Cortical structure and the risk for Alzheimer's disease: a bidirectional Mendelian randomization study.
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ABSTRACT:
SUBMITTER: Wu BS
PROVIDER: S-EPMC8443658 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alzheimer'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. We 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. The 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. Our 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.
| S-EPMC11337634 | biostudies-literature
Project description:Increased expression of CD33 in the brain has been suggested to be associated with increased amyloid plaque burden, while the peripheral level of CD33 in Alzheimer's disease (AD) patients and its role in AD remain unclear. The current study aimed to systematically explore the bidirectional relationship between peripheral CD33 and AD. Genome-wide association study (GWAS) datasets of AD (Ncases: 21982; Ncontrols: 41944), blood CD33 mRNA level, the plasma CD33 protein level, and CD33 expression on immune-cell subtypes were obtained from GWASs conducted in the European population. Eligible IVs were extracted from the GWASs. MR estimates were calculated by inverse-variance weighting (IVW) and other sensitivity analyses. The main statistical analyses were conducted using TwoSampleMR (v.0.5.5) in R package (V.4.1.2).In the forward MR analysis (CD33 as exposure and AD as outcome), the IVW results indicated that elevated blood CD33 mRNA level (OR [95% CI] = 1.156[1.080, 1.238], p = 3.25e-05), elevated serum CD33 protein level (OR [95% CI] = 1.08 [1.031, 1.139], p = 1.6e-03) and increased CD33's expression on immune cell subtypes (p < 0.05) were all leading to a higher risk of AD. And sensitivity analyses supported these findings. While the reverse MR analysis (AD as exposure and CD33 as outcome) indicated that AD was not leading to the elevation of CD33's protein level in the blood (p > 0.05). In conclusion, our results indicated that elevated peripheral expression of CD33 was causal to the development of AD. Future studies are needed to work on developing CD33 as a biomarker and therapeutic target in AD.
| S-EPMC9529877 | biostudies-literature
Project description:Background: Traditional observational studies have demonstrated an association between heart failure and Alzheimer's disease. The strengths of observational studies lie in their speed of implementation, cost, and applicability to rare diseases. However, observational studies have several limitations, such as uncontrollable confounders. Therefore, we employed Mendelian randomization of genetic variants to evaluate the causal relationships existing between AD and HF, which can avoid these limitations. Materials and Methods: A two-sample bidirectional MR analysis was employed. All datasets were results from the UK's Medical Research Council Integrative Epidemiology Unit genome-wide association study database, and we conducted a series of control steps to select the most suitable single-nucleotide polymorphisms for MR analysis, for which five primary methods are offered. We reversed the functions of exposure and outcomes to explore the causal direction of HF and AD. Sensitivity analysis was used to conduct several tests to avoid heterogeneity and pleiotropic bias in the MR results. Results: Our MR studies did not support a meaningful causal relationship between AD on HF (MR-Egger, p = 0.634 > 0.05; weighted median (WM), p = 0.337 > 0.05; inverse variance weighted (IVW), p = 0.471 > 0.05; simple mode, p = 0.454 > 0.05; weighted mode, p = 0.401 > 0.05). At the same time, we did not find a significant causal relationship between HF and AD with four of the methods (MR-Egger, p = 0.195 > 0.05; IVW, p = 0.0879 > 0.05; simple mode, p = 0.170 > 0.05; weighted mode, p = 0.110 > 0.05), but the WM method indicated a significant effect of HF on AD (p = 0.025 < 0.05). Because the statistical powers of IVW and MR-Egger are more than that of WM, we think that there is no causal effect of HF on AD. Sensitivity analysis and horizontal pleiotropy were not detected in the MR analysis. Conclusion: Our results did not provide significant evidence indicating any causal relationships between HF and AD in the European population. Therefore, more large-scale datasets or datasets related to similar factors are expected for further MR analysis.
| S-EPMC8787319 | biostudies-literature
Project description:Recent experimental studies indicated that a periodontitis-causing bacterium might be a causal factor for Alzheimer's disease (AD). We applied a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD bidirectionally in the population of European ancestry. We used publicly available data of genome-wide association studies (GWAS) on periodontitis and AD. Five single-nucleotide polymorphisms (SNPs) were used as instrumental variables for periodontitis. For the MR analysis of periodontitis on risk of AD, the causal odds ratio (OR) and 95% confidence interval (CI) were derived from the GWAS of periodontitis (4,924 cases vs. 7,301 controls) and from the GWAS of AD (21,982 cases vs. 41,944 controls). Seven non-overlapping SNPs from another latest GWAS of periodontitis was used to validate the above association. Twenty SNPs were used as instrumental variables for AD. For the MR analysis of liability to AD on risk of periodontitis, the causal OR was derived from the GWAS of AD including 30,344 cases and 52,427 controls and from the GWAS of periodontitis consisted of 12,289 cases and 22,326 controls. We employed multiple methods of MR. Using the five SNPs as instruments of periodontitis, there was suggestive evidence of genetically predicted periodontitis being associated with a higher risk of AD (OR 1.10, 95% CI 1.02 to 1.19, P = 0.02). However, this association was not verified using the seven independent SNPs (OR 0.97, 95% CI 0.87 to 1.08, P = 0.59). There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00, 95% CI 0.96 to 1.04, P = 0.85). In summary, we did not find convincing evidence to support periodontitis being a causal factor for the development of AD. There was also limited evidence to suggest genetic liability to AD being associated with the risk of periodontitis.
| S-EPMC6980529 | biostudies-literature
Project description:BackgroundPrevious observational researchers have found an inverse bidirectional link between Alzheimer's disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted.MethodsThis study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran's Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results.ResultsThe causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables.ConclusionThe results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD.
| S-EPMC10965771 | biostudies-literature
Project description:ObjectivePrevious observational studies have suggested that antioxidant imbalance is correlated with neurodegenerative diseases, while its cause-effect remains unclear. Thus, the goal of the present study is to explore the causal relationship between 11 antioxidant biomarkers and 3 most common neurodegenerative diseases [Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD)].MethodsA bidirectional Mendelian randomization (MR) study was performed to investigate the causal effects by using 3 main methods (Variance Weighted (IVW), Weighted Median (WM), and MR-Egger regression) in the European population. The data of 11 antioxidant biomarkers were obtained from the open database by the most up-to-date Genome-Wide Association Studies (GWAS), the summary statistics of PD and ALS were obtained from the International Parkinson's Disease Genomics Consortium (IPDGC) (33,674 cases, and 449,056 controls), and the International Amyotrophic Lateral Sclerosis Genomics Consortium (IALSC) (20,806 cases and 59,804 controls), respectively. For AD, we specifically used two recently published GWAS data, one from the International Genomics of Alzheimer's Project (IGAP) (21,982 cases and 41,944 controls), and the other from a large meta-analysis (71,880 cases and 383,378 controls) as validation data.ResultsBased on the Bonferroni correction p < 0.0015, there was no significant causal evidence for the antioxidant biomarkers on neurodegenerative diseases, however, the reverse analysis found that AD was significantly related to the decrease in retinol (IVW: beta = -0.023, p = 0.0007; WM: beta = -0.025, p = 0.0121), while the same analysis was carried out between the AD validation database and retinol, the results were consistent (IVW: beta = -0.064, p = 0.025). Moreover, AD on Glutathione S-transferase (GST), PD on Glutathione Peroxidase (GPX) as well as PD on uric acid (UA) also indicated potential causal-and-effect associations (IVW: p = 0.025; p = 0.027; p = 0.021, respectively).ConclusionsThere was no sufficient evidence that antioxidant imbalance has a significant causal effect on neurodegenerative diseases. However, this study revealed that genetically predicted AD was significantly related to the decrease in retinol, which provides a new insight into previous research and indicates the possibility to regard retinol as potential biomarker for the diagnosis and progress of AD.
| S-EPMC10076659 | biostudies-literature
Project description:IntroductionAlthough the relationship between psychiatric disorders and Parkinson's disease (PD) has attracted continuous research attention, the causal linkage between them has not reached a definite conclusion.MethodsTo identify the causal relationship between psychiatric disorders and PD, we used public summary-level data from the most recent and largest genome-wide association studies (GWASs) on psychiatric disorders and PD to conduct a bidirectional two-sample Mendelian randomization (MR). We applied stringent control steps in instrumental variable selection using the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) method to rule out pleiotropy. The inverse-variance weighted (IVW) method was used to identify the causal relationship between psychiatric disorders and PD. Multiple MR analysis methods, including MR-Egger, weighted-median, and leave-one-out analyses, were used for sensitivity analysis, followed by heterogeneity tests. Further validation and reverse MR analyses were conducted to strengthen the results of the forward MR analysis.ResultsThe lack of sufficient estimation results could suggest a causal relationship between psychiatric disorders and PD in the forward MR analysis. However, the subsequent reverse MR analysis detected a causal relationship between PD and bipolar disorder (IVW: odds ratios [OR] =1.053, 95% confidence interval [CI] =1.02-1.09, p = 0.001). Further analysis demonstrated a causal relationship between genetically predicted PD and the risk of bipolar disorder subtype. No pleiotropy or heterogeneity was detected in the analyses.DiscussionOur study suggested that while psychiatric disorders and traits might play various roles in the risk of developing PD, PD might also be involved in the risk of developing psychiatric disorders.
| S-EPMC10045982 | biostudies-literature
Project description:BackgroundThe frequent coexistence of Graves' disease (GD) and rheumatoid arthritis (RA) has been cited and discussed in observational studies, but it remains a question as to whether there is a causal effect between the two diseases.MethodsWe retrieved genome-wide association study (GWAS) summary data of GD and RA from BioBank Japan (BBJ). Single nucleotide polymorphisms (SNPs) associated with diseases of interest were selected as instrumental variables (IVs) at a genome-wide significance level (P < 5.0 × 10-8). The random-effects inverse variance weighted method (IVW) was used to combine the causal effect of IVs. The horizontal pleiotropy effect was analyzed by MR-Egger and weighted median method sensitivity test. A leave-one-out analysis was conducted to avoid bias caused by a single SNP. The statistical power of our MR result was calculated according to Brion's method.ResultsOur study discovered a bidirectional causal effect between GD and RA. The presence of RA may increase the risk of GD by 39% (OR 1.39, 95% CI 1.10-1.75, P = 0.007). Similarly, the existence of GD may increase the risk of RA by 30% (OR 1.30, 95% CI 0.94-1.80, P = 0.112). Our study provides 100% power to detect the causal effect of RA on GD risk, and vice versa.ConclusionsWe found a bidirectional causal effect between GD and RA in an Asian population. Our study supported the clinical need for screening GD in RA patients, and vice versa. The potential benefit of sound management of RA in GD patients (or GD in RA patients) merits excellent attention. Moreover, novel satisfactory medicine for RA may be applicable to GD and such potential is worthy of further investigation.
| S-EPMC8416061 | biostudies-literature
Project description:PurposeObservational studies have suggested that polyunsaturated fatty acids (PUFAs) may decrease Alzheimer's disease (AD) risk. In the present study, we examined this hypothesis using a Mendelian randomization analysis.MethodsWe used summary statistics data for single-nucleotide polymorphisms associated with plasma levels of n-6 PUFAs (linoleic acid, arachidonic acid) and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid), and the corresponding data for AD from a genome-wide association meta-analysis of 63,926 individuals (21,982 diagnosed AD cases, 41,944 controls).ResultsNone of the genetically predicted PUFAs was significantly associated with AD risk; odds ratios (95% confidence interval) per 1 SD increase in PUFA levels were 0.98 (0.93, 1.03) for linoleic acid, 1.01 (0.98, 1.05) for arachidonic acid, 0.96 (0.88, 1.06) for alpha-linolenic acid, 1.03 (0.93, 1.13) for eicosapentaenoic acid, 1.03 (0.97, 1.09) for docosapentaenoic acid, and 1.01 (0.81, 1.25) for docosahexaenoic acid.ConclusionsThis study did not support the hypothesis that PUFAs decrease AD risk.
| S-EPMC7230050 | biostudies-literature
Project description:BACKGROUND:Alzheimer's disease (AD) and Parkinson's disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the ?-synuclein have a key role in AD. Although many clinical and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether ?-synuclein in PD genetically alters AD risk. RESULTS:We did not obtain any significant result (OR?=?0.918, 95% CI: 0.782-1.076, P?=?0.291) in MR analysis between PD and AD risk. In MR between ?-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR?=?0.638, 95% CI: 0.485-0.838, P?=?1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results. CONCLUSION:The overall PD genetic risk factors did not predict AD risk, but the ?-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases.
| S-EPMC6311900 | biostudies-literature