Dataset Information

The bidirectional relationship between Alzheimer's disease (AD) and epilepsy: A Mendelian randomization study.

ABSTRACT:

Background

There is a complex, bidirectional relationship between Alzheimer's disease (AD) and epilepsy. However, the causality of this association is unclear, as confounders play a role in this association.

Methods

We conducted a Mendelian randomization (MR) study to clarify the causal relationship and direction of epilepsy on AD risk. We used publicly available summary statistics to obtain all genetic datasets for the MR analyses. AD and AD-by-proxy and late-onset AD (LOAD) cohorts were included in our study. The epilepsy cohort comprised all epilepsy, generalized epilepsy, focal epilepsy, and its subtypes, as well as some epilepsy syndromes. Next, we conducted validation using another AD cohort.

Results

Two correlations between AD and epilepsy using the inverse variance-weighted (IVW) method are as follows: LOAD and focal epilepsy (OR_IVW = 1.079, p_IVW = .013), focal epilepsy-documented hippocampal sclerosis (HS) and AD (OR_IVW = 1.152, p_IVW = .017). The causal relationship between epilepsy-documented HS and AD has been validated (OR_IVW = 3.994, p_IVW = .027).

Conclusions

Our MR study provides evidence for a causal relationship between focal epilepsy-documented HS and AD.

SUBMITTER: Xu L

PROVIDER: S-EPMC10636418 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

The bidirectional relationship between Alzheimer's disease (AD) and epilepsy: A Mendelian randomization study.

Xu Lianping L Wang Qun Q

Brain and behavior 20230904 11

<h4>Background</h4>There is a complex, bidirectional relationship between Alzheimer's disease (AD) and epilepsy. However, the causality of this association is unclear, as confounders play a role in this association.<h4>Methods</h4>We conducted a Mendelian randomization (MR) study to clarify the causal relationship and direction of epilepsy on AD risk. We used publicly available summary statistics to obtain all genetic datasets for the MR analyses. AD and AD-by-proxy and late-onset AD (LOAD) coho ...[more]

PMID: 37666799

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Project description:BackgroundAlzheimer's disease (AD) manifests with a higher rate of occurrence in women. Previous epidemiological studies have suggested a potential association between AD and gynecological cancers, but the causal relationship between them remains unclear. This study aims to explore the causal link between 12 types of gynecological cancers and AD using a bidirectional Mendelian randomization (MR) approach.MethodsWe obtained genetic correlation tools for AD using data from the most extensive genome-wide association study. Genetic correlation data for 12 types of gynecological cancers were also sourced from the Finnish Biobank. These cancers include breast cancer (BC), cervical adenocarcinoma (CA), cervical squamous cell carcinoma (CSCC), cervical cancer (CC), endometrial cancer (EC), ovarian endometrioid carcinoma (OEC), ovarian cancer (OC), ovarian serous carcinoma (OSC), breast carcinoma in situ (BCIS), cervical carcinoma in situ (CCIS), endometrial carcinoma in situ (ECIS), and vulvar carcinoma in situ (VCIS). We used the inverse-variance weighted (IVW) model for causal analysis and conducted horizontal pleiotropy tests, heterogeneity tests, MR-PRESSO tests, and leave-one-out analyses to ensure the robustness of our results. We also applied replication analysis and meta-analysis to further validate our experimental results.ResultsThe study found that EC (P_IVW =0.037, OR [95% CI] = 1.032 [1.002, 1.064]) and CCIS (P_IVW = 0.046, OR [95% CI] = 1.032 [1.011, 1.064]) increase the risk of AD, whereas OC was negatively correlated with AD (P_IVW = 0.016, OR [95% CI] = 0.974[0.954, 0.995]). In reverse MR analysis, AD increased the risk of CC (P_IVW = 0.039, OR [95% CI] = 1.395 [1.017, 1.914]) and VCIS (P_IVW = 0.041, OR [95% CI] = 1.761 [1.027, 2.021]), but was negatively correlated with OEC (P_IVW = 0.034, OR [95% CI] = 0.634 [0.417, 0.966]). Sensitivity analysis results demonstrated robustness. These findings were further substantiated through replication and meta-analyses.ConclusionsOur MR study supports a causal relationship between AD and gynecological cancers. This encourages further research into the incidence of gynecological cancers in female Alzheimer's patients and the active prevention of AD.

Project description:BackgroundIschemic Heart Disease (IHD) is a leading cause of morbidity and mortality worldwide. Hypercholesterolaemia, a metabolic syndrome distinguished by elevated cholesterol levels, is positively correlated with IHD, yet the precise causal relationship between these two health conditions remains to be clearly defined.MethodsWe conducted a two-sample MR analysis using genetic variants associated with hypercholesterolemia and IHD. Various statistical techniques including MR-Egger, Weighted Median, Inverse Variance Weighted (IVW), Simple Mode, and Weighted Mode were employed. We also performed sensitivity analyses to assess pleiotropy, heterogeneity, and influence of individual SNPs. Furthermore, genetic co-localization analysis was performed to identify shared genes between hypercholesterolemia and IHD.ResultsOur MR study illuminated a bidirectional causal relationship between hypercholesterolaemia and ischaemic heart disease. Utilising the IVW with multiplicative random effects, upon considering IHD as the outcome, we identified an OR of 2.27 (95% CI: 1.91-2.70, p = 1.68 × 10-20). Conversely, when hypercholesterolaemia was viewed as the outcome, the OR detected was 1.80 (95% CI: 1.58-2.05, p = 2.79 × 10-19). These findings remained consistent across various MR methods and sensitivity analyses. Additionally, our research pinpointed four co-localised genes CELSR2, PCSK9, LPA, and APOE as integral candidates implicated in the pathogenesis of both conditions, thereby suggesting shared common genetic causal variants and offering potential targets for innovative therapeutic strategies.Conclusionbidirectional MR studies reveal genetic evidence of a potential causal link between hypercholesterolaemia and IHD. Notably, these findings also lend credence to the less traditional hypothesis that IHD may instigate hypercholesterolaemia episodes. Moreover, co-localisation analyses intimate the presence of shared genetic causal variants, paving the way for the development of new therapeutic strategies.

Project description:IntroductionObservational studies have indicated widespread comorbidity of white matter (WM) lesions and Alzheimer's disease (AD) in the elderly, but the causality and direction of their relationship remained unclear. Our study aims to examine the bidirectional causal relationship between WM change and AD using a genetically informed method.MethodsWe performed a bidirectional two-sample mendelian randomization (MR) study to investigate the correlation of three WM phenotypes-white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467)-with AD (N = 63,926) using summary statistics from genome-wide association studies (GWAS). The inverse variance weighted method (IVW) was used to evaluate the causal estimate and alternative methods to test the heterogeneity, horizontal pleiotropy, and outliers.ResultsThere was no significant causal evidence of WM MRI markers on AD across all MR methods. We identified significant evidence of causal effects of AD on the risk of WMH (OR 1.06, 95% CI 1.03-1.10, p < 0.01). The same direction of effects was observed in MR-Egger, weighted median, and weighted mode analysis. Besides, we also observed a risk causal relationship between AD with MD in MR-Egger, weighted median, and weighted mode-based methods (MR-Egger OR 1.38, 95% CI 1.07-1.79, p = 0.02; weighted median OR 1.21, 95% CI 1.02-1.45, p = 0.03; weighted mode-based OR 1.32, 95% CI 1.14-1.53, p < 0.01). However, the general significance of the causal effect of AD on WMH and MD disappeared when we removed the single nucleotide polymorphisms (SNPs) near the APOE regions, revealing that the ability of AD to increase the risk of white matter damage might be mediated by APOE to some extent. Unfortunately, we did not observe significant causal evidence of AD on FA across all MR analyses.ConclusionsIn this bidirectional MR study, we did not observe that WM injuries were associated with a higher risk of AD. Likewise, genetically predicted AD did not result in a causal effect on white matter damage. However, our research revealed that underlying mechanisms linking AD and white matter lesions might be related to the SNPs near APOE regions.

Dataset Information

The bidirectional relationship between Alzheimer's disease (AD) and epilepsy: A Mendelian randomization study.

Background

Methods

Results

Conclusions

Publications

The bidirectional relationship between Alzheimer's disease (AD) and epilepsy: A Mendelian randomization study.

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