Reverse Causality Research Articles

Identifying modifiable factors and their joint effect on brain health: an exposome-wide association study.

Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.

Unveiling the shadows: School bullying and students' ability erosions in Chinese compulsory schools

Drawing upon data from the National Children's Study of China, this research investigates the school bullying victimization and its associations with the ability erosions among students in Chinese schools. Three key findings emerge. First, results suggest that the primary factors affecting bullying victimization mainly include authoritarian parenting, limited positive social interactions on campus, adverse experiences, and exposure to teacher and peer smoking. Second, estimates indicate that bullying victimization is significantly associated with ability erosions, particularly among students from relatively advantaged backgrounds. The further Oster's test, falsification test, and reverse causality check confirm the validity of the associations and suggest some causal effect of victimization on the student outcomes. Lastly, the Oaxaca-Blinder decomposition shows that lower human capital investments derived from social interactions are the most significant contributors to the ability erosion linked to bullying victimization. These findings highlight the critical importance of social interactions both at home and in schools.

Causal relationship between benign prostatic hyperplasia and prostate cancer: a bidirectional Mendelian randomization analysis.

Our aim is to explore the relation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) from a genetic level utilizing Mendelian randomization (MR). The IEU genome-wide association studies database was surveyed for single nucleotide polymorphisms (SNPs) associated with BPH, PCa, and PCa (validation cohort). Single nucleotide polymorphisms were subjected to stringent quality control based on rigorous screening criteria. BPH and PCa risk were evaluated using the inverse-variance weighted method (IVW), MR-Egger, simple mode, weighted median, and weighted mode. Horizontal pleiotropy of single nucleotide polymorphisms was assessed using the MR-Egger intercept test, while heterogeneity was evaluated using Cochran's Q test. Reverse causality was assessed by evaluating PCa as the exposure and BPH as the outcome. A validation database was used to verify the exposure and outcome. The risk of PCa increased significantly with genetically predicted BPH (IVW: OR [95% CI] = 1.3849 × 107 [2330, 8.2294 × 1010], P = 2.0814 × 10-4). In reverse MR analysis, PCa also increased the risk of BPH (IVW: OR [95% CI] = 1.0011 [1.0003, 1.0019], P = 0.0031). The findings were consistent with the MR analysis results of the PCa validation cohort. Sensitivity analyses indicated the presence of heterogeneity but no horizontal pleiotropy. The study presents proof of a significant bidirectional causal relationship between genetically predicted BPH and an increased risk of PCa. Key message Three research questions and three bullet points What is already known on this topic? Observational studies suggest a controversial relationship between BPH and PCa. MR allows investigation of causality using genetic variants as instrumental variables (IVs). What does this study add? The study presents proof of a significant bidirectional causal relationship between genetically predicted BPH and an increased risk of PCa. How this study might affect research, practice, or policy? Recognizing the bidirectional relationship between BPH and PCa, men diagnosed with BPH may benefit from more stringent PCa screening protocols.

Is there a genetic relationship between blood glucose and osteoarthritis? A mendelian randomization study.

The relationship between blood glucose levels and osteoarthritis (OA) is unclear. This study aimed to investigate the genetic causal relationship between blood glucose-related traits and OA. We first performed univariate Mendelian randomization (UVMR) analyses using published genome-wide association study (GWAS) datasets with fasting glucose (FG), 2h-glucose post-challenge glucose (2hGlu), and glycosylated hemoglobin (HbA1c) as exposures, and hip osteoarthritis (HOA) and knee osteoarthritis (KOA) as outcomes; then, we performed inverse analyses of them. We used Inverse-variance weighted (IVW) analysis as the primary analysis, and sensitivity analyses were performed. Moreover, we performed multivariate Mendelian randomization (MVMR) to estimate the independent effect of exposure on outcome after adjusting for body mass index (BMI). Summarized data for blood glucose-related traits were obtained from the MAGIC Consortium study of the glucose trait genome and for OA from the UK Biobank and arcOGEN. Summarized data for BMI were obtained from the GIANT Consortium meta-analysis of individuals of European ancestry. A two-sided p value < 0.05 in UVMR was considered suggestive of significance when p < 0.0167 (Bonferroni correction p = 0.05/3 exposures) was considered statistically significant. We found significant negative genetic causality of FG for HOA and KOA, and these associations remained significant after we adjusted for the effect of BMI [odds ratios (ORs) of 0.829 (0.687-0.999, p = 0.049) and 0.741 (0.570-0.964, p = 0.025)]. HbA1c also had an independent negative genetic causal effect on HOA after adjustment for BMI [0.665 (0.463-0.954, p = 0.027)]. At the same time, there was no evidence of reverse genetic causality of OA on blood glucose-related traits. We further elucidated the relationship between blood glucose-related traits and OA by adjusting for the effect of BMI from a genetic causal perspective. This study provides new insights to further clarify the relationship between blood glucose levels and OA, as well as the pathogenesis, etiology and genetics of OA.

Estimating the True Effect of Lifestyle Risk Factors for Myopia: A Longitudinal Study of UK Children.

Lifestyle risk factors are implicated in driving the current surge in myopia prevalence yet, paradoxically, known risk factors explain little of the variation in refractive error in the population. Here, we applied "instrumental variable" (IV) methods designed to avoid reverse causation and decrease confounding bias, to gauge lifestyle risk factor effect sizes. Three myopia risk factors (time outdoors, time reading, and sleep duration) were assessed in participants of the Avon Longitudinal Study of Parents and Children: a cross-sectional sample of 2302 children aged 15years old and a longitudinal sample of 3086 children followed from age 7 to 15years. Seven IVs were considered jointly: dog ownership, cat ownership, bedtime variability, birth order, and polygenic scores quantifying genetic predisposition to spend additional time outdoors, years in fulltime education, and time asleep overnight. Risk factor effect sizes were 4-fold to 9-fold higher in the IV analyses compared with conventional regression analyses. In IV analyses, one extra hour spent outdoors every day during childhood was associated with a shift toward hyperopia of +0.53 to +0.94 diopters (D), whereas 1 extra hour spent reading every day was associated with a shift toward myopia of -0.44 to -0.88 D. There was inconsistent evidence that sleep duration influenced refractive error. Myopia risk factor effects were underestimated up to 9-fold in conventional analyses in this sample, compared with IV analyses. We speculate that the effects of lifestyle risk factors for myopia have been underestimated in past studies.

Gut Microbial Metabolites and Future Risk of Parkinson's Disease: A Metabolome-Wide Association Study.

Alterations in gut microbiota are observed in Parkinson's disease (PD). Previous studies on microbiota-derived metabolites in PD were small-scale and post-diagnosis, raising concerns about reverse causality. Our goal was to prospectively investigate the association between plasma microbial metabolites and PD risk within a metabolomics framework. A nested case-control study within the prospective EPIC4PD cohort, measured pre-diagnostic plasma microbial metabolites using untargeted metabolomics. Thirteen microbial metabolites were identified nominally associated with PD risk (P-value < 0.05), including amino acids, bile acid, indoles, and hydroxy acid, although none remained significant after multiple testing correction. Three pathways were implicated in PD risk: valine, leucine, and isoleucine degradation, butanoate metabolism, and propanoate metabolism. PD-associated microbial pathways were more pronounced in men, smokers, and overweight/obese individuals. Changes in microbial metabolites may represent a pre-diagnostic feature of PD. We observed biologically plausible associations between microbial pathways and PD, potentially influenced by individual characteristics. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Immune cells mediate the effects of gut microbiota on neuropathic pain: a Mendelian randomization study.

The gut microbiota may be involved in neuropathic pain. However, the causal association between gut microbiota and neuropathic pain remains unclear. Whether immune cells and inflammatory factors mediate the pathway from gut microbiota to neuropathic pain has not been elucidated. We obtained the summary data of 412 gut microbiota, 731 immune cells, 91 inflammatory factors, and five types of neuropathic pain (drug-induced neuropathy, postherpetic neuralgia, sciatica, trigeminal neuralgia, and unspecified neuralgia) from large-scale genome-wide association study (GWAS) datasets and the FinnGen database. We used bidirectional Mendelian randomization (MR) analysis to explore the causal association between gut microbiota and neuropathic pain. Additionally, we conducted a mediation analysis to identify whether immune cells and inflammatory factors act as mediators within these causal relationships. Our study revealed 30 causal relationships between 26 gut bacterial taxa and five types of neuropathic pain, including four associated with drug-induced neuropathy, six with postherpetic neuralgia, five with sciatica, eight with trigeminal neuralgia, and seven with unspecified neuralgia. Moreover, we identified 35 gut bacterial pathway abundances causally involved in neuropathic pain. The reverse MR analysis showed no evidence of reverse causality from gut microbiota to neuropathic pain. Mediation analysis demonstrated that the immune cell phenotype "HLA-DR++ monocyte % leukocyte" mediated the causal relationship between p_Proteobacteria and sciatica with a mediation proportion of 36.15% (P = 0.038), whereas "CD11c on CD62L+ myeloid dendritic cell" mediated the causal pathway from assimilatory sulfate reduction to trigeminal neuralgia with a mediation proportion of 27.90% (P = 0.041). This study identified the causal relationships between several specific gut microbiota and various neuropathic pain subtypes. Additionally, two immune cells may act as potential mediators in the pathways from gut microbiota to neuropathic pain.

Digital transformation and supply chain concentration: evidence from China

ABSTRACT Excessive supply chain concentration (SCC) introduces various risks, and the factors contributing to SCC are complex and have been rarely explored. This study examines the economic impact of digital transformation on supply chains by analysing data from China’s A-share listed companies (2010–2021) using regression models. The findings demonstrate that digital transformation significantly reduces supply chain concentration and increases the firms’ influence within the supply chain. The mechanism analysis shows that digital transformation makes firms more attractive to suppliers and customers, eases financing constraints, boosts firm reputation, and reduces SCC. The impact is more pronounced in firms facing higher environmental uncertainty or those positioned upstream in the supply chain. Except for blockchain, all five dimensions of digital transformation help to reduce SCC, thereby improving total factor productivity and economic growth. Digital transformation also creates a spillover effect, raising expectations for digital transformation and productivity among suppliers and customers. These findings have significant implications for understanding digital transformation practices and advancing supply chain management. The conclusions remain robust after various tests, including changes to the measures of variables and controls for reverse causality using lagged treatment and instrumental variables.

Effect of smoking behaviour and related blood DNA methylation on visceral adipose tissues.

Recent studies have found that tobacco smoking is associated with fat distribution, yet limited research has focused on its relationship with visceral adipose tissues (VATs). Furthermore, the cellular and molecular mechanisms underlying the interactions among smoking, epigenetic modifications, and VATs remain unknown. We performed univariable Mendelian randomization (MR) analysis to elucidate the causal relationship between smoking behaviours and VATs, including epicardial and pericardial adipose tissue (EPAT), liver fat (LF), and pancreas fat (PF). This approach could minimize the impact of confounders and reverse causality through utilizing genetic variants to proxy the smoking behaviours. Mediation MR analysis were conducted to detect potential mediators. Additionally, summary-data-based MR (SMR) and colocalization analysis were performed to explore the association between smoking-related DNA methylation and VATs. We identified a convincing association between smoking initiation and increased EPAT (beta: 0.15, 95% CI: 0.06, 0.23, p = 7.01 × 10-4) and LF area (beta: 0.15, 95% CI = 0.05, 0.24, p = 2.85 × 10-3), respectively. Further mediation analysis suggested type 2 diabetes mellitus (T2DM) as a potential mediator within these co-relationships. When further exploring the associations between the smoking related DNA methylation and VATs, we identified that WT1 methylation at cg05222924 was significantly linked to a lower EPAT area (beta: -0.12, 95% CI: -0.16, -0.06, PFDR = 2.24 × 10-3), while GPX1 methylation at cg18642234 facilitated the deposition of EPAT (beta: 0.15, 95% CI: 0.10, 0.20, PFDR = 1.66 × 10-4). Our study uncovered a significant causal effect between smoking and VATs, with T2DM identified as a potential mediator. Further investigation into DNA methylation yielded novel insights into the pathogenic role of smoking on EPAT.

Causal correlations between inflammatory proteins and heart failure: A two-sample Mendelian randomization analysis.

Inflammation plays a critical role in both the development and progression of heart failure (HF), which is a leading cause of morbidity and mortality worldwide. However, the causality between specific inflammation-related proteins and HF risk remains unclear. This study aims to investigate the genetically supported causality between inflammatory proteins and HF using a two-sample Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data of 91 inflammation-related proteins as exposures from the SCALLOP Consortium (14,824 participants), alongside outcome GWAS summary statistics from FinnGen (29,218 cases/381,838 controls) and HERMES (47,309 cases/930,014 controls) for HF, to conduct a two-sample MR analysis. For each inflammatory protein, instrumental variables (IVs) were chosen following the three foundational assumptions of the MR analysis, requiring a minimum of three qualifying single nucleotide polymorphisms (SNPs) each with a P<5e-8. Associations between inflammatory proteins and HF were assessed through inverse-variance weighted (IVW), MR-Egger regression, weighted median and weighted mode analysis. The reliability and validity of the results were evaluated by examining heterogeneity, horizontal pleiotropy, leave-one-out analysis, meta-analysis and reverse MR analysis. Heterogeneity refers to the variation in results across different genetic variants. Horizontal pleiotropy occurs when a genetic variant influences multiple traits through different biological pathways. Addressing both heterogeneity and horizontal pleiotropy is crucial for ensuring the reliability and interpretability of MR results. Our analysis identified associations between three inflammatory proteins and HF risk. Matrix metalloproteinase-1 (MMP-1) (OR, 1.09; 95% CI, 1.00-1.18; P=0.04) and TNF-beta (OR, 1.05; 95% CI, 1.01-1.09; P=0.01) were positively associated with HF risk in FinnGen. In contrast, urokinase-type plasminogen activator (uPA) was inversely associated with HF risk in both FinnGen (OR, 0.85; 95% CI, 0.78-0.92; P=3.27e-5) and HERMES (OR, 0.93; 95% CI, 0.87-0.99; P=0.03). No evidence of heterogeneity and horizontal pleiotropy was observed in the MR analysis, indicating the robustness of our findings. A meta-analysis further supported this association, indicating a reduced risk (OR, 0.89; 95% CI, 0.81-0.98; P=0.02). No reverse causality was found between HF and these three inflammatory proteins (P>0.05 for all). This study provides genetically supported evidence of the causal association of specific inflammatory proteins with HF risk. The positive association of MMP-1 and TNF-beta with HF suggests their roles in disease pathogenesis, whereas the inverse association of the uPA indicates its potential protective effect. Our findings highlight the potential of targeting specific inflammatory pathways as a therapeutic strategy for HF.

PFAS and menopause onset: Is it just a matter of reverse causation? Cross-sectional and longitudinal analyses in highly exposed women in the Veneto Region

IntroductionSeveral cross-sectional studies have linked perfluoroalkyl substances (PFAS) to prevalence of menopause. These findings might be influenced by reverse causation mechanism, making longitudinal studies more suitable. However, existing longitudinal studies are limited and present conflicting results. AimThis study investigates the association between PFAS and both prevalence and incidence of menopause, using longitudinal designs to limit the impact of reverse causation. MethodsA surveillance program on a PFAS highly exposed population in the Veneto region started in 2017 with two rounds of screening, on average 3.8 years apart. Women who participated in the first screening (n = 11,046) were included in the cross-sectional analysis. Multivariate logistic regression models were used to estimate the Odds Ratios (ORs) of menopause associated with exposure to different PFAS. For incidence analysis a retrospective-prospective design used PFOA concentrations reconstructed to 2013 (n = 8536), and a prospective design involved women participating in both screenings (n = 1709), evaluating their baseline concentrations of PFOA, PFOS, and PFHxS. Cox proportional hazards models with age as the timescale were used to estimate Hazard Ratios (HRs), adjusting for sociodemographic and lifestyle factors. ResultsIncreased menopause prevalence was associated with higher ln-concentrations of PFOA, PFOS, and PFHxS, with ORs of 1.31 (CI: 1.25–1.38), 1.51 (CI: 1.38–1.66), and 1.42 (CI: 1.34–1.51), respectively. The retrospective-prospective study showed increased risk of menopause in higher PFOA reconstructed quartiles, with HRs of 1.01 (CI: 0.87–1.18), 1.17 (CI: 1.02–1.37), and 1.07 (CI: 0.93–1.23) for the second, third and fourth quartiles. The prospective longitudinal study found no association between PFAS and menopause onset. ConclusionsOur results showed a strong cross-sectional association between PFAS exposure and menopause, a weak positive association in the retrospective-prospective study, and no association in the prospective study. This suggests that cross-sectional associations may largely result from reverse causality due to early menopause on reducing PFAS excretion.

Identifying causal relationships between 35 blood and urine biomarkers and urologic cancers: MR-meta combined with Bayesian colocalization Mendelian randomization analysis

BackgroundBlood and urine biomarkers have been associated with urologic tumors, but their causal relationship with urologic tumors is unclear.MethodsWe performed a bidirectional Mendelian randomization (MR) analysis of the association between 35 blood and urine biomarkers and urological tumors in our discovery cohort. A Bayesian weighting approach was used to validate the positive results identified in the discovery cohort, and steiger filtering analysis was used to distinguish causality from reverse causality. Bayesian colocalization analysis was used to analyze which single nucleotide polymorphisms (SNPs) specifically co-located between the positive blood and urine biomarkers and the disease phenotypes were driven, and MR-positive results from the discovery cohort and the validation cohort were combined using the MR-meta method.ResultsSeveral blood and urine biomarkers were found to be significantly and causally associated with urologic cancers. Notably, calcium (OR: 1.34, 95%CI 1.10–1.63, P = 0.0040) and sex hormone-binding globulin (SHBG) (OR: 0.81, 95%CI 0.70–0.95, P = 0.0092) were associated with bladder cancer; gamma glutamyl transferase (GGT) (OR: 0.91, 95%CI 0.83–0.99, P = 0.0209), lipoprotein A (Lp(a)) (OR: 1.12, 95%CI 1.01–1.24, P = 0.0399), and insulinlike growth factor 1 (IGF 1) (OR: 1.10, 95%CI 1.01–1.20, P = 0.0220) were linked to prostate cancer (PCa); non albumin protein (OR: 0.78, 95%CI 0.65–0.93, P = 0.0065) and total protein (OR: 0.80, 95%CI 0.64–0.99, P = 0.0380) were linked to renal cancer; and apolipoprotein A (Apo-A) (OR: 0.56, 95%CI 0.32–0.98, P = 0.0426) and urate (OR:1.89, 95%CI 1.03–3.47, P = 0.0399) were associated with renal pelvis cancer. These associations were validated in an independent cohort, with GGT, IGF 1, and Lp(a) being consistently linked to PCa.ConclusionThis study identified significant biomarkers associated with urological cancers in blood and urine. These include GGT, IGF 1, and Lp(a), which are strong biomarkers for PCa. In addition, the findings of this study provide evidence for a handful of risk and protective factors for the development of urologic cancers.

Mendelian Randomization Estimates the Effects of Plasma and Cerebrospinal Fluid Proteins on Intelligence, Fluid Intelligence Score, and Cognitive Performance.

Observational studies have revealed associations between levels of plasma and cerebrospinal fluid (CSF) proteins and cognition-related traits. However, these associations may be influenced by confounding factors inherent in observational research. This study aims to identify plasma and CSF proteins associated with intelligence, fluid intelligence score, and cognitive performance through the application of Mendelian randomization (MR). Proteomic quantitative trait locus (pQTL) data for plasma and CSF proteins were sourced from existing genome-wide association study (GWAS). Intelligence, fluid intelligence score, and cognitive performance GWAS summary statistics provided comprehensive data for two-sample MR analysis. Extensive sensitivity analyses, including Steiger testing, reverse MR analysis, and Bayesian co-localization, were conducted to validate associations and identify shared genetic variants. Phenotype scanning explored potential pleiotropic effects. MR analysis identified several proteins in plasma and CSF significantly associated with intelligence, fluid intelligence scores, and cognitive performance. For intelligence, negatively associated proteins in plasma include endoplasmic reticulum aminopeptidase 2 (ERAP2) and secretogranin III (SCG3), while positively associated proteins are myeloperoxidase (MPO), signal regulatory protein alpha (SIRPA), regulator of microtubule dynamics 1 (RMDN1), and endoplasmic reticulum lectin 1 (ERLEC1). In CSF, C1-esterase inhibitor and carboxypeptidase E (CBPE) both exhibited positive associations with intelligence. For fluid intelligence scores, negatively associated proteins in plasma are copine 1 (CPNE1) and SCG3, while positively associated proteins are nudix hydrolase 12 (NUDT12) and RMDN1.In CSF, Macrophage Stimulating Protein (MSP) demonstrated a significant negative impact. For cognitive performance, negatively associated proteins in plasma include ERAP2, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), and SCG3, while positively associated proteins are NUDT12, RMDN1, ERLEC1, and ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (ENPP5). In CSF, C1-esterase inhibitor was positively associated, while MSP and soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 1(sTie-1) showed a negative association. Bayesian co-localization analysis revealed significant genetic overlaps between SIRPA, RMDN1, and ERLEC1 in plasma with intelligence; NUDT12 and SCG3 in plasma with fluid intelligence scores; and TIE1, NUDT12, RMDN1, ERLEC1, and ENPP5 in plasma with cognitive performance. Additionally, significant co-localization was identified between C1-esterase inhibitor and CBPE in CSF with intelligence, as well as between C1-esterase inhibitor and sTie-1 in CSF with cognitive performance. Reverse causality analysis confirmed the causal direction from proteins to cognitive traits. This study identifies specific plasma and CSF proteins that significantly impact intelligence, fluid intelligence scores, and cognitive performance. These proteins could serve as biomarkers and targets for future research and therapeutic interventions aimed at sustaining cognitive abilities and reducing impairment risks.

Lipid metabolism disorders and albuminuria risk: insights from National Health and Nutrition Examination Survey 2001–2018 and Mendelian randomization analyses

Background Previous studies have revealed an underlying connection between abnormal lipid metabolism and albuminuria. We aim to investigate the causal relationship between lipid metabolism disorders and the risk of albuminuria from both a population and genetic perspective. Methods A cross-sectional study was conducted by using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Multivariable-adjusted logistic regression, subgroup analysis, interaction tests and restricted cubic spline (RCS) were employed statistically. Mendelian randomization (MR) analysis was performed to validate the causal relationship between exposure and outcome to mitigate confounding factors and reverse causation interference. Results After adjusting for confounders, HDL levels (1.03-2.07 nmol/L) were associated with a reduced risk of albuminuria. In contrast, elevated cholesterol levels (>6.2 nmol/L) and triglyceride levels (>2.3 nmol/L) were associated with an increased risk of albuminuria. Serum triglyceride concentration emerged as a potential risk factor for albuminuria. In MR analysis, a reduced risk of albuminuria was associated with serum total HDL level (IVW: OR = 0.91, 95% CI = 0.86-0.97, p = 0.002). In contrast, cholesterol esters in medium VLDL (IVW: OR = 1.05, 95% CI = 1.00-1.10, p = 0.032), chylomicrons and extremely large VLDL (IVW: OR = 1.08, 95% CI = 1.03-1.14, p = 0.003), and triglycerides (IVW: OR = 1.14, 95% CI = 1.09-1.19, p < 0.001) were associated with an increased risk of albuminuria. Conclusion A causal relationship exists between serum lipid metabolism disorder and albuminuria risk. Further validation of additional blood lipid metabolism biomarkers is imperative for future studies.

Does board gender diversity improve stock liquidity?

PurposeFirms with gender diverse boards have been shown to have increased transparency and disclosure, resulting in reduced information asymmetry, which is a key factor influencing stock liquidity. This paper explores the influence of information asymmetry resulting from board gender diversity on stock liquidity. We examine the impact of gender diverse firms on stock liquidity in US listed firms from 2006 to 2022, capturing 28,280 firm-year observations across 4,349 firms. Using mediation models, we distinguish between direct and mediated effects to examine the impact of gender diverse boards on three dimensions of stock liquidity. We find a positive and significant relation between board gender diversity and stock liquidity, and our findings highlight the substantial mediating role of information disclosure in this association. To address concerns of endogeneity, we use instrumental variables regression, and our conclusions remain robust to a range of alternatives.Design/methodology/approachTo investigate the association between board gender diversity and stock liquidity and the underling mechanism that drives the relation, we utilize a dataset comprising 4,349 listed US firms from 2006 to 2022. We adopt a comprehensive approach to measure stock liquidity that spans three dimensions: Amihud illiquidity (LIQ) as a representation of price impact, the quoted spread (SPREAD) to gauge transaction costs and the stock turnover (TURNOVER) to assess trading frequency. To evaluate board gender diversity, we examine female directors and female independent directors, utilizing both the percentage and the presence (as a binary variable).FindingsThe results of our analysis reveal not only a statistically significant effect of board gender diversity on liquidity but also demonstrate its economic significance. One standard deviation increase in the percentage of female directors (12% more female directors) is associated with a 5.8% decrease in price impact, a 5.1% reduction in transaction costs and a 3% increase in trading frequency. These findings highlight the material economic importance of the relationship, which stands in contrast to previous studies reporting only a 1% change in average stock liquidity in the Australian stock markets (Ahmed and Ali, 2017). To further investigate the underlying mechanism driving the association between board gender diversity and liquidity, we employ mediation models to separate the direct and mediated channels. Our results indicate that the effects of the percentage of female directors are mediated on liquidity (LIQ, SPREAD, and TURNOVER) through information disclosure, albeit with a relatively small magnitude (mediation proportion is 18.2, 3.9 and 22.9%, respectively).Research limitations/implicationsWe include a comprehensive set of variables in our analysis and adopt an instrumental approach to mitigate endogeneity concern. However, we acknowledge the possibility of omitted variable biases or reverse causality in our empirical analysis.Practical implicationsOur study contributes to the understanding of the association between board gender diversity and stock liquidity, focusing on the underlying mechanisms. Gender diversity on boards enhances corporate governance, leading to reduced managerial opportunism (Adams and Ferreira, 2009; Nielsen and Huse, 2010). This, in turn, increases information transparency and results in increased stock liquidity. By exploring the empirical evidence of the impact of gender diverse boards on stock liquidity through the information channel, we provide valuable insights to the existing literature. Our study uses US data to examine this association, addressing the small sample concerns of prior research that may have contributed to inconsistent findings.Social implicationsThis research can drive both economic and social transformations as it provides evidence that gender diverse boards lead to improved market outcomes.Originality/valueOur study differs from previous research by incorporating all three dimensions of liquidity, ensuring a comprehensive analysis. Through our investigation, we aim to deepen understanding of how gender diversity on corporate boards shapes market dynamics and contributes to understanding of corporate governance and market efficiency. Our study investigates how the impact occurs by employing mediation models to separate the direct and mediated channels of impact. We show that the effects of gender diverse boards on liquidity are mediated through information disclosure.

How spousal cognitive functioning affects the level of depression in middle-aged and older adults: An instrumental variable study based on CHARLS in China.

A better understanding of the causal relationship between spousal cognitive functioning and depression levels among middle-aged and older adults is vital for effective health policymaking under the globally severe aging challenge. However, the related evidence is often limited by potential omitted-variable bias and reverse causation. This study uses an instrumental variables approach, namely the two-stage least squares (2SLS) method, to examine the impact of spousal cognitive functioning on depression levels among middle-aged and older adults in China. The data were sourced from the China Health and Retirement Longitudinal Study (CHARLS) of 2020, including a total of 3,710 couples aged 45 years and above. Depression levels were measured using the Center for Epidemiologic Studies Depression Scale (CES-D-10), while cognitive functioning was assessed using the Mini-Mental State Examination (MMSE). Spousal social participation was employed as the instrumental variable to address omitted-variable bias and reverse causation. Additionally, an interaction effect test between gender and spousal cognitive functioning was conducted. The results show that for each one-point increase in the spouse's MMSE score, the CES-D-10 score of middle-aged and older adults decreased by 17.1% to 68.2%. The OLS results indicated that women, rural residents, and middle-aged individuals were more sensitive to these changes. The interaction effect test results confirmed that women were more affected by changes in spousal cognitive functioning. However, after a more reliable 2SLS analysis, the results for age groups shifted, showing that middle-aged individuals were more sensitive to these changes, with a decrease in depression levels reaching 70.0%, compared to 60.2% for the elderly group. Nonetheless, given the prevalence of depression among the elderly, the impact of spousal cognitive decline on depression in this group should not be overlooked. Our findings highlight the importance of spousal cognitive health in managing depression among both middle-aged and older adults, with particular attention to women and rural populations.

Democracy as a cause of semi-presidential regimes: On reverse causality between democracy and semi-presidential establishment

This article re-examines the relationship between democracy and semi-presidential regimes. While numerous scholars have traced the effects of semi-presidential regimes on democracy, few have addressed the risk of reverse causality, namely, that democracy influences the establishment of semi-presidential regimes. This article uses statistical analyses to test whether the level of democracy in a country affects its choice of semi-presidential regime subtype: a premier–presidential or a president–parliamentary. Including all semi-presidential regimes from 1919 until 2015 and controlling for other conditions such as colonial legacy, the level of development and regime diffusion, our results confirm the hypothesis. The higher the level of democracy – the higher the probability of a premier–presidential regime. Our results underline that democracy is a highly influential cause of the type of semi-presidential regime chosen, a conclusion that places a question mark on the self-evident use of the semi-presidential subtypes as an independent variable.

Investigating the metabolomic pathways in female reproductive endocrine disorders: a Mendelian randomization study.

Reproductive endocrine disorders (RED), including polycystic ovary syndrome (PCOS), endometriosis (EMs), and female infertility (FI), significantly affect women's health globally, with varying prevalence across different regions. These conditions can be addressed through medication, surgical interventions, and lifestyle modifications. However, the limited understanding of RED's etiology and the substantial economic burden of its treatment highlight the importance of investigating its pathogenesis. Metabolites play a critical role in metabolic processes and are potentially linked to the development of RED. Despite existing studies suggesting correlations between metabolites and RED, conclusive evidence remains scarce, primarily due to the observational nature of these studies, which are prone to confounding factors. This study utilized Mendelian Randomization (MR) to explore the causal relationship between metabolites and RED, leveraging genetic variants associated with metabolite levels as instrumental variables to minimize confounding and reverse causality. Data were obtained from the Metabolomics GWAS Server and the IEU OpenGWAS project. Instrumental variables were selected based on their association with the human gut microbiota composition, and the GWAS summary statistics for metabolites, PCOS, EMs, and FI were analyzed. The MR-Egger regression and random-effects inverse-variance weighted (IVW) methods were employed to validate the causal relationship. Cochran's Q test was employed to evaluate heterogeneity, sensitivity analysis was performed using leave-one-out analysis, and for pleiotropy analysis, the intercept term of MR-Egger's method was investigated. The MR analysis revealed significant associations between various metabolites and RED conditions. For instance, a positive association was found between 1-palmitoylglycerophosphocholine and PCOS, while a negative association was noted between phenylacetate and FI. The study identified several metabolites associated with an increased risk and others with protective effects against PCOS, EMs, and FI. These findings highlight the complex interplay between metabolites and RED, suggesting potential pathways through which these conditions could be influenced or treated. This MR study provides valuable insights into the causal relationship between metabolites and female reproductive endocrine disorders, suggesting that metabolic alterations play a significant role in the pathogenesis of PCOS, EMs, and FI, and offering a foundation for future research and therapeutic development.

Correlation between gut microbiota and pancreatitis: a bidirectional Mendelian randomization.

The causative role of gut microbiota in pancreatitis remains unknown. This study aimed to investigate potential causal associations between gut microbiota and pancreatitis, using bidirectional Mendelian randomization (MR) analysis. We analyzed genome-wide association study (GWAS) summary statistics for gut microbiota (211 taxa from gut microbiota, n = 18 340) and two types of pancreatitis, namely acute pancreatitis (AP, 5509 cases and 301 383 controls) and chronic pancreatitis (CP, 3002 cases and 301 383 controls). A reverse MR analysis was also performed to assess the possibility of reverse causation. Nine features (one family + eight genera) showed a causal association with AP. According to inverse-variance weighted (IVW) estimates, phylum Firmicutes (P = 4.10 × 10-2), genus Erysipelatoclostridium (P = 4.80 × 10-2), genus Flavonifractor (P = 4.10 × 10-2), genus Methanobrevibacter (P = 3.40 × 10-2), and genus Prevotella9 (P = 4.60 × 10-2) were found to have a protective effect on AP. Additionally, genus Eubacteriumeligensgroup (P = 4.10 × 10-2), genus Eubacteriumfissicatenagroup (P = 4.00 × 10-3), genus Coprococcus3 (P = 4.10 × 10-2), and genus Haemophilus (P = 4.60 × 10-2) exhibited a positive correlation with AP. Four features (two families + two genera) were causally associated with CP. IVW results also confirmed that family Clostridiaceae1 (P = 3.30 × 10-2), genus LachnospiraceaeFCS020group (P = 4.60 × 10-2), and genus Prevotella9 (P = 1.90 × 10-2) were protective factors for CP, whereas the presence of family Victivallaceae (P = 2.60 × 10-2) correlated with CP risk. No causal effects of pancreatitis (AP or CP) on these gut microbiota taxa were found in the reverse MR analysis. This study confirms a potential causal relationship between gut microbiota and pancreatitis, highlighting the gut microbiota-pancreas axis in the pathogenesis of pancreatitis.

Enhancing SME performance through innovation: evidence from a transition economy – Kosovo

Purpose – What are the effects of implementing various types of innovation, including product, process, and technological innovations, on the performance of SMEs in the manufacturing sector? This is a question that preoccupies us a lot. This study seeks to examine the individual and integrated effects of these innovations. Indeed, we examine the impact of three categories of innovation – product, process, and technological innovation – on the performance of SMEs in the manufacturing industry. Research methodology – We used a quantitative approach to execute this research, selecting SMEs at random using self-administered questionnaires. The data collected from 153 manufacturing SMEs was analyzed using hierarchical linear regression to investigate, evaluate, and refine the relation among product, process, and technological innovation and SME performance. Findings – This study’s findings reveal a clear and direct relationship between these three forms of innovation and SMEs’ performance. This study also provides empirical evidence that various forms of innovation, either examined individually or as integrated, exert a positive effect on the performance of SMEs in the manufacturing industry. Limitations – This study focuses on Kosovo-based SMEs, with the assumption of an upright connection between variables. Future studies can examine the existence of reverse causality in a variety of regional, cultural, and industrial settings. Originality/Value – This study significantly advances existing knowledge by providing useful insights into the complex interplay among product, process, and technological innovation (examined from both individual and integrated perspectives) as well as the performance of SMEs in the manufacturing industry.