Multivariable Mendelian Randomization Research Articles

Causal effect of the age at first birth with depression: a mendelian randomization study

BackgroundThis study aimed to explore the causal relationship between age at first birth (AFB) and depression.MethodsUsing the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result.ResultsWe found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793 − 0.861; P = 4.51 × 10− 20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P < 0.05). During the sensitivity analysis, the heterogeneity test (Q-value = 55.061, df = 48, P = 2.81 × 10− 01, I2 = 12.82%) and the leave-one-out plot analysis confirmed the stability of the results. The outcomes of the pleiotropy test (MR-Egger intercept = 8.932 × 10− 3. SE = 6.909 × 10− 3. P = 2.02 × 10− 01) and MR_PRESSO global test (P = 2.03 × 10− 01) indicated there is no pleiotropy.ConclusionThere is solid evidence that a higher age at first birth is associated with a lower risk of major depressive disorder.

An integrative multi-context Mendelian randomization method for identifying risk genes across human tissues

Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often context- or tissue-specific eQTL effects challenge the MR assumption of consistent IV effects across eQTL and GWAS data. To address these challenges, we propose a multi-context multivariable integrative MR framework, mintMR, for mapping expression and molecular traits as joint exposures. It models the effects of molecular exposures across multiple tissues in each gene region, while simultaneously estimating across multiple gene regions. It uses eQTLs with consistent effects across more than one tissue type as IVs, improving IV consistency. A major innovation of mintMR involves employing multi-view learning methods to collectively model latent indicators of disease relevance across multiple tissues, molecular traits, and gene regions. The multi-view learning captures the major patterns of disease relevance and uses these patterns to update the estimated tissue relevance probabilities. The proposed mintMR iterates between performing a multi-tissue MR for each gene region and joint learning the disease-relevant tissue probabilities across gene regions, improving the estimation of sparse effects across genes. We apply mintMR to evaluate the causal effects of gene expression and DNA methylation for 35 complex traits using multi-tissue QTLs as IVs. The proposed mintMR controls genome-wide inflation and offers insights into disease mechanisms.

Causal relevance of different blood pressure traits on risk of cardiovascular diseases: GWAS and Mendelian randomisation in 100,000 Chinese adults

Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk.

Calcium homeostasis and endometriosis: A Mendelian randomization study

BackgroundPrevious observational studies have investigated the correlation between calcium homeostasis modulator levels and endometriosis risk. Yet, the genetic association between body calcium homeostasis and endometriosis risk remains to be elucidated. MethodsFour tiers of Mendelian randomization (MR) analysis were conducted, as follows: (1) single univariate MR and (2) multivariate MR to evaluate the correlation between calcium homeostasis regulators and endometriosis; (3) inverse MR to probe the influence of endometriosis on body calcium homeostasis; (4) two-sample MR to scrutinize the connection between calcium levels and endometriosis categories. ResultsThe two-sample MR analysis unveiled a robust positive correlation between genetically inferred calcium levels and endometriosis risk (IVW: OR = 1.15, 95 % CI: 1.02–1.29, p = 0.018). The MVMR analysis corroborated that the positive correlation of calcium levels with endometriosis persisted after adjusting for 25(OH)D and PTH. The inverse MR analysis disclosed a significant association between endometriosis and 25(OH)D (β = 0.01, 95 % CI: 0.00–0.02, p = 0.007) and calcium (β = 0.02, 95 % CI: 0.00–0.04, p = 0.035). The two-sample MR analysis further demonstrated that calcium levels were positively linked solely to endometriosis of uterus (i.e. adenomyosis, IVW: OR = 1.23, 95 % CI: 1.01–1.49, p = 0.038), with no evidence of a influence on other endometriosis categories. ConclusionsThis study, employing various types of MR, offers some genetic evidence for the relationship between calcium homeostasis and endometriosis, augmenting the current comprehension of the complex association between the two and suggesting that calcium levels are a risk factor for endometriosis. These findings provide a unique genetic perspective that may spur further investigation and may inform future strategies for managing patients with endometriosis.

Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine

IntroductionMigraine, as a complex neurological disease, brings heavy burden to patients and society. Despite the availability of established therapies, existing medications have limited efficacy. Thus, we aimed to find the drug targets that improve the prognosis of migraine.MethodWe used Mendelian Randomization (MR) and Summary-data-based MR (SMR) analyses to study possible drug targets of migraine by summary statistics from FinnGen cohorts (nCase = 44,616, nControl = 367,565), with further replication in UK Biobank (nCase = 26,052, nControl = 487,214). Genetic instruments were obtained from eQTLGen and UKB-PPP to verify the drug targets at the gene expression and protein levels. The additional analyses including Bayesian co-localization, the heterogeneity in dependent instruments(HEIDI), Linkage Disequilibrium Score(LDSC), bidirectional MR, multivariate MR(MVMR), heterogeneity test, horizontal pleiotropy test, and Steiger filtering were implemented to consolidate the findings further. Lastly, drug prediction analysis and phenome-wide association study(PheWAS) were employed to imply the possibility of drug targets for future clinical applications.ResultThe MR analysis of eQTL data showed that four drug targets (PROCR, GSTM4, SLC4A1, and TNFRSF10A) were significantly associated with migraine risk in both the FinnGen and UK Biobank cohorts. However, only GSTM4 exhibited consistent effect directions across the two outcomes(Discovery cohort: OR(95%CI) = 0.94(0.93–0.96); p = 2.70e − 10; Replication cohort: OR(95%CI) = 0.93(0.91–0.94); p = 4.21e − 17). Furthermore, GSTM4 passed the SMR at p < 0.05 and HEIDI test at p > 0.05 at both the gene expression and protein levels. The protein-level MR analysis revealed a strong correlation between genetically predicted GSTM4 with a lower incidence of migraine and its subtypes(Overall migraine: OR(95%CI) = 0.91(0.87–0.95); p = 6.98e-05; Migraine with aura(MA): OR(95%CI) = 0.90(0.85–0.96); p = 2.54e-03; Migraine without aura(MO): OR(95%CI) = 0.90(0.83–0.96); p = 2.87e-03), indicating a strong co-localization relationship (PPH4 = 0.86). Further analyses provided additional validation for the possibility of GSTM4 as a migraine treatment target.ConclusionThis study identifies GSTM4 as a potential druggable gene and promising therapeutic target for migraine.

Genetic predisposition to type 2 diabetes mellitus and aortic dissection: a Mendelian randomisation study.

This Mendelian randomization (MR) study aimed to explore the causal relationship between the genetic predisposition to type 2 diabetes mellitus (T2DM) and aortic dissection (AD), and to assess associations with genetically predicted glycemic traits. The study sought to verify the inverse relationship between T2DM and AD using a more robust and unbiased method, building on the observational studies previously established. The study employed a two-sample and multivariable MR approach to analyze genetic data from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) with 74,124 cases and 824,006 controls, and the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) involving up to 196,991 individuals. For AD data, FinnGen Release 10 was used, including 967 cases and 381,977 controls. The research focused on three foundational MR assumptions and controlled for confounders like hypertension. Genetic instruments were selected for their genome-wide significance, and multiple MR methods and sensitivity analyses were conducted. The study revealed no significant effect of genetic predisposition to T2DM on the risk of AD. Even after adjusting for potential confounders, the results were consistent, indicating no causal relationship. Additionally, glycemic traits such as fasting glucose, fasting insulin, and HbA1c levels did not show a significant impact on AD susceptibility. The findings remained stable across various MR models and sensitivity analyses. In contrast, genetic liability to T2DM and glycemic traits showed a significant association with coronary artery disease (CAD), aligning with the established understanding. Contrary to previous observational studies, this study concludes that genetic predisposition to T2DM does not confer protection against AD. These findings underscore the imperative for further research, particularly in exploring the preventative potential of T2DM treatments against AD and to facilitate the development of novel therapeutic interventions.

Association between genetically proxied PPARG activation and psoriasis vulgaris: a Mendelian randomization study

Background Psoriasis is a common autoimmune disease in clinical practice, and previous observational studies have suggested that PPARG agonists such as Pioglitazone may be potential therapeutic agents. However, due to interference from various confounding factors, different observational studies have not reached a unified conclusion. We aim to evaluate the potential use of PPARG agonists for treating psoriasis from a new perspective through drug-targeted Mendelian randomization (MR) analysis. Materials and methods This study includes data on 8,876 individuals for acute myocardial infarction from GWAS, and LDL cholesterol data from 343,621 Europeans. FinnGen contributed psoriasis vulgaris data for 403,972 individuals. The DrugBank10 databases function to identify genes encoding protein products targeted by active constituents of lipid-modifying targets. A two-sample MR analysis and summary-data-based MR (SMR) analysis estimated the associations between expressions of drug target genes and symptoms of psoriasis vulgaris. A multivariable MR study was further conducted to examine if the observed association was direct association. Results SMR analysis revealed that enhanced PPARG gene expression in the blood (equivalent to a one standard deviation increase) was a protective factor for psoriasis vulgaris (beta = −0.2017, se = 0.0723, p = 0.0053). Besides, there exists an MR association between LDL mediated by PPARG and psoriasis vulgaris outcomes (beta = −3.9169, se = 0.5676, p = 5.17E-12). These results indicate that PPARG is a therapeutic target for psoriasis, suggesting that psoriasis may be a potential indication for PPARG agonists. Conclusion This study confirms that therapeutic activation of PPARG helps suppress the development of psoriasis. Psoriasis may be a new indication for PPARG agonists, such as Pioglitazone. In the future, new anti-psoriatic drugs could be developed targeting PPARG.

Crosstalk between gastrointestinal tract disorders and obstructive sleep apnea.

Clinical studies suggested associations between obstructive sleep apnea (OSA) and gastrointestinal tract disorders. This study aims to investigate the genetic causal relationship between OSA and gastrointestinal tract disorders, specifically gastroesophageal reflux disease (GERD) and inflammatory bowel disease (IBD). In this study, we employed two-sample Mendelian Randomization (MR) analysis to investigate the potential relationships between OSA and GERD, and between OSA and IBD. More specifically, the primary analysis utilized inverse variance weighting (IVW). Weighted median, MR Egger, and MR PRESSO were applied to complicate potential violations of MR assumptions. Also, sensitivity analysis was evaluated and similar analysis was performed again after outliers were removed. Additionally, multivariable MR (MVMR) was conducted for associated pairs to adjust for obesity. Genetically predicted risk of GERD increased OSA risk by approximately 60% (ORIVW = 1.62, 95%CI = [1.43,1.84]) which was also stable by other complicated approaches, and even with BMI adjusted by MVMR (ORadjBMI[95%CI] = 1.26 [1.15,1.37]). Besides, OSA showed a mild causal effect on increased GERD risk after adjusting for obesity (ORadjBMI[95%CI] = 1.05 [1.02,1.08]). Additionally, OSA increased the risks for IBD (ORIVW[95%CI] = 1.36 [1.12,1.65]), including a higher risk of CD (ORIVW[95%CI] = 1.41 [1.08,1.83]), and a trend for increasing UC risk (ORIVW[95%CI] = 1.29 [0.99,1.67]). GERD exerts a substantial causality on increasing the risk of OSA. Conversely, the potential for a causal relationship that OSA contributes to the development of GERD or IBD remains probable. These findings support the crosstalk between gastrointestinal tract disorders and OSA.

Inflammatory bowel disease and risk for hemorrhoids: a Mendelian randomization analysis

Observational studies have reported an association between inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), and hemorrhoids (HEM). However, the presence of a causal relationship within this observed association remains to be confirmed. Consequently, we utilized the Mendelian randomization (MR) method to assess the causal effects of IBD on hemorrhoids. We validated the association between IBD and hemorrhoids in humans based on genome-wide association studies (GWAS) data. To investigate the causal relationship between IBD and hemorrhoids, we performed a two-sample Mendelian randomization study using training and validation sets. The genetic variation data for IBD, CD, UC, and hemorrhoids were derived from published genome-wide association studies (GWAS) of individuals of European. Two-sample Mendelian randomization and Multivariable Mendelian randomization (MVMR) were employed to determine the causal relationship between IBD (CD or UC) and hemorrhoids. Genetically predicted overall IBD was positively associated with hemorrhoids risk, with ORs of 1.02 (95% CIs 1.01–1.03, P = 4.39 × 10−4) and 1.02 (95% CIs 1.01–1.03, P = 4.99 × 10−5) in the training and validation sets, respectively. Furthermore, we found that CD was positively associated with hemorrhoids risk, with ORs of 1.02 (95% CIs 1.01–1.03, P = 4.12 × 10−6) and 1.02 (95% CIs 1.01–1.02, P = 3.78 × 10−5) for CD in the training and validation sets, respectively. In addition, we found that UC in the training set was positively associated with hemorrhoids risk (ORs 1.02, 95% CIs 1.01–1.03, P = 4.65 × 10−3), while no significant causal relationship between UC and hemorrhoids was shown in the validation set (P > 0.05). However, after MVMR adjustment, UC in the training set was not associated with an increased risk of hemorrhoids. Our study showed that there is a causal relationship between CD and hemorrhoids, which may suggest that clinicians need to prevent the occurrence of hemorrhoids in CD patients.

Mendelian randomization analysis revealed that albuminuria is the key factor affecting socioeconomic status in CKD patients

Previous studies indicate a strong correlation between the incidence of chronic kidney disease (CKD) and lower economic status. However, these studies often struggle to delineate a clear cause–effect relationship, leaving healthcare providers uncertain about how to manage kidney disease in a way that improves patients’ financial outcomes. Our study aimed to explore and establish a causal relationship between CKD and socioeconomic status, identifying critical influencing factors. We utilized summary meta-analysis data from the CKDGen Consortium and UK Biobank. Genetic variants identified from these sources served as instrumental variables (IVs) to estimate the association between CKD and socioeconomic status. The presence or absence of CKD, estimated glomerular filtration rate (eGFR), and albuminuria were used as exposures, while income and regional deprivation were analyzed as outcomes. We employed the R packages ‘TwoSampleMR’ and ‘Mendelianrandomization’ to conduct both univariable and multivariable Mendelian randomization (MR) analyses, assessing for potential pleiotropy and heterogeneity. Our univariable MR analysis revealed a significant causal relationship between high levels of albuminuria and lower income (OR = 0.84, 95% CI: 0.73–0.96, p = 0.013), with no significant pleiotropy detected. In the multivariable MR analysis, both CKD (OR = 0.867, 95% CI: 0.786–0.957, p = 0.0045) and eGFR (OR = 0.065, 95% CI: 0.010–0.437, p = 0.0049) exhibited significant effects on income. This study underscores that higher albuminuria levels in CKD patients are associated with decreased income and emphasizes the importance of effective management and treatment of albuminuria in CKD patients to mitigate both social and personal economic burdens.

Association of education with cholelithiasis and mediating effects of cardiometabolic factors: A Mendelian randomization study.

Education, cognition, and intelligence are associated with cholelithiasis occurrence, yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationship remain unelucidated. To explore the causal associations between education, cognition, and intelligence and cholelithiasis, and the cardiometabolic risk factors that mediate the associations. Applying genome-wide association study summary statistics of primarily European individuals, we utilized two-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, and cognition on cholelithiasis and cholecystitis (FinnGen study, 37041 and 11632 patients, respectively; n = 486484 participants) and performed two-step Mendelian randomization to evaluate 21 potential mediators and their mediating effects on the relationships between each exposure and cholelithiasis. Inverse variance weighted Mendelian randomization results from the FinnGen consortium showed that genetically higher education, cognition, or intelligence were not independently associated with cholelithiasis and cholecystitis; when adjusted for cholelithiasis, higher education still presented an inverse effect on cholecystitis [odds ratio: 0.292 (95%CI: 0.171-0.501)], which could not be induced by cognition or intelligence. Five out of 21 cardiometabolic risk factors were perceived as mediators of the association between education and cholelithiasis, including body mass index (20.84%), body fat percentage (40.3%), waist circumference (44.4%), waist-to-hip ratio (32.9%), and time spent watching television (41.6%), while time spent watching television was also a mediator from cognition (20.4%) and intelligence to cholelithiasis (28.4%). All results were robust to sensitivity analyses. Education, cognition, and intelligence all play crucial roles in the development of cholelithiasis, and several cardiometabolic mediators have been identified for prevention of cholelithiasis due to defects in each exposure.

Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis

BackgroundThe relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis.MethodsInstruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction.ResultsOur univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880–1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970–1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350–1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983–1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671–1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919–1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644–1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137–1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results.ConclusionThe results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future.

Assessment of glycemic susceptibility across multiple urological and reproductive disorders

ObjectiveTo test the glycemic susceptibility in three urological cancers and eight urological/reproductive diseases using the Mendelian randomization (MR) method.Materials and methodsTwo-sample MR was applied to investigate the causal role of three glycemic traits (type II diabetes, fasting glucose and glycated hemoglobin (HbA1c)) in eleven urological/reproductive diseases (kidney cancer, bladder cancer, prostate cancer, kidney/ureter stone, urinary incontinence, benign prostatic hyperplasia, erectile dysfunction, female infertility, male infertility, abnormal spermatozoa and polycystic ovary syndrome). Further multivariate MR (MVMR) and mediating analysis were performed to investigate the associations.ResultsAmong all the 11 diseases, type II diabetes was positively associated with erectile dysfunction, which was stable across both cohorts [odds ratio (OR): 1.59, 95% confidence interval (CI): 1.15–2.20, P = 0.005 for FinnGen Biobank and OR: 1.14, 95% CI: 1.08–1.21, P < 0.001 for the other cohort]. Also, type II diabetes was negatively associated with male infertility (OR: 0.57, 95% CI: 0.39–0.84, P = 0.005). In addition, all three glycemic traits were observed to be positively associated with polycystic ovary syndrome (OR: 2.36, 95% CI: 1.16–4.76, P = 0.017 for fasting glucose per mmol/L; OR: 3.04, 95% CI: 1.10–8.39, P = 0.032 for HbA1c per percentage; and OR: 1.21, 95% CI: 1.00-1.46, P = 0.046 for type II diabetes). Mediating analysis confirmed the effect of type II diabetes on these diseases.ConclusionsThere existed glycemic susceptibility in erectile dysfunction, male infertility and polycystic ovary syndrome. We could not conclude stable glycemic susceptibility in other urological/reproductive diseases.

Causal links between serum micronutrients and epilepsy: a Mendelian randomization analysis.

Micronutrient levels play a critical role in epilepsy. This study investigates the impact of micronutrient levels on epilepsy via Mendelian randomization (MR). A two-sample MR framework evaluated the genetic association between 15 serum micronutrients and epilepsy phenotypes. The analysis included calcium, iron, zinc, selenium, copper, magnesium, potassium, folate, vitamins B6, B12, C, D, E, retinol, and carotene against all epilepsy, generalized epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized tonic-clonic seizures alone and with spike-wave electroencephalography (GTCS), and various focal epilepsy phenotypes [with hippocampal sclerosis (HS), lesions other than HS, lesion-negative]. The random-effects inverse-variance weighted (IVW) model was the primary method used, supported by heterogeneity and pleiotropy assessments. Multivariable Mendelian randomization analyses (MVMR) were used to identify micronutrients that are significantly causally associated with different epilepsy subtypes and to confirm the most potential causal risk factors for these subtypes. Zinc conferred an increased risk of focal epilepsy with HS (OR = 1.01; p = 0.045). Carotene was similarly linked to higher risks of lesion-negative cases (OR = 1.129; p = 0.037). Conversely, vitamin B6 was associated with reduced risks of focal epilepsy with HS (OR = 0.949; p = 0.020), and vitamin D was linked to decreased risks of both CAE (OR = 0.976, 95% CI: 0.959-0.993, p = 0.006) and JAE (OR = 0.986, 95% CI: 0.973-0.999, p = 0.032). These associations were robust, showing minimal heterogeneity and no evidence of pleiotropy across various sensitivity analyses. After adjustment using MVMR, significant causal relationships between vitamin D and both CAE and JAE remained. Furthermore, the causal relationship between zinc and vitamin B6 on focal epilepsy with HS became non-significant, while carotene shifted from a risk factor to a protective factor for focal epilepsy lesion-negative after adjusting for vitamin D. MR estimates provide robust evidence for the causal effects of vitamin D on reducing the risk of CAE, and JAE, which might provide alternative treatment strategies.

Elucidating the causal nexus and immune mediation between frailty and chronic kidney disease: integrative multi-omics analysis

Background Empirical research has consistently documented the concurrent manifestation of frailty and chronic kidney disease (CKD). However, the existence of a reverse causal association or the influence of confounding variables on these correlations remains ambiguous. Methods Our analysis of 7,078 participants from National Health and Nutrition Examination Survey(NHANES) (1999–2018) applied weighted logistic regression and Mendelian Randomization (MR) to investigate the correlation between the frailty index (FI) and renal function. The multivariate MR analysis was specifically adjusted for type 2 diabetes and hypertension. Further analysis explored 3282 plasma proteins to link FI to CKD. A two-step network MR highlighted immune cells’ mediating roles in the FI-CKD relationship Result Genetically inferred FI and various renal function markers are significantly correlated, as supported by NHANES analyses. Multivariate MR analysis revealed a direct causal association between the FI and CKD. Additionally, our investigation into plasma proteins identified Tmprss11D and MICB correlated with FI and CKD, respectively. A two-step network MR to reveal 15 immune cell types, notably Central Memory CD4+ T cells and Lymphocytes, as crucial mediators between FI and CKD. Conclusion Our work establishes a causal connection between frailty and CKD, mediated by specific immune cell profiles. These findings highlight the importance of immune mechanisms in the frailty-CKD interplay and suggest that targeting shared risk factors and immune pathways could improve management strategies for these conditions. Our research contributes to a more nuanced understanding of frailty and CKD, offering new avenues for intervention and patient care in an aging population.

Gut microbiota linked to hydrocephalus through inflammatory factors: a Mendelian randomization study.

The gut microbiota (GM) has been implicated in neurological disorders, but the relationship with hydrocephalus, especially the underlying mechanistic pathways, is unclear. Using Mendelian randomization (MR), we aim to discover the mediating role of inflammatory factors in the relationship between GM and hydrocephalus. After removing confounders, univariable and multivariable MR analyses were performed using summary statistics to assess the causal relationships between GM, inflammatory factors (IL-17A and IL-27), and types of hydrocephalus. Meta-analyses were used to reconcile the differences in MR results between different hydrocephalus sources. Finally, mediator MR analyses were applied to determine the mediating effect of inflammatory factors. Various sensitivity analysis methods were employed to ensure the reliability and stability of the results. After correction for P-values, Firmicutes (phylum) (OR, 0.34; 95%CI, 0.17-0.69; P = 2.71E-03, P FDR = 2.44E-02) significantly reduced the risk of obstructive hydrocephalus. The remaining 18 different taxa of GM had potential causal relationships for different types of hydrocephalus. In addition, Firmicutes (phylum) decreased the risk of obstructive hydrocephalus by increasing levels of IL-17A (mediating effect = 21.01%), while Eubacterium ruminantium group (genus) increased the risk of normal-pressure hydrocephalus by decreasing levels of IL-27 (mediating effect = 7.48%). We reveal the connection between GM, inflammatory factors (IL-17A and IL-27), and hydrocephalus, which lays the foundation for unraveling the mechanism between GM and hydrocephalus.

Birth weight and risk of cerebral aneurysm: A multivariable Mendelian randomization study

BackgroundBirth weight has been linked with various health outcomes. The association between birth weight and cerebral aneurysm remains unknown. MethodsThe two-sample Mendelian randomization (MR) approach was used to evaluate the causal effect of birth weight on cerebral aneurysm based on genome-wide association studies (GWAS), comprising 261,932 UKB participants for birth weight and 204,060 FinnGen participants for cerebral aneurysm. The inverse variance weighted (IVW) method was used as the primary method. Alternative methods were used for comparison. Sensitivity analysis was conducted to evaluate the robustness of the results. Multivariable MR (MVMR) was further conducted to evaluate the direct effect of the birth weight on cerebral aneurysm. ResultsThe IVW detected a causal association between higher birth weight and increased risk of cerebral aneurysm (OR = 0.521, 95% CI = 0.356 ∼ 0.763, P = 7.88 × 10−4), which was supported by alternative MR models. Sensitivity analysis did not find any evidence of heterogeneity or pleiotropy. MVMR further identified a direct effect of birth weight on cerebral aneurysm, independent of obesity-related traits or smoking. ConclusionThis MR study found evidence of the association between birth weight and cerebral aneurysm, providing novel insight into the etiology of cerebral aneurysm, indicating the promising role of birth weight as a marker for screening populations at higher risk of cerebral aneurysm.

Causal effects of denture wearing on epigenetic age acceleration and the mediating pathways: a mendelian randomization study

BackgroundThe epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators.MethodsUsing summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy.ResultsUnivariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93–4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15–4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58–3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05).ConclusionsOur findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

Type 2 Diabetes, Circulating Metabolites, and Calcific Aortic Valve Stenosis: A Mendelian Randomization Study.

Epidemiological studies have shown an association between type 2 diabetes (T2D) and calcific aortic valve stenosis (CAVS), but the potential causal relationship and underlying mechanisms remain unclear. Therefore, we conducted a two-sample and two-step Mendelian randomization (MR) analysis to evaluate the association of T2D with CAVS and the mediating effects of circulating metabolites and blood pressure using genome-wide association study (GWAS) summary statistics. The inverse variance weighted (IVW) method was used for the primary MR analysis, and comprehensive sensitivity analyses were performed to validate the robustness of the results. Our results showed that genetically predicted T2D was associated with increased CAVS risk (OR 1.153, 95% CI 1.096-1.214, p < 0.001), and this association persisted even after adjusting for adiposity traits in multivariable MR analysis. Furthermore, the two-step MR analysis identified 69 of 251 candidate mediators that partially mediated the effect of T2D on CAVS, including total branched-chain amino acids (proportion mediated: 23.29%), valine (17.78%), tyrosine (9.68%), systolic blood pressure (8.72%), the triglyceride group (6.07-11.99%), the fatty acid group (4.78-12.82%), and the cholesterol group (3.64-11.56%). This MR study elucidated the causal impact of T2D on CAVS risk independently of adiposity and identified potential mediators in this association pathways. Our findings shed light on the pathogenesis of CAVS and suggest additional targets for the prevention and intervention of CAVS attributed to T2D.

Association between immune cells, inflammatory cytokines, and sarcopenia: Insights from a Mendelian randomization analysis

BackgroundRecent studies have suggested a possible link between sarcopenia, immune dysregulation, and chronic inflammation, although the specific immune components implicated remain unclear. This investigation employs Mendelian Randomization (MR) to explore the reciprocal relationship between immune cells, inflammatory markers, and sarcopenia. MethodWe performed two-sample and multivariate MR analyses using publicly accessible genome-wide association studies (GWAS) summary statistics. Our analyses included 731 immune cells, 41 inflammatory cytokines, and sarcopenia related traits (appendicular lean mass [ALM], low hand-grip strength [LHS], and walking pace [WP]), with additional sensitivity analyses conducted to confirm the findings. ResultsAfter false discovery rate (FDR) correction, significant associations were found between ten immune traits and ALM, with the CD127 marker in the Treg panel showing consistent positive correlation across four sites. In contrast, NKT%lymphocyte negatively correlated with WP (OR = 0.99, P = 0.023). In terms of inflammatory cytokines, macrophage colony-stimulating factor (MCSF) (OR = 1.03, P = 0.024) and hepatocyte growth factor (HGF) (OR = 1.03, P = 0.002) demonstrated positive associations with ALM, while interleukin-16 (IL-16) (OR = 0.99, P = 0.006) was inversely related. The reverse Mendelian randomization analysis found no direct causal links between sarcopenia traits and immune or inflammatory markers. Sensitivity analyses underscored the findings' resilience to pleiotropy, and adjusting for inter-trait dynamics weakened these relationships in the multivariable MR analysis. ConclusionOur study reveals causal associations between specific immune phenotypes, inflammatory cytokines, and sarcopenia, providing insight into the development of sarcopenia and potential treatment strategies.