Multivariable Mendelian Randomization Research Articles

Tracing links between micronutrients and type 2 diabetes risk: the singular role of selenium.

Type 2 diabetes (T2D) is a growing global health concern. While micronutrients are crucial for physiological functions and metabolic balance, their precise links to T2D are not fully understood. We investigated the causal relationships between 15 key micronutrients and T2D risk using both univariate and multivariate Mendelian randomization (MR) methods. Our analysis leveraged data from a large prospective cohort genome-wide association study (GWAS) on these micronutrients and T2D. We employed MR techniques such as inverse variance weighting (IVW), MR Egger, weighted median, and simple models. Multivariate analysis adjusted for diabetes-related factors like body mass index (BMI) and hypertension to assess the independent effects of micronutrients, particularly selenium, on T2D risk. Selenium intake was associated with an increased risk of T2D, with an odds ratio (OR) of 1.045, a 95% confidence interval (CI) ranging from 1.009 to 1.082, and a P-value of 0.015. This association was consistent in multivariate analyses, suggesting an independent effect of selenium on T2D risk after adjusting for confounders. Our study presents novel evidence of a positive correlation between selenium intake and T2D risk, underscoring the importance of micronutrients in diabetes prevention and treatment strategies. Further research is necessary to confirm these findings and to clarify the specific biological mechanisms through which selenium influences diabetes risk.

Exploring the link between sedentary behavior and cognitive decline: a comprehensive study combining Mendelian randomization and animal model experiments.

The causal link between detrimental behaviors and cognitive performance remains unclear. This research seeks to investigate the causal impact of adjustable lifestyle factors on cognitive deterioration, including frequency of alcohol intake, onset of smoking, and sedentary activities like prolonged television viewing. This research combines large-scale genetic data obtained from univariable and multivariable Mendelian randomization analyses with experimental findings obtained from animal models. Our findings reveal that the odds ratio (OR) for cognitive function deterioration was 0.445 (inverse variance weighted [IVW] 95% CI: 0.370 to 0.536, p < 0.001) for each standard deviation increase in television watching time. After adjustment for body mass index (BMI), number of days walked /moderate activity over 10+ min and education in Multivariable Mendelian Randomization (MVMR), only the genetic predisposition to increased television watching time remained significantly associated with worse cognitive function (OR 0.659, 95% CI: 0.452 to 0.960, p = 0.030). The other two habits had no significant effects. Sensitivity analyses have confirmed that genetic pleiotropy did not influence the results. To further explore the relationship between sedentary behavior and cognitive function, as well as the underlying mechanisms, we conducted a restricted cage housing experiment and a physical exercise training experiment in mice. The results showed that physical exercise significantly improved spatial memory, as assessed by the Morris water maze, and increased exploratory interest, as evaluated by the open field test (OFT) and the elevated plus-maze test, compared to the sedentary control group. These cognitive advantages may be mediated through mechanisms involving free radical scavenging and enhanced synaptic plasticity. Our research provides genetic evidence indicating that extended television viewing is linked to an elevated risk of cognitive decline. Additionally, experimental data from mouse models suggest that physical exercise can counteract cognitive decline and anxiety-like behaviors induced by sedentary behavior. This protective effect is likely mediated by reactive oxygen species (ROS)-dependent mechanisms that enhance synaptic plasticity within the hippocampus.

Lifelong impacts of puberty timing on human plasma metabolic profiles: A metabolome-wide Mendelian randomization study.

The aim was to investigate the causal relationship between puberty timing and plasma metabolites, accounting for birth weight, childhood and adulthood adiposity. The meta-analysis of genome-wide association studies (GWAS) for puberty timing was extracted from the ReproGen Consortium, involving 329 345 women of European ancestry. Summary data for 174 plasma metabolites were retrieved from a recently conducted cross-platform GWAS that involved a meta-analysis of three cohort studies (i.e. the Fenland, European Prospective Investigation into Cancer-Norfolk and INTERVAL studies) and three publicly available studies and included up to 86 507 participants. We conducted a two-sample Mendelian randomization (MR) analysis to infer the causal relationship of puberty timing on 174 plasma metabolites, complemented by a two-step and multivariable Mendelian randomization (MVMR) analysis to assess direct and indirect effects. Additionally, summary-level data from the UK Biobank were used for our replication analysis. The results of the two-sample MR provide moderate evidence supporting a causal relationship between puberty timing and 23 of 174 plasma metabolites (i.e. 7 acylcarnitines, 8 amino acids, 2 biogenic amines and 6 lysophosphatidylcholines). Even after single-nucleotide polymorphisms associated with birth weight and childhood adiposity were excluded, causal effects persisted for 16 metabolites (i.e. 8 acylcarnitines, 4 amino acids, 2 biogenic amines and 2 lysophosphatidylcholines). The two-step MR analysis provided evidence that the relationship between puberty timing and plasma metabolites was mediated by adulthood adiposity. Additionally, moderate evidence emerged for an independent causal effect of puberty timing on 10 metabolites through an MVMR analysis (i.e. 5 acylcarnitines, 2 amino acids, 1 biogenic amine, 1 lysophosphatidylcholine and 1 phosphatidylcholine). Furthermore, the replication analysis suggested the robustness of our results. In summary, our study provides compelling evidence that puberty timing has a causal influence on certain plasma metabolites, although this influence is largely mediated by adulthood adiposity.

Causality Between ADHD, ASD, and CVDs: A Two-Step, Two-Sample Mendelian Randomization Investigation.

While observational studies have established a connection between attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and heightened risk for cardiovascular diseases (CVD), the causal relationships are not well-defined. This study is designed to examine the causality between ASD, ADHD, and CVD risk as well as investigate the mediating factors through which ADHD and ASD influence CVD. Leveraging two-sample Mendelian randomization (MR) approaches and large scale GWAS summary stats, we examined underlying causal links between ASD and ADHD and the risk of CVDs. The analysis indicated that ADHD was related to an increased likelihood of developing coronary heart disease (OR [95% CI] 1.12 [1.03, 1.21], p = .008), heart failure (OR [95% CI] 1.14 [1.07, 1.22], p = 1.45 × 10-4), and large-artery stroke (OR [95% CI] 1.35 [1.09, 1.66], p = .005). In parallel, ASD showed a correlation with a greater atrial fibrillation risk (OR [95% CI] 1.09 [1.03, 1.16], p = .005] and heart failure (OR [95% CI] 1.11 [1.04, 1.19], p = .004). Additionally, we explored the mediating role of CVD risk factors through two-step MR and multivariable MR, highlighting the possible role of smoking, prescription opioid use, triglycerides, education, income, Townsend deprivation index, and obesity in the causal association of ADHD, ASD, on CVDs. This MR study highlights the necessity for rigorous cardiovascular surveillance and interventions to decrease adverse cardiovascular events in people with ADHD or ASD by preventing identified mediating risk factors.

HMGCR as a promising molecular target for therapeutic intervention in aortic aneurisms: a mendelian randomization study

BackgroundDespite the exploration of the connections between serum low-density lipoprotein cholesterol (LDL-C) levels and aneurisms in epidemiological studies, causality remains unclear. Therefore, this study aimed to assess the causal impact of LDL-C-lowering targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, and LDLR) on various forms of aneurisms using Mendelian Randomization (MR) analysis.MethodsTwo genetic instruments acted as proxies for exposure to LDL-C-lowering drugs: expression quantitative trait loci of drug target genes and genetic variants linked to LDL-C near drug target genes. Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) methods were employed to compute the effect estimates.ResultsThe SMR analysis revealed substantial associations between increased HMGCR expression and a heightened risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209–2.124), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122–2.475), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278–2.856). Likewise, IVW-MR analysis demonstrated positive correlations between HMGCR-mediated LDL-C and aortic aneurism (OR = 2.228, 95% CI = 1.702–2.918), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191–2.575), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257–7.028), and cerebral aneurism (OR = 1.993, 95% CI = 1.277–3.110). Furthermore, in the MVMR analysis, accounting for body mass index, smoking, and hypertension, a significant positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, encompassing both thoracic and abdominal subtypes. Similarly, consistent positive associations were observed for PCSK9 and CETP genes, as well as PCSK9-mediated and CETP-mediated LDL-C levels, with the occurrence of aortic aneurism and abdominal aortic aneurism. Nonetheless, the evidence for potential associations between APOB, NPC1L1 and LDLR with specific subtypes of aortic aneurisms lacked consistent support from both SMR and IVW-MR analyses.ConclusionsOur MR analysis offered compelling evidence of a plausible causal link between HMGCR and an increased risk of aortic aneurism, encompassing both thoracic and abdominal types. These groundbreaking findings further bolster the case for the deployment of HMGCR inhibitors in the treatment of aortic aneurisms, including both thoracic and abdominal variants.

Breast cancer and neoplasms of the thyroid gland: a bidirectional two-sample Mendelian randomization study.

With the rising incidence of breast cancer (BC) and neoplasms of the thyroid gland, a potential link between the two has drawn increasing attention. However, the causal relationship remains unclear due to various confounding factors. This study aims to investigate the causality between BC and thyroid tumors using Mendelian Randomization (MR) analysis. We conducted a bidirectional two-sample MR analysis, utilizing breast cancer-associated single nucleotide polymorphisms (SNPs) from the Breast Cancer Association Consortium (BCAC) and thyroid tumor-related SNPs from the FinnGen (https://www.finngen.fi/) database. First, we performed univariable MR (UVMR) to assess the causal relationship between BC and both malignant and benign thyroid tumors, followed by reverse causality analysis. To account for potential confounders, we applied multivariable MR (MVMR). The inverse-variance weighted (IVW) method was primarily used, with secondary analyses performed using the weighted median and MR-Egger regression approaches. UVMR analysis revealed a significant positive causal relationship between BC and malignant thyroid tumors (odds ratio [OR] and 95% confidence interval [CI]: 1.291, 1.143-1.458, P = 3.90×10-5). No causal relationship was found between BC and benign thyroid tumors. The MVMR analysis, adjusting for confounding factors such as smoking, drinking, and body mass index (BMI), confirmed the robustness of the results. This study provides genetic evidence supporting a causal relationship between BC and malignant thyroid tumors. These findings highlight the importance of thyroid cancer screening in BC patients. However, further MR studies or randomized controlled trials (RCTs) are necessary to assess small effects accurately.

The impact of sleep problems on cerebral aneurysm risk is mediated by hypertension: a mediated Mendelian randomization study.

Cerebral aneurysm (CA) is a common vascular disease. The risk factors of CA include hypertension, smoking, and a family history of genetic predisposition. Although sleep-related problems have been found to have a strong association with cardiovascular disease, there is a lack of research regarding the causal relationship with cerebral aneurysms. In this study, we investigated the causal relationship between four sleep-related problems, including snoring, insomnia, narcolepsy, and napping during the day, and CA using a two-sample Mendelian randomization (MR) analysis. Moreover, the potential confounders before sleep problems and CA were further analyzed by multivariate MR (MVMR). The causal relationship between insomnia and CA was obtained analytically by means of sixMR analyses. There was a strong causal effect relationship between insomnia and CA, which suggests this as a potential risk factor [odds ratio (OR) = 8.35, 95% confidence interval (CI) = 2.422-28.791, p = 7.772e-04]. On this basis, hypertension was identified as a mediator between insomnia and CA by MVMR, with a mediating effect of 52.538% (OR = 3.05, 95% CI = 1.549-4.55, p = 0.015). The causal relationship between insomnia and CA was predicted using genetic variance data, and insomnia was found to be a potential risk factor. Furthermore, hypertension is a mediator between insomnia and CA. Therefore, focusing on sleep problems and improving sleep quality may be an active and effective strategy to prevent CA.

Association between dietary fat intake and the risk of Alzheimer's disease: Mendelian randomisation study.

Observational studies have shown a controversial relationship between dietary fat intake and Alzheimer's disease, and the causal effects are unclear. To assess the causal effects of total fat, saturated fat and polyunsaturated fat (PUF) intakes on the risk of Alzheimer's disease. A two-sample Mendelian randomisation analysis was performed using genome-wide association study summary statistics on different types of fat intake from UK Biobank (n = 51 413) and on late-onset Alzheimer's disease (LOAD; 4282 cases, n = 307 112) and all forms of Alzheimer's disease (6281 cases, n = 309 154) from the FinnGen consortium. In addition, a multivariable Mendelian randomisation (MVMR) analysis was conducted to estimate the effects independent of carbohydrate and protein intakes. Genetically predicted per standard deviation increase in the total fat and saturated fat intakes were associated with 44 and 38% higher risks of LOAD (total fat: odds ratio = 1.44, 95% CI 1.03-2.02; saturated fat: odds ratio = 1.38, 95% CI 1.002-1.90; P = 0.049). The associations remained significant in the MVMR analysis (total fat: odds ratio = 3.31, 95% CI 1.74-6.29; saturated fat: odds ratio = 2.04, 95% CI 1.16-3.59). Total fat and saturated fat intakes were associated with a higher risk of all forms of Alzheimer's disease in the MVMR analysis (total fat: odds ratio = 2.09, 95% CI 1.22-3.57; saturated fat: odds ratio = 1.60, 95% CI 1.01-2.52). The PUF intake was not associated with LOAD or all forms of Alzheimer's disease. This study indicated that total dietary fat intake, especially saturated fat, contributed to the risk of Alzheimer's disease, and the effects were independent of other nutrients. These findings informed prevention strategies and management for Alzheimer's disease directly towards reducing dietary saturated fat intake.

Novel Insights into Causal Effects of Serum Lipids and Apolipoproteins on Cardiovascular Morpho-Functional Phenotypes.

Previous observational studies have explored the association between serum lipids, apolipoproteins, and adverse ventricular/aortic structure and function. However, whether a causal link exists is uncertain. This study employed a two-sample Mendelian randomization (MR), colocalization, reverse, and multivariable MR (MVMR) approach to examine the causal associations among five serum lipids, two apolipoproteins, and 32 cardiac magnetic resonance (CMR) traits. Utilizing single-nucleotide polymorphisms (SNPs) linked to serum lipids and apolipoproteins as instrumental variables. CMR traits from seven independent genome-wide association studies served as preclinical endophenotypes, offering insights into aortic and cardiac structure/function. The primary analysis utilized a random-effects inverse variance method (IVW), followed by sensitivity and validation analyses. In the primary IVW MR analyses, genetically predicted low-density lipoprotein cholesterol (LDL-C) levels were positively correlated with increased descending aorta strain (DAo strain) (β = 0.098; P = 2.69E-07) and ascending aorta strain (AAo strain) (β = 0.079; P = 5.19E-05). Genetically predicted high-density lipoprotein cholesterol (HDL-C) levels were positively correlated with left ventricular radial peak diastolic strain rate (LV-PDSRll) (β = 0.176; P = 2.89E-05) and the left ventricular longitudinal peak diastolic strain rate (LV-PDSRrr) (β = 0.059; P = 2.44E-06), and negatively correlated with left ventricular regional wall thickness (LVRWT). While apolipoprotein B (ApoB) levels were positively correlated with AAo strain (β = 0.076; P = 1.16E-05), DAo strain (β = 0.065; P = 2.77E-05). A shared causal variant was identified to demonstrate the associations of ApoB with AAo strain and DAo strain using colocalization analysis. Sensitivity analyses confirmed the robustness of these associations. Targeting lipid and apolipoprotein levels through interventions may provide novel strategies for the primary prevention of CVDs.

Causal relationship between Women's reproductive traits and postpartum depression: a multivariate mendelian randomization analysis.

The relationship between women's reproductive traits and postpartum depression (PPD) has not been clarified. We reveal the association between genetically predicted modifiable women's reproductive traits and PPD using two-sample Mendelian randomization (MR). We used genome-wide association studies (GWASs) to obtain instrumental variables (IVs) of 9 women's reproductive traits. Univariate and multivariate MR analyses were used to examine the association between traits and the risk of PPD (13,657 cases and 236,178 controls). The primary causal effect assessment employed the IVW method. Heterogeneity was assessed using Cochran's Q test. Multiple horizontal effects were assessed using the MR-PRESSO and MR-Egger intercept. Leave-one-out and LASSO regression analyses were used to check the robustness of the UVMR and MVMR results, respectively. In the UVMR result, genetic prediction showed that age at first sexual intercourse (AFS) (OR = 0.474, 95% CI 0.396-0.567; p = 4.6 × 10-16), age at first birth (AFB) (OR = 0.865, 95% CI 0.805-0.930; p = 8.02 × 10-5), and age at last live birth (ALLB) (OR = 0.296, 95% CI 0.138-0.636; p = 0.002) were significantly inversely associated with PPD, while a higher lifetime number of sexual partners (LNSP) (OR = 1.431, 95% CI 1.009-2.031; p = 0.045) and a greater number of spontaneous miscarriages (OR = 1.519, 95% CI 1.021-2.262; p = 0.039) are suggested to be associated with an increased risk of PPD. In the MVMR result, only AFB (OR = 0.804, 95% CI 0.661-0.978; p = 0.029) retained a direct causative relationship with PPD. The study indicates that AFB is a significant risk factor for PPD. Furthermore, the likelihood of developing PPD appears to decrease with increasing gestational age at the time of the first childbirth.

Association between vitamin B6 levels and rheumatoid arthritis: a two-sample Mendelian randomization study.

Micronutrients play a crucial role in rheumatoid arthritis (RA). Changes in micronutrient levels in RA patients can lead to the worsening of their condition. Though significant correlations between RA and micronutrients have been found in earlier observational studies, their underlying causal relationship is still unknown. This study aimed to elucidate the causal genetic relationships between 15 micronutrients (copper, zinc, magnesium, vitamins A, C, E, D, B6, B12, folate, carotene, iron, selenium, calcium, potassium) and RA. The exposure factors and outcome data used in the two-sample Mendelian randomization (MR) were derived from publicly available summary statistics data of European populations. The GWAS data for exposure factors were obtained from the OpenGWAS database. For the outcome data of RA, we utilized data from the FinnGen database. We used the MR principle to remove confounding factors and conducted MR analyses using five methods: inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode, with IVW as the primary method. Then, we identified micronutrients related to RA and performed MR analyses on these elements, including heterogeneity analysis and pleiotropy analysis such as MR-Egger intercept, MR-PRESSO method, and "leave-one-out" analysis. Finally, we conducted multivariable MR analyses and performed sensitivity analyses again. The IVW analysis revealed a relationship between vitamin B6 and RA (p: 0.029, OR: 1.766, and 95% CI: 1.062-2.938). Sensitivity analysis confirmed the validity and reliability of this result. This study revealed a causal relationship between vitamin B6 and RA, with vitamin B6 being identified as a risk factor for RA. This finding could contribute to the diagnosis and supplementary treatment of RA patients, providing a reference for subsequent basic research and developing new drugs.

Effects of multiple fluid intake on Urolithiasis by mendelian randomization study

Urolithiasis, a common and recurrent condition, imposes a significant global health burden. This study investigates the causal relationship between various types of fluid intake and urolithiasis using univariable and multivariable Mendelian randomization (MR) approaches. Genetic data for urolithiasis were obtained from the FinnGen Consortium (n = 400,681), while genetic measures for nine fluid types were sourced from meta-analyses of genome-wide association studies (GWAS). The analysis revealed that genetically predicted coffee intake (OR: 0.571, 95% confidence interval (CI): 0.341–0.958, p = 0.034) and ground coffee intake (OR: 0.219, 95% CI: 0.005–0.923, p = 0.038) were protective factors for upper urinary calculi. Additionally, a standard deviation (SD) increase in tea intake was associated with a 53% reduction in risk (OR: 0.473, 95% CI: 0.320–0.700, p < 0.001). Conversely, milk intake (OR: 1.072, 95% CI: 1.018–1.130) and alcohol intakefrequency (OR: 1.304, 95% CI: 1.083–1.570, p = 0.005) increased the risk of upper urinary calculi. These findings highlight the association of tea with reduced risk of urolithiasis, instead for milk and alcohol intake, in formulating prevention strategies for urolithiasis.

Serum liver enzymes and risk of stroke: Systematic review with meta-analyses and Mendelian randomization studies.

Previous observational studies have identified correlations between liver enzyme levels and stroke risk. However, the strength and consistency of these associations vary. To comprehensively evaluate the relationship between liver enzymes and stroke risk, we conducted meta-analyses complemented by Mendelian randomization (MR) analyses. Following the PRISMA guidelines, we performed meta-analyses of prospective studies and conducted subgroup analyses stratified by sex and stroke subtype. Subsequently, adhering to the STROBE-MR guidelines, we performed two-sample bidirectional univariable MR (UVMR) and multivariable MR (MVMR) analyses using the largest genome-wide association studies summary data. Finally, the single-nucleotide polymorphisms associated with liver enzymes on sex differences underwent gene annotation, gene set enrichment, and tissue enrichment analyses. In the meta-analyses of 17 prospective studies, we found the relative risks for serum γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) were 1.23 (95% CI: 1.16-1.31) and 1.3 (95% CI: 1.19-1.43), respectively. Subgroup analyses revealed sex and stroke subtype differences in liver enzyme-related stroke risk. Bidirectional UVMR analyses confirmed that elevated GGT, alanine aminotransferase, and aspartate aminotransferase levels were associated with increased stroke occurrence. The primary results from the MVMR analyses revealed that higher ALP levels significantly increased the risk of stroke and ischemic stroke. Gene set and tissue enrichment analyses supported genetic differences in liver enzymes across sexes. Our study provides evidence linking liver enzyme levels to stroke risk, suggesting liver enzymes as potential biomarkers for early identification of high-risk individuals. Personalized, sex-specific interventions targeting liver enzymes could offer new strategies for stroke prevention.

Circulating levels of cytokines and risk of urologic cancers: a two-sample Mendelian randomization study

BackgroundChronic inflammation is associated with the etiology of various cancers. However, there is a lack of systematic research in urologic cancers. This study aims to use a two-sample Mendelian randomization (MR) approach to evaluate the role of circulating cytokines in the development of urologic cancers.MethodsWe obtained the summary-level data for bladder cancer (373,295 cases and 372,016 controls), prostate cancer (462,933 cases and 459,664 controls), and kidney cancer (463,010 cases and 461,896 controls) from the UK Biobank. Genetic variations linked to 41 circulating cytokines were used as instrumental variables (IVs) in meta-analyses of genome-wide association studies (GWASs) involving 8,293 individuals from Finland. We primarily used the inverse-variance weighted (IVW) method to assess the potential associations between the 41 cytokines and the risk of 3 common urologic cancers. Weighted-median method, weighted mode and simple-median method were used to assess the sensitivity. Heterogeneity and pleiotropic outlier were evaluated by Cochran's Q test and MR-Egger regression. Genetic correlation, colocalization analysis and multivariable MR analysis were used to further validate the potential pleiotropy.ResultsAfter the Bonferroni correction, there was an observed association between elevated genetically predicted levels of CCL27 and a heightened risk for bladder cancer. Conversely, IL-12p70 levels were found to have a protective association against the risk of bladder cancer. Sensitivity analyses utilizing various IV sets and MR approach remained robust. Furthermore, we found potential associations of 7 cytokines with urologic cancers (4.07 × 10−4 ≤ P < 0.05).ConclusionOur study supported causal associations between CCL27, IL-12p70 and bladder cancer risk and potential associations of 7 cytokines with the risk of urologic cancers, helping us to further understand the pathogenesis of urologic cancers and providing clues for improving diagnostic accuracy and therapies.

Genetic basis and causal relationship between atrial fibrillation and sinus node dysfunction: Evidence from comprehensive genetic analysis

BackgroundAtrial fibrillation (AF) and sinus node dysfunction (SND) are commonly observed together clinically. However, little is known about the genetic background and causal relationship between the two. MethodsFirstly, we investigated the global and local genetic correlations between AF and SND using LDSC and HESS. Then, we identified shared “Novel SNPs” between AF and SND through two complementary cross-trait meta-analyses and mapped the “pleiotropic genes” behind these SNPs, validated by colocalization analysis. Additionally, we explored the degree of genetic enrichment of SNPs in specific tissues using LDSC-SEG and MAGMA, and identified potential functional genes in tissues using summary data-based Mendelian randomization (SMR). Finally, two-sample Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) were used to explore the causal relationship between AF and SND. ResultsBoth global and local genetic correlation analyses revealed a high positive genetic correlation between AF and SND. HESS identified 9 shared loci, with chr4(q25-q26) and chr11(p11.12-q11) being prominent. Cross-trait meta-analysis and colocalization analysis identified ENPEP and PITX2 as novel pleiotropic genes. MAGMA revealed genetic enrichment of SNPs for AF and SND in the “Heart Left Ventricle” and “Heart Atrial Appendage” tissues, with CEP68 and BEST3 identified as potential functional genes through SMR. MR analysis indicated that AF increases the risk of SND, even after adjusting for confounding factors. ConclusionThis study provides genetic evidence for the increased risk of SND associated with AF, identifying multiple shared risk loci and enriched tissues, and discovering 2 novel pleiotropic genes and 2 new functional genes.

Relationship between hearing impairment and dementia and cognitive function: a Mendelian randomization study

BackgroundThere is a substantial body of observational research indicating an association between hearing impairment and dementia, yet the causal relationship and underlying mechanisms remain uncertain. This study aims to investigate the causal relationship between hearing impairment and its subtypes with dementia and cognitive function using two-sample Mendelian randomization (MR) analysis.MethodsWe performed two-sample MR analysis to examine the causal effects of hearing impairment and its subtypes, including conductive and sensorineural hearing loss (CSHL), conductive hearing loss (CHL), sensorineural hearing loss (SHL), and sudden sensorineural hearing loss (SIHL), on six dementia phenotypes (overall dementia, Alzheimer’s disease [AD], Lewy body dementia [DLB], frontotemporal dementia [FTD], Parkinson’s disease dementia, and vascular dementia) and four cognitive functions. Additionally, multivariable MR (MVMR) analysis was employed to investigate potential mediating mechanisms.ResultsGenetically determined CSHL was associated with an elevated risk of DLB (odds ratio [OR] 1.69; 95% CI 1.08 to 2.63; P = 0.021) and FTD (OR 1.66; 1.04 to 2.67; P = 0.035), but not AD (P = 0.958). Genetic predisposition to CHL was found to link with increased risks of AD (OR 1.07; 1.01 to 1.14; P = 0.031). Genetically determined SHL was causally associated with an elevated risk of semantic dementia (OR 3.81; 1.09 to 13.37; P = 0.037). Genetically predicted CHL and SIHL were both causally associated with lower general cognitive performance (β -0.015 and − 0.043; P = 0.007 and 0.013) and fluid intelligence score (β -0.045 and − 0.095; P = 0.037 and 0.040). In MVMR analysis, the causal relationship between hearing impairment and dementia was mediated by loneliness, depressed mood, and brain cortical volume, particularly the medial temporal lobe, but not by aging or ischemic stroke.ConclusionOverall, the study provides evidence supporting a causal relationship between hearing impairment and increased risks of different types of dementia (including AD, FTD, and DLB), as well as poorer general cognitive function. These findings underscore the importance of addressing hearing impairment as a modifiable risk factor for dementia.

Vitamin D levels and risk of ocular disorders: insights from bidirectional and multivariable Mendelian randomization analysis.

This study aimed to assess the causal relationships between vitamin D levels and ocular disorders. Independent genetic variables were obtained from genome-wide association studies (GWAS) and publicly available databases. The summary statistics for 25-hydroxyvitamin D (25(OH)D) were obtained from two large-scale GWAS studies, with sample sizes of 324,105 and 417,580 European individuals. The genetic variants of myopia, primary open angle glaucoma (POAG), anterior iridocyclitis, senile cataract, diabetic retinopathy (DR), retinal vein occlusion (RVO), wet age-related macular degeneration (WAMD) and optic neuritis were extracted from the latest release of FinnGen consortium, which contains genome data from Finnish participants. Subsequently, Mendelian randomization (MR) analyses were conducted to obtain effect estimates. Additionally, we performed multivariable MR analysis and mediation analysis to validate the results. In the discovery dataset, genetically predicted vitamin D concentration was found to be causally associated with an increased risk of WAMD, (odd ratio (OR) = 1.35, 95% confidence interval (CI) = 1.09-1.67, P IVW = 0.005). However, no causal effects of genetically predisposed vitamin D levels on the risk of most types of ocular disorders were observed. Reverse MR revealed no causal relationships between the ocular diseases and vitamin D concentrations. The MR analyses of the validation dataset yielded consistent results. Additionally, the causal effect of vitamin D levels on the risk of WAMD remained significant after adjusting for potential confounders in the multivariable MR analysis (OR = 1.86, 95% CI = 1.26-2.73, P IVW = 0.002). Our MR analysis results provide robust evidence of a causal relationship between genetically predicted 25(OH)D levels and an increased risk of WAMD in European population. These findings offer important insights into the management and control of ocular disorders.

Causal Association of Chronic Venous Insufficiency and Cardiovascular Diseases: A Univariable and Multivariable Mendelian Randomization Study.

The causal relationship between chronic venous insufficiency (CVI) and cardiovascular diseases (CVDs) has yet to be elucidated. Herein, we implement Mendelian randomization (MR) analysis to investigate the causal association. A two-sample MR approach using genetic data from FinnGen and genome-wide association studies (GWAS) Catalog was applied to investigate the causal relationship between CVI and CVDs. This study assessed 77 single nucleotide polymorphisms (SNPs) as instrumental variables, employing random-effect inverse-variance-weighted MR, weighted median, Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and Robust Adjusted Profile Score (RAPS) methods. Multivariable MR (MVMR) considered confounding factors. Genetically predicted CVI was associated with reduced heart failure risk (odds ratio (OR) = 0.96, 95% confidence interval (95% CI): 0.93-0.99, p = 0.025) and increased atrial fibrillation risk (OR = 1.06, 95% CI: 1.03-1.09, p = 0.0002). MVMR, adjusting for venous thromboembolism (VTE), lower limb ulceration, obesity, smoking, and alcohol, attenuated these associations. No significant links were found with hypertension, aortic aneurysm, coronary artery disease, myocardial infarction, valvular heart disease, or stroke. This MR study supports an association between CVI and CVDs, which may imply CVI should be monitored during the treatment of heart failure and atrial fibrillation.

Causal impacts of smoking on pain conditions and the mediating pathways: a mendelian randomization study.

Smoking is a risk factor for multiple diseases. We performed mendelian randomization (MR) analyses to investigate the causal association of smoking initiation on pain conditions and the potential mediating pathways. Genetic associated with smoking initiation at the genome-wide significance level were selected as instrumental variables. Genetic associations with 10 pain conditions were derived from the FinnGen and UK Biobank study. Multivariable MR analysis was conducted to explore the mediation effects of depression, insomnia and sedentary behavior. A series of sensitivity analyses were conducted to assess the stability of our research findings. Genetic liability to smoking initiation was associated with an increased risk of angina pectoris, dorsalgia, low back pain, pain in limb, pain in joint, pain in thoracic spine and sciatica in both FinnGen and UK Biobank study. These causal associations were largely mediated by major depression (2.9- 39.5%), sedentary behavior (13.0- 31.2%), insomnia (10.3- 33.1%) and combination of all three mediators (30.2- 65.3%). The effects of smoking on outcomes were partly attenuated after adjusting for depression, sedentary behavior and insomnia respectively, and the direct effect of smoking initiation on pain was diminished toward null after adjusting for combined three mediators. These results were robust to sensitivity analyses. Our findings illustrated the causal effect of smoking and a broad range of pain conditions, and major depression, sedentary behavior and insomnia mediate many of these associations.

Antidepressants account for the causal effect of major depressive disorder on type 2 diabetes

BackgroundPatients with major depressive disorder (MDD) face an elevated risk of type 2 diabetes (T2D). However, the contribution of the disease itself versus the side effects of antidepressants to this increased risk remains unclear. ObjectiveThis study aimed to investigate the overall and independent effects of MDD and exposure to antidepressants on T2D risk. MethodsSummary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for MDD (N = 500,199), antidepressants (N = 175,161), and T2D (N = 933,970). Bayesian colocalization analysis was used to reveal shared genetic variation between MDD, antidepressants, and T2D. ResultsWe found that both MDD (OR: 1.15, CI: 1.03–1.30, P = 0.016) and antidepressants (OR: 1.37, CI: 1.22–1.53, P = 2.75E-08) have overall causal effects on T2D. While T2D was associated with the risk of antidepressant use (OR: 1.08, CI: 1.06–1.11, P = 8.80E-10), but not with the risk of MDD (OR: 1.00, CI: 0.98–1.01, P = 0.661). Our MVMR analysis showed that the use of antidepressants is associated with higher risks of T2D (OR: 1.21, CI: 1.07–1.37, P = 7.19E-04), while MDD is not linked to the risk of T2D (OR: 1.01, CI: 0.86–1.18, P = 0.799). Colocalization analysis identified two shared genetic loci between antidepressants and T2D. ConclusionsThe elevated T2D risk in MDD patients is chiefly caused by antidepressant use. These findings emphasize the importance of considering the impact of antidepressants on metabolic health in individuals with MDD.