Multivariable Mendelian Randomization Analysis Research Articles

Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis

BackgroundFew studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on women’s health. Here we assess whether adiposity at different points in the lifecourse affects reproductive factors differently and independently, and the plausibility of the impact of reproductive factors on adiposity.MethodsWe used genetic data from UK Biobank (273,238 women) and other consortia (EGG, GIANT, ReproGen and SSGAC) for eight reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners, and two adiposity traits: childhood and adulthood body size. We applied multivariable Mendelian randomization to account for genetic correlation and to estimate the causal effects of childhood and adulthood adiposity, independently of each other, on reproductive factors. Additionally, we estimated the effects of reproductive factors, independently of other relevant reproductive factors, on adulthood adiposity.ResultsWe found a higher childhood body size leads to an earlier age at menarche, and an earlier age at menarche leads to a higher adulthood body size. Furthermore, we find contrasting and independent effects of childhood and adulthood body size on age at first birth (beta 0.22 SD (95% confidence interval: 0.14, 0.31) vs − 2.49 (− 2.93, − 2.06) per 1 SD increase), age at last birth (0.13 (0.06,0.21) vs − 1.86 (− 2.23, − 1.48) per 1 SD increase), age at menopause (0.17 (0.09, 0.25) vs − 0.99 (− 1.39, − 0.59) per 1 SD increase), and likelihood of having children (Odds ratio 0.97 (0.95, 1.00) vs 1.20 (1.06, 1.37) per 1 SD increase).ConclusionsOur findings demonstrate the importance of considering a lifecourse approach when investigating the inter-relationships between adiposity measures and reproductive events, as well as the use of ‘age specific’ genetic instruments when evaluating lifecourse hypotheses in a Mendelian randomization framework.

Causality of Diabetic Nephropathy and Age-Related Macular Degeneration: A Mendelian Randomization Study

PurposeAge-related macular degeneration (AMD) currently stands as the leading cause of irreversible vision loss in the present era. The primary objective of this study was to investigate the causal relationships between diabetic nephropathy (DN), its associated risk factors, and AMD among participants of European descent. MethodsGenetic variants associated with DN and its risk factors, encompassing glycemic traits, lipidemic traits, systolic/diastolic blood pressure, obesity, and urate, were obtained from previously published genome-wide association studies. Summary-level statistics for AMD were acquired from the FinnGen database. Univariable and multivariable Mendelian randomization (MR) were employed to conduct this investigation. ResultsOur MR analyses indicated that per 1-standard deviation (SD) increase of DN heightened the risk of overall AMD (p = 1.03 × 10–8, OR = 1.24). And these findings remained consistent when examining both dry AMD (p = 2.27 × 10–4, OR = 1.17) and wet AMD (p = 5.15 × 10–6, OR = 1.33). Additionally, there was a causal association between high-density lipoprotein-cholesterol (HDL-C) levels and an increased risk of AMD (p = 2.69 × 10−3, OR = 1.23), while triglycerides were found to mitigate the risk (p = 0.02, OR = 0.83). Notably, no significant associations were observed between other risk factors of DN and AMD. ConclusionsThese findings suggest that the impact of DN on the development of AMD may be more substantial than previously believed. Furthermore, elevated HDL-C levels appear to heighten the risk of AMD, whereas triglycerides may provide a protective effect.

Genetically predicted plasma cortisol and common chronic diseases: A Mendelian randomization study.

Cushing's syndrome is characterized by hypercortisolaemia and is frequently accompanied by comorbidities such as type 2 diabetes, hypertension, osteoporosis, depression and schizophrenia. It is unclear whether moderate but lifelong hypercortisolaemia is causally associated with these diseases in the general population. We aimed to address this research gap using a Mendelian randomization approach. We used three cortisol-associated genetic variants in the SERPINA6/SERPINA1 region as genetic instruments in a two-sample, inverse-variance-weighted Mendelian randomization analysis. We obtained summary-level statistics for cortisol and disease outcomes from publicly available genetic consortia, and meta-analysed them as appropriate. We conducted a multivariable Mendelian randomization analysis to assess potential mediating effects. A 1 standard deviation higher genetically predicted plasma cortisol was associated with greater odds of hypertension (odds ratio: 1.12; 95% confidence interval [CI]: 1.05-1.18) as well as higher systolic blood pressure (mean difference [MD]: 0.03 SD change; 95% CI: 0.01-0.05) and diastolic blood pressure (MD: 0.03 SD change; 95% CI: 0.01-0.04). There was no evidence of association with type 2 diabetes, osteoporosis, depression and schizophrenia. The association with hypertension was attenuated upon adjustment for waist circumference, suggesting potential mediation through central obesity. There is strong evidence for a causal association between plasma cortisol and greater risk for hypertension, potentially mediated by obesity.

Exploring the causality between educational attainment and gastroesophageal reflux disease: A Mendelian randomization study.

Observational studies suggest that higher educational attainment (EA) contributes to the prevention and treatment of gastroesophageal reflux disease (GERD). However, the causality of this relationship is not supported by strong evidence. We used publicly available genetic summary data, including that on EA, GERD, and the common risk of GERD, to prove this causality. Multiple methods in Mendelian randomization (MR) were employed to evaluate the causality. The leave-one-out sensitivity test, MR-Egger regression, and multivariable MR (MVMR) analysis were applied to evaluate the MR results. Higher EA was significantly associated with lower GERD risk (inverse variance weighted method, odds ratio [OR]: 0.979, 95% confidence interval [CI]: 0.975-0.984, P <0.001). Similar results were obtained when the weighted median and weighted mode were used for causal estimation. After adjusting for potential mediators, the MVMR analysis showed that body mass index (BMI) and EA were still significantly correlated and negatively correlated with GERD (OR: 0.997, 95% CI: 0.996-0.998, P =0.008 and OR: 0.981, 95% CI: 0.977-0.984, P <0.001), respectively. Higher levels of EA may have a protective effect against GERD by having a negative causal relationship. Additionally, BMI may be a crucial factor in the EA-GERD pathway.

Severe mental illness and the risk of breast cancer: A two-sample, two-step multivariable Mendelian randomization study.

Based on epidemiological reports, severe mental illness (SMI) and breast cancer (BC) risk are linked positively. However, it is susceptible to clinical confounding factors, such as smoking, alcohol consumption, etc. Here, we performed a two-sample, two-step multivariable Mendelian randomization (MR) research to explore how the SMI etiologically influences BC risk and to quantify mediating effects of known modifiable risk factors. Data concerning the single nucleotide polymorphism (SNP)-associated with schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), and BC were obtained from two large consortia: the Breast Cancer Association Consortium (BCAC) and the Psychiatric Genomics Consortium (PGC). Then, the correlations of the previous SMI with the BC prevalence and the potential impact of mediators were explored through the two-sample and two-step MR analyses. In two-sample MR, schizophrenia increased BC incidence (odds ratio (OR) 1.06, 95% confidence interval (CI) 1.02-1.10, P = 0.001). In subgroup analysis, schizophrenia increased ER+ BC (OR 1.06, 95% CI 1.03-1.10, P = 0.0009) and ER-BC (OR 1.06, 95% CI 1.01-1.11, P = 0.0123) incidences. Neither MDD nor BD elevated the BC risk. In two-step MR, smoking explained 11.29% of the schizophrenia-all BC risk association. Our study indicates that schizophrenia increases susceptibility to breast cancer, with smoking playing a certain mediating role. Therefore, BC screening and smoking should be incorporated into the health management of individuals with schizophrenia.

The role of NSAID in mediating the effect of genetically predicted major depressive disorder on osteomyelitis: A Mendelian randomization study

BackgroundOsteomyelitis and major depressive disorder (MDD) are significant health concerns with potential interconnections. However, the underlying mechanisms linking these conditions remain unknown. This study aimed to investigate the potential mediating role of non-steroidal anti-inflammatory drug (NSAID) medication in the association between MDD and the risk of osteomyelitis. MethodsWe utilized summary data from large-scale genome-wide association studies (GWAS) to perform Mendelian randomization (MR) mediation analysis. Instrumental variables were selected based on genome-wide significance, and instrumental strength was assessed using F-statistics. Univariable and multivariable MR analyses were conducted to estimate causal effects and proportions mediated by NSAID medication. ResultsThe univariable MR analysis revealed significant associations between MDD and osteomyelitis (odds ratio [OR] = 1.44, 95 % confidence interval [CI]: 1.18–1.874) and between MDD and NSAID medication (OR = 1.36, 95 % CI 1.24–1.49). In the multivariable MR analysis, the direct effect of MDD on osteomyelitis was OR 1.35 (95 % CI: 1.09, 1.67) after adjusting for NSAID medication. The proportion of mediation by NSAID medication was 23 % (95 % CI: 0.05 %, 38.6 %). ConclusionThis MR study provides evidence for a genetically predicted causal association between MDD, NSAID medication, and osteomyelitis. The findings emphasize the need for a comprehensive approach in managing individuals with comorbid depression and osteomyelitis, considering the potential risks and benefits of NSAID medication. Future research should address limitations and explore additional mediators and confounding factors to enhance understanding of this complex relationship.

Univariable and multivariable mendelian randomization study revealed the modifiable risk factors of urolithiasis.

Urolithiasis is a common urological disease with increasing incidence worldwide, and preventing its risk poses significant challenges. Here, we used Mendelian randomization (MR) framework to genetically assess the causal nature of multifaceted risk factors on urolithiasis. 17 potential risk factors associated with urolithiasis were collected from recently published observational studies, which can be categorized basically into lifestyle factors and circulating biomarkers. The instrumental variables of risk factors were selected from large-scale genome-wide association studies (N ≤ 607,291). Summary-level data on urolithiasis were obtained from UK Biobank (UKB) (3,625 cases and 459,308 noncases) and the FinnGen consortium (5,347 cases and 213,445 noncases). The univariable and multivariable MR analyses were applied to evaluate the causal, independent effect of these potential risk factors upon urolithiasis. Effects from the two consortia were combined by the meta-analysis methods. Higher genetically predicted sex hormone-binding globulin (SHBG, OR, 0.708; 95% CI, 0.555 to 0.903), estradiol (OR, 0.179; 95% CI, 0.042 to 0.751), tea intake (OR, 0.550; 95% CI, 0.345 to 0.878), alcoholic drinks per week (OR, 0.992; 95% CI, 0.987 to 0.997), and some physical activity (e.g., swimming, cycling, keeping fit, and bowling, OR, 0.054; 95% CI, 0.008 to 0.363) were significantly associated with a lower risk of urolithiasis. In the Multivariate Mendelian Randomization (MVMR) analyses, the significant causal associations between estradiol, SHBG, tea intake, and alcoholic drinks per week with urolithiasis were robust even after adjusting for potential confounding variables. However, the previously observed causal association between other exercises and urolithiasis was no longer significant after adjusting for these factors. The univariable and multivariable MR findings highlight the independent and significant roles of estradiol, SHBG, tea intake, and alcoholic drinks per week in the development of urolithiasis, which might provide a deeper insight into urolithiasis risk factors and supply potential preventative strategies.

Mendelian randomization shows depression increases the risk of type 2 diabetes.

Introduction: Type 2 diabetes (T2D) is associated with severe mental illnesses (SMIs), such as schizophrenia, bipolar disorder, and depression. However, causal relationships between SMIs and T2D remain unclear owing to potential bias in observational studies. We aimed to characterize the causal effect of SMI liability on T2D using two-sample Mendelian randomization (MR). Methods: The causality between liability to SMI and T2D was investigated using the inverse-variance weighted (IVW), MREgger, MR-Egger with a simulation extrapolation, weighted median, and the MR pleiotropy residual sum and outlier method. Similarly, we performed additional MR which can detect the reverse causation effect by switching exposure and outcome for T2D liability for SMI. To further consider pleiotropic effects between SMIs, multivariable MR analysis was performed after accounting for the other traits. Results: In the univariable IVW method, depression showed a causal effect on T2D (odds ratio [OR]: 1.128, 95% confidence interval [CI]: 1.024-1.245, p = 0.014). Multinomial MR more strongly supported these results (IVW OR: 1.197, 95% CI: 1.069, 1.340, p = 0.002; MR-Egger OR: 1.198, 95% CI: 1.062, 1.349, p = 0.003). Bidirectional MR showed absence of reversecausality between depression and T2D. However, causal relationship of bipolar and schizophrenia on T2D was not detected. Discussion: Careful attention is needed for patients with depression regarding T2D prevention and treatment.

The causal relationship between multiple autoimmune diseases and nasal polyps.

Although previous sporadic studies have reported the associations between a few autoimmune diseases and nasal polyps, these studies have limitations such as conflicting results, small sample sizes, and low levels of evidence. Several autoimmune diseases were selected as exposures while the nasal polyps were selected as outcomes. Bidirectional univariable Mendelian randomization and multivariable Mendelian randomization analyses were performed after rigorous screening of instrumental variables. Then mediation analyses were conducted to further investigate the underlying mechanisms. For the first time, we investigated the causal relationships between nine autoimmune diseases and nasal polyps in different genders and found: (1) there was a causal association between adult-onset Still's disease and nasal polyps; (2) sarcoidosis, ulcerative colitis, type 1 diabetes, and Crohn's disease had no significant associations with nasal polyps; (3) celiac disease showed a suggestive positive association with female nasal polyps, whereas juvenile arthritis and multiple sclerosis showed suggestive positive associations with male nasal polyps. By contrast, arthropathic psoriasis showed a suggestive negative association with nasal polyps. In addition to these nine diseases, previous controversial issues were further investigated: (1) there was a causal relationship between rheumatoid arthritis and nasal polyps, which was partially mediated by "BAFF-R for IgD+ B cells"; (2) ankylosing spondylitis showed suggestive positive associations with the female but not the male nasal polyps. Besides, we validated that there was no causal effect of autoimmune hyperthyroidism on nasal polyps. Specific conclusions regarding the causal effects of multiple autoimmune diseases on nasal polyps are the same as above. By comparing results between different genders, we have initially observed the sex bimodality in the causal effects between autoimmune diseases and nasal polyps, with those on male nasal polyps being stronger than those on female nasal polyps. Our study lays a solid foundation for further research in the future, not only helping identify individuals susceptible to nasal polyps early but also improving our understanding of the immunopathogenesis of these heterogeneous diseases.

COVID-19 and cognitive performance: a Mendelian randomization study.

A substantial proportion of individuals with COVID-19 experienced cognitive impairment after resolution of SARS-CoV-2 infection. We aimed to evaluate whether genetic liability to SARS-CoV-2 infection per se, or more severe COVID-19, is causally linked to cognitive deficit. We firstly performed univariable Mendelian randomization (MR) analysis to examine whether genetic liability to SARS-CoV-2 infection, hospitalized and severe COVID-19 is causally associated with cognitive performance. To dissect the causal pathway, multivariable MR (MVMR) analysis was conducted by adjusting for five inflammatory markers [C-reactive protein, interleukin (IL)-1β, IL-6, IL-8, and tumour necrosis factor α, as proxies of systemic inflammation]. In univariable MR analysis, host genetic liability to SARS-CoV-2 infection was associated with lower cognitive performance [inverse variance weighted (IVW) analysis, estimate: -0.023; 95% Confidence Interval (CI): -0.038 to -0.009]. Such causal association was attenuated in MVMR analysis when we adjusted for the five correlated inflammatory markers in one analysis (IVW analysis, estimate: -0.022; 95% CI: -0.049 to 0.004). There was insufficient evidence of association for genetic liability to hospitalized and severe COVID-19 with cognitive performance. The causal effect of host genetic liability to SARS-CoV-2 infection on reduced cognitive performance may be mediated by systemic inflammation. Future studies examining whether anti-inflammatory agents could alleviate cognitive impairment in SARS-CoV-2-infected individuals are warranted.

Transient ischemic attack and coronary artery disease: a two-sample Mendelian randomization analysis.

Although observational studies have shown that patients who experienced transient ischemic attacks (TIAs) had a higher risk of coronary artery disease (CAD), the causal relationship is ambiguous. We conducted a two-sample Mendelian randomization (MR) study to analyze the causal relationship between TIA and CAD using data from the FinnGen genome-wide association study. Analysis was performed using the inverse-variance weighted (IVW) method. The robustness of the results was evaluated using MR-Egger regression, the weighted median, MR pleiotropy residual sum, and outlier (MR-PRESSO) and multivariable MR analysis. Results from IVW random-effect model showed that TIA was associated with an increased risk of coronary artery atherosclerosis (OR 1.17, 95% CI 1.06-1.28, P = 0.002), ischemic heart disease (OR 1.15, 95% CI 1.04-1.27, P = 0.007), and myocardial infarction (OR1.15, 95% CI 1.02-1.29, P = 0.025). In addition, heterogeneity and horizontal pleiotropy were observed in the ischemic heart disease results, while the sensitivity analysis revealed no evidence of horizontal pleiotropy in other outcomes. This MR study demonstrated a potential causal relationship between TIA and CAD. Further research should be conducted to investigate the mechanism underlying the association.

Fatty acids and pregnancy-induced hypertension: a Mendelian randomization study

BackgroundIt is well known that pregnancy-induced hypertension (PIH) contributes significantly to the mortality rates of both mothers and babies during pregnancy. The relationship between fatty acids (FAs) and PIH remains debatable, with the causality between the two yet to be definitively established.MethodsTwo-sample univariable and multivariable Mendelian Randomization (MR) analyses were executed, based on pooled data from Genome-Wide Association Studies (GWAS), to investigate any causal impact of FAs on PIH. A suite of methods was employed to assess causality, including inverse variance weighting (IVW), weighted median, MR Egger, simple mode, and weighted mode. Subsequently, the data underwent a sensitivity analysis (using Leave-One-Out analysis), a heterogeneity test (with MR-PRESSO and Cochran’s Q test), as well as a multiple validity test (using MR-Egger regression). In multivariable analyses, fatty acids were first grouped to observe the effect of individual FAs on PIH. Subsequently, factors such as diabetes, high blood pressure, and body mass index (BMI) were incorporated into a multivariable examination of the impact of each FA on PIH. During this process, the IVW, weighted median, MR-Lasso, and MR-Egger methods were employed.ResultsA systematic investigation was conducted into the causal impact of each FA on PIH. The findings indicated that Polyunsaturated Fatty Acids (PUFA), Omega3, the ratio of Omega6 to Omega3, and Docosahexaenoic Acid (DHA) have a causal relationship with PIH. Increases in PUFA, Omega3, and DHA could potentially reduce the risk of PIH, while an increase in the Omega6/Omega3 ratio could heighten the risk. The impacts of other FAs (including Total Fatty Acids, Monounsaturated Fatty Acids (MUFA), Saturated Fatty Acids (SFA), and Omega 6) on PIH were not substantiated by the MR analysis. In the univariate leave-one-out analysis, rs174564 was identified in PUFA, Omega3, and DHA as having a significant role. The tests with MR-Egger and MR-PRESSO found that the results were not influenced by pleiotropy and heterogeneity. After adjusting for BMI, Diabetes Mellitus, and pre-existing hypertension in the multivariable analysis, the results mirrored those obtained univariable.ConclusionThe research implies that elevated levels of circulating PUFA, DHA, and Omega3 may serve as a protective mechanism against PIH, while higher Omega6/Omega3 ratios could potentially increase the risk of PIH. These findings may inform clinical strategies for PIH prevention.

Effect of genetically determined BCAA levels on cardiovascular diseases and their risk factors: A Mendelian randomization study

Background and aimsObservational studies have demonstrated that serum branched-chain amino acids (BCAAs) are associated with the risk of various cardiovascular diseases (CVDs) and their risk factors. However, the causal effect is unclear. The aim of this study was to investigate the effect of genetically determined BCAA levels on CVDs and their risk factors using Mendelian randomization (MR). Methods and resultsWe performed univariable and multivariable MR analyses using summary-level data from multiple GWASs and the FinnGen consortium to investigate the association between BCAA levels and the risk of CVDs (myocardial infarction, ischemic stroke, and intracerebral hemorrhage) and their risk factors (atrial fibrillation, hypertension, heart failure, and valvular heart disease). We used the random-effects IVW approach as the primary statistical method and incorporated MR estimates from different data sources using the fixed-effects model. We found genetically determined total and individual BCAA levels and a high risk of hypertension. However, there is no evidence of a causal relationship between BCAA levels and 3 cardiovascular diseases and other their risk factors. The odds of hypertension increased per 1-SD increase in BCAA levels (OR = 1.02 95% CI: 1.01, 1.04; P = 0.005), valine (OR = 1.02 95% CI: 1.01, 1.03; P<0.0001), leucine (OR = 1.02 95% CI: 1.01, 1.04; P＜0.01), and isoleucine (OR = 1.02 95% CI: 1.01, 1.03; P < 0.0001). This result was also significant in the multivariable MR. ConclusionsThis MR study suggests that total and individual BCAA levels could be associated with a high risk of hypertension.

Causal associations of remnant cholesterol with cardiometabolic diseases and risk factors: a mendelian randomization analysis

BackgroundEmerging evidence suggests that remnant cholesterol (RC) is strongly associated with an increased incidence of cardiometabolic diseases (CMD). However, the causality have not been confirmed. We aimed to evaluate the causal associations of RC with CMD and the relative risk factors using two-sample Mendelian randomization (MR) methods.MethodsSummary-level statistics of RC, CMD, and cardiometabolic risk factors were obtained from the published data from individuals with a predominantly European ancestry mainly from the UK Biobank and the FinnGen biobank. Univariable and multivariable MR analyses were used to evaluate the causal relationships between RC and CMD. A bidirectional MR analysis was performed to estimate the causality between RC and cardiometabolic risk factors. The main MR method was conducted using the inverse-variance weighted method.ResultsUnivariable MR analyses showed that genetically predicted RC was causally associated with higher risk of ischemic heart disease, myocardial infarction, atrial fibrillation and flutter, peripheral artery disease, and non-rheumatic valve diseases (all P < 0.05). Multivariable MR analyses provided compelling evidence of the harmful effects of RC on the risk of ischemic heart disease (P < 0.05). Bidirectional MR analysis demonstrated that RC was bidirectionally causally linked to total cholesterol, triglycerides, low-density lipoprotein cholesterol, hypercholesterolemia (all P < 0.05). However, no genetic association was found between RC and metabolic disorders or the other cardiometabolic risk factors.ConclusionsThis MR study demonstrates that genetically driven RC increases the risk of several CMD and cardiometabolic risk factors, suggesting that targeted RC-lowering therapies may be effective for the primary prevention of CMD.

Genetically Proxied Sarcopenia-Related Muscle Traits and Depression: Evidence from the FinnGen Cohort

Sarcopenia and depression are common and often coexist in the elderly. This study aims to determine the impact of sarcopenia-related muscle traits on depression. A two-sample Mendelian randomization (MR) study was performed on the summary-level data from the FinnGen cohort to estimate the causal association of appendicular lean mass (ALM), walking pace, or low hand grip strength with depression. Additionally, multivariable MR (MVMR) was performed to assess the dependence of each muscle trait in the causality and adjust the effect of body mass index (BMI). Supplementary backward MR analyses were performed to estimate the effect of depression on sarcopenia-related muscle traits. Univariable MR analyses demonstrated that there were causal associations of ALM (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.88-0.99), walking pace (OR: 0.53; 95% CI: 0.32-0.88), and low hand grip strength (OR: 1.20; 95% CI: 1.05-1.38) with depression. MVMR analyses showed that ALM was the only trait that had a significant causal relationship with depression (OR: 0.91; 95% CI: 0.85-0.98) after accounting for the other two muscle traits. Moreover, the independent association of ALM with depression remained (OR: 0.92; 95% CI: 0.85-0.99) after being adjusted by BMI. The backward MR analyses showed no causal associations of depression with any sarcopenia-related muscle traits. Low muscle mass independently increases the risk of depression. This study determined the muscle-related risk factors of depression, which may help establish the causality between sarcopenia and depression and provide evidence-based recommendations for improving mental health in the elderly.

Genetic Evidence for Causal Association Between Atrial Fibrillation and Dementia: AMendelian Randomization Study.

Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2-sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance-weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023-1.271]; P=0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076-1.695]; P=0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953-1.197]; P=0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926-1.181]; P=0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small-vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention.

Causal association between basal metabolic rate and risk of cardiovascular diseases: a univariable and multivariable Mendelian randomization study

Basal metabolic rate (BMR) is associated with cardiovascular health; however, the causal relationship between BMR and the risk of cardiovascular diseases (CVDs) remains unclear. This study aimed to investigate the potential causal relationship of BMR on common CVDs including aortic aneurysm (AA), atrial fibrillation and flutter (AFF), calcific aortic valvular stenosis (CAVS), heart failure (HF), and myocardial infarction (MI) by Mendelian randomization (MR). The univariable MR analysis using inverse variance weighted (IVW) model as the primary analysis method revealed that genetically predicted higher BMR causally increased the risk of AA [IVW odds ratio (OR) = 1.34, 95% confidence interval CI 1.09–1.65, p = 0.00527], AFF (IVW OR = 1.87, 95% CI 1.65–2.12, p = 1.697 × E-22), and HF (IVW OR = 1.35, 95% CI 1.20–1.51, p = 2.364 × E-07), while causally decreasing the risk of MI (IVW OR = 0.83, 95% CI 0.73–0.93, p = 0.00255). In the multivariable MR analysis, which controlled for common cardiovascular risk factors, direct effects of BMR on an increased risk of AA and AFF, as well as a decreased risk of MI, but an attenuated causal effect on HF, were observed. In conclusion, the current MR study provides evidence for a causal relationship between BMR and the risk of AA, AFF, HF, and MI.

The causality of physical activity status and intelligence: A bidirectional Mendelian randomization study.

Observational studies suggest physical activity (PA) enhances intelligence, while sedentary behavior (SB) poses a risk. However, causality remains unclear. We extracted genetic instruments from large genome-wide association studies summary data and employed an inverse-variance weighted (IVW) approach within a random-effects model as the primary method of Mendelian randomization (MR) analysis to estimate the overall effect of various physical activity statuses on intelligence. To assess IVW stability and MR sensitivity, we also utilized supplementary methods including weighted median, MR-Egger, and MR-PRESSO. Furthermore, multivariable MR analysis was conducted to examine the independent effects of each physical activity trait on intelligence. The MR primary results indicated that LST was negatively associated with intelligence (β = -0.133, 95%CI: -0.177 to -0.090, p = 1.34×10-9), while SBW (β = 0.261, 95% CI: 0.059 to 0.463, p = 0.011) may have a positive effect on intelligence; however, MVPA and SC did not show significant effects on intelligence. Inverse causality analyses demonstrated intelligence significantly influenced all physical activity states. Our study highlights a bidirectional causal relationship between physical activity states and intelligence.

Causal relationship between circulating lipid traits and periodontitis: univariable and multivariable Mendelian randomization.

The correlation between dyslipidemia and periodontitis is revealed through epidemiological studies. However, the results are affected by several confounding factors. This study aims to elucidate the genetic causal association between circulating lipid traits and periodontitis by two-sample Mendelian randomization (MR) analysis. After the different screening processes, two cohorts of circulating lipid traits from the UK Biobank were used as exposure data, including five circulating lipid traits. The Periodontitis cohort was selected from the GeneLifestyle Interactions in Dental Endpoints (GLIDE) consortium as outcome data. In univariable MR, the inverse variance weighted (IVW) was used in conjunction with six additional analytical methods to assess causality. The Cochran Q test, IGX 2 statistic, MR-PRESSO, and MR-Egger intercept were used to quantify heterogeneity and pleiotropy. The multivariable MR-IVW (MVMR-IVW) and MVMR-robust were mainly used as analytical methods in the multiple MR analyses. The IVW estimates showed that genetically predicted Apolipoprotein A1 (apo A1) [odds ratio (OR)=1.158, 95% confidence interval (CI)=1.007-1.331, P-value=0.040] was potentially associated with the risk of periodontitis, but the statistical power of the results was low. Multivariable MR analysis did not reveal any significant causal relationship between apo A1 and periodontitis (OR=0.72, 95% CI=0.36-1.41, P-value=0.34). In the validation cohort, there was also no significant causal relationship between apo A1 and periodontitis (OR=1.079, 95% CI=0.903-1.290, P-value=0.401). Meanwhile, genetically predicted Apolipoprotein B (apo B), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) (all P-values>0.05) were not significantly associated with the risk of periodontitis causal inference. This MR analysis was unable to provide genetic evidence for the influence of these five circulating lipid traits on periodontitis. However, a more extensive study with a more comprehensive circulating lipid profile and periodontitis data is needed due to study limitations.

Evidence for a causal effect of major depressive disorder, anxiety on prostatitis risk: A univariate and multivariate Mendelian randomization study.

Observational studies have shown an association between major depressive disorder (MDD), anxiety, and prostatitis. However, the causal relationship between MDD, anxiety, and prostatitis remains controversial. Therefore, we aimed to use two-sample Mendelian randomization (MR) to assess the causal effects of MDD and anxiety on prostatitis. We conducted univariable and multivariable MR analyses using summary statistics from publicly available genome-wide association studies to estimate the causal relationships between MDD, anxiety, and prostatitis risk. In the main MR analysis, the inverse-variance weighted (IVW) method was used, while secondary methods included the weighted median, weighted mode, MR-Egger regression, and MR pleiotropy residual and outlier (MR-PRESSO) tests to detect and correct for the presence of pleiotropy. MDD had 97 independent instrumental variables (IVs) and anxiety had 15 IVs. Univariable MR analysis showed that genetically determined MDD had a detrimental causal effect on prostatitis (IVW: odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.12-1.92, p = 0.005), while no causal relationship was found between anxiety and prostatitis (IVW: OR = 0.25, 95% CI = 0.02-2.82, p = 0.26). More convincingly, after adjusting for confounding factors such as body mass index, alcohol consumption, and smoking, the genetic liability for MDD remained associated with prostatitis risk, with no strong evidence of anxiety affecting prostatitis incidence. This study supports the notion that MDD has a detrimental effect on prostatitis risk, and strategies focused on addressing MDD may be one of the cornerstones for treating prostatitis. The potential preventive value of treating MDD for prostatitis should be further investigated in future research.