject Mood Rationality. But, I argue, Mood Rationality is true despite its unpopularity. Thus, we need another way of resolving the puzzle. To do so, I distinguish intentionality as a first‐personal, phenomenological notion from representation as a third‐personal, cognitive scientific notion. I then argue that moods satisfy a revised version of the Content Constraint and sketch an account of moods as representational but non‐intentional mental states, drawing on the Valuationist paradigm in affective neuroscience. I end by showing how this account enables us to explain moods’ rationality.

Causal Relationship Between Obstructive Sleep Apnea and Temporomandibular Disorders: A Bidirectional Mendelian Randomization Analysis.

This study was conducted to investigate the bidirectional causal relationship between obstructive sleep apnea (OSA) and temporomandibular disorders (TMD). Using an online pooled dataset of genome-wide association studies (GWAS), a two-sample bi-directional Mendelian randomization (MR) method was implemented. Inverse variance weighting was used as the primary analyses approach, and other methods of MR Egger, weighted median method, MR-Egger, Simple mode, and Weighted mode analysis were conducted as supplements to evaluate the causal relationship between OSA and TMD with odds ratios (OR) and 95% confidence interval (CI). Furthermore, the Cochran Q, MR-Egger, and MR-PRESSO approaches were used to perform the heterogeneity test and multiple validity. The general results of the forward MR analysis indicated that OSA had a significant causal influence on TMD (OR=1.241, 95% CI: 1.009-1.526, P=0.041), but no significant correlation was observed in the reverse MR analysis (IVW: OR=0.975, 95% CI=0.918-1.036, P=0.411). In summary, our research demonstrated a hereditary causative relationship between OSA and TMD, indicating that appropriate intervention is required for both prevention and treatment of TMD.

Linked Exposures Across Databases: an exposure common data elements aggregation framework to facilitate clinical exposure review.

Understanding the health outcomes of military exposures is of critical importance for Veterans, their health care team, and national leaders. Approximately 43% of Veterans report military exposure concerns to their VA providers. Understanding the causal influences of environmental exposures on health is a complex exposure science task and often requires interpreting multiple data sources; particularly when exposure pathways and multi-exposure interactions are ill-defined, as is the case for complex and emerging military service exposures. Thus, there is a need to standardize clinically meaningful exposure metrics from different data sources to guide clinicians and researchers with a consistent model for investigating and communicating exposure risk profiles. The Linked Exposures Across Databases (LEAD) framework provides a unifying model for characterizing exposures from different exposure databases with a focus on providing clinically relevant exposure metrics. Application of LEAD is demonstrated through comparison of different military exposure data sources: Veteran Military Occupational and Environmental Exposure Assessment Tool (VMOAT), Individual Longitudinal Exposure Record (ILER) database, and a military incident report database, the Explosive Ordnance Disposal Information Management System (EODIMS). This cohesive method for evaluating military exposures leverages established information with new sources of data and has the potential to influence how military exposure data is integrated into exposure health care and investigational models.

Two fractional order cumulative residual time series measures based on Rényi entropy

In the study of time series analysis, Kullback-Leibler divergence can measure the difference between the distribution diverges of time series, and transfer entropy is usually used to quantify the causal influence among time series. In order to analyze the relationship between time series more comprehensively, two novel fractional order times series measures, i.e., Rényi cumulative residual Kullback-Leibler (RCRKL) and Rényi cumulative residual transfer entropy (RCRTE), are proposed in this paper. Some mathematical properties of RCRKL are proved as a distance metric, and the zeros and bounds of RCRTE are studied. Then, some examples on synthetic data are provided to study the effect of parameter changes on metric values. Finally, the proposed two fractional-order time series measures are applied to pavement rutting time series, for which a RCRKL-based clustering is designed and the causal relationships between influence factors and rutting are detected by RCETE. The results demonstrate that the RCRKL-based clustering algorithm performs better than those based on the baseline distance measures. Meanwhile, RCRTE can also detect the true causality between rutting and its influence factors and reject the false causality. In summary, the proposed RCRKL and RCRTE take the advantages of both cumulative residual entropy and Rényi entropy, and provide a more comprehensive insight for time series analysis.

The causal relationship and potential mediators between plasma lipids and atopic dermatitis: a bidirectional two-sample, two-step mendelian randomization

BackgroundObservational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway.MethodsWe utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran’s Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings.ResultsThe Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929–0.972, p = 6.65 × 10− 6), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906–0.971, p = 2.79 × 10− 4), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906–0.969, p = 1.48 × 10− 4) and TAG (56:8) (OR: 0.918, 95% CI: 0.876–0.961, p = 2.72 × 10− 4) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028–1.079, p = 2.11 × 10− 5) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039–1.135, p = 2.47 × 10− 4) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%.ConclusionOur research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach.

The causal relationship between blood cell indices and 28-day mortality in sepsis: a retrospective study and bidirectional Mendelian randomization analysis

BackgroundDespite emerging evidence linking blood cell indices (BCIs) to sepsis mortality, the inconsistency of observational studies obscures the clarity of these associations. This study aims to clarify the causal influence of BCIs on 28-day mortality rates in sepsis patients.MethodsUtilizing univariable and multivariable Mendelian randomization (MR) analyses, we examined the impact of BCIs on sepsis mortality by analyzing data from extensive genome-wide association studies. The inverse-variance weighted (IVW) method was our primary analytic tool, complemented by several robustness checks to mitigate pleiotropy, including weighted median, mode-based estimates, MR-Egger regression, and MR-PRESSO. Subsequently, we conducted a retrospective study to further explore the correlation between platelet indices and 28-day mortality of sepsis using real-world data.ResultsOur findings highlight a significant causal relationship between platelet distribution width (PDW) and 28-day mortality in sepsis, with the univariable Mendelian randomization approach yielding an odds ratio of 1.12 (95% CI, 1.06–1.26; P < 0.05). Multivariable analysis further substantiated PDW’s robust association with mortality risk (OR 1.23; 95% CI, 1.03–1.48; P < 0.05). Conversely, our analysis did not uncover significant correlations between the genetic predispositions to other BCIs—including red blood cell count, erythrocyte distribution width, platelet count, mean platelet volume, white blood cell count, neutrophil count, neutrophil percentage, lymphocyte count, and lymphocyte percentage—and 28-day mortality in sepsis. Additionally, an inverse MR analysis did not establish a causal impact of 28-day mortality in sepsis on PDW (OR 1.00; 95% CI, 1.00—1.07; P = 0.29). Moreover, a similar result was observed in the retrospective study.ConclusionsThe study underscores the independent causal role of PDW in predicting 28-day mortality in sepsis, suggesting its potential utility in early patient assessment, risk stratification, and tailoring of therapeutic interventions.

Investigating psychobiological causes and mechanisms in functional seizures and functional motor symptoms: Study protocol.

Advances have been made in understanding the aetiology of functional neurological disorder (FND); however, its pathophysiological mechanisms have not been definitively demonstrated. Evidence suggests interacting roles for altered emotional processing and interoception, elevated autonomic arousal, and dissociation, but there is limited evidence demonstrating their causal influence on specific FND symptoms. Our superordinate aim is to elucidate potentially shared and distinct aetiological factors and mechanisms in two common FND subtypes, functional seizures (FS) and functional motor symptoms (FMS). This study has a multimodal, mixed between- and within-groups design. The target sample is 50 individuals with FS, 50 with FMS, 50 clinical controls (anxiety/depression), and 50 healthy controls. Potential aetiological factors (e.g., adverse life events, physical/mental health symptoms, dissociative tendencies, interoceptive insight/sensibility) will be assessed with a detailed medical history interview and self-report questionnaires. A laboratory session will include a neurocognitive battery, psychophysiological testing, cardiac interoception and time estimation tasks and an isometric handgrip task. A subsample will undergo magnetic resonance imaging, including structural, resting-state and task-based scans combined with psychophysiological recording. Remote monitoring with ecological momentary assessment and wearables will measure variability in FND symptoms and their potential predictors/correlates for ≥2 weeks in patients' daily lives. Longitudinal follow-ups at 3, 6, and 12-months will monitor longer-term outcomes in the clinical groups. This study employs multimodal research methods to rigorously examine several putative mechanisms in FND, at subjective/experiential, behavioural, and physiological levels. The study will test causal hypotheses about the role of altered emotional processing, autonomic arousal, dissociation and interoception in the initiation or exacerbation of FND symptoms, directly comparing these processes in FS and FMS to healthy and clinical controls. This is the first study of its kind, with potential to reveal important targets for prevention and treatment of FND in future.