Causal Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.
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ABSTRACT: Background
There is now increasing evidence that type 2 diabetes mellitus (T2DM) is associated with Alzheimer's disease (AD). However, it is unclear whether the two are causally related.Objective
To reveal the causal association between T2DM and AD, we performed a bidirectional Mendelian randomization (MR) analysis.Methods
Genetic instrumental variables were systematically screened, and inverse-variance weighting, MR-Egger regression, weighted median, simple mode, and weighted mode were applied to assess the pathogenic associations between the two diseases, and sensitivity analyses were used to further validate the robustness of the results.Results
The results of forward MR analysis with T2DM as the exposure were [OR = 0.998, 95% CI (0.975∼1.021), p = 0.857], and the results of reverse MR analysis with AD as the exposure were [OR = 0.966, 95% CI (0.934∼0.999), p = 0.043]. The results showed no significant association between T2DM and AD at the gene level (p < 0.025). Sensitivity analyses were consistent with the results of the main analysis, confirming the robustness of the study.Conclusions
T2DM and AD may not be genetically causally associated.
SUBMITTER: Li C
PROVIDER: S-EPMC11305840 | biostudies-literature | 2024
REPOSITORIES: biostudies-literature
Publications
Causal Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.
Li Cong C Qian Haifeng H Feng Lina L Li Mingquan M
Journal of Alzheimer's disease reports 20240618 1
<h4>Background</h4>There is now increasing evidence that type 2 diabetes mellitus (T2DM) is associated with Alzheimer's disease (AD). However, it is unclear whether the two are causally related.<h4>Objective</h4>To reveal the causal association between T2DM and AD, we performed a bidirectional Mendelian randomization (MR) analysis.<h4>Methods</h4>Genetic instrumental variables were systematically screened, and inverse-variance weighting, MR-Egger regression, weighted median, simple mode, and wei ...[more]
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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.
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Project description:BackgroundGestational diabetes mellitus (GDM) constitutes a significant contributor to maternal and fetal morbidity, which is observed to be associated with future risks of offspring health. Nevertheless, it is essential to acknowledge that observational findings may be susceptible to residual confounding and bias.MethodsTo investigate the association of GDM with offspring health, a genome-wide genetic association study employing Mendelian Randomization (MR) is conducted between May 31 and November 30, 2023. The inverse-variance-weighted (IVW) is utilized in the primary analysis stage. The study data of the majority patients are European ancestry, which are sourced from the IEU open genome-wide association study project.ResultsGenetically predicted GDM is associated with an increased risk of various short- and long-term health problem in offspring. For fetal and neonatal conditions, GDM is linked to an elevated risk of preterm delivery [ odd ratio (OR) = 1.150, false discovery rate (FDR)-adjusted PIVW = 0.009] and placental disorders (OR = 2.143, FDR-adjusted PIVW = 0.028). In respiratory diseases, it is associated with a higher likelihood of influenza (OR = 1.175, FDR-adjusted PIVW = 0.008), bacterial pneumonia (OR = 1.141, FDR-adjusted PIVW = 0.008), congenital malformations of the respiratory system (OR = 1.673, FDR-adjusted PIVW = 0.033), influenza with pneumonia (OR = 1.078, FDR-adjusted PIVW = 0.008), and need for non-invasive ventilation (OR = 1.265, FDR-adjusted PIVW = 0.028). In terms of neurodevelopmental and psychiatric outcomes, GDM is linked to a higher risk of cerebral palsy (OR = 1.721, FDR-adjusted PIVW = 0.008). For urinary conditions, GDM increases the risk of acute tubulo-interstitial nephritis (OR = 1.098, FDR-adjusted PIVW = 0.008). No association is identified between genetically predicted GDM and major digestive diseases, such as gastroesophageal reflux, or cardiovascular conditions in offspring.ConclusionsThe findings of this study provide genetic evidence supporting an association between GDM and higher risk of offspring diseases. This supports classification of GDM as risk factors for short- and long-term offspring health.
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