Dataset Information

Shared Causal Paths underlying Alzheimer's dementia and Type 2 Diabetes.

ABSTRACT: Although Alzheimer's disease (AD) is a central nervous system disease and type 2 diabetes MELLITUS (T2DM) is a metabolic disorder, an increasing number of genetic epidemiological studies show clear link between AD and T2DM. The current approach to uncovering the shared pathways between AD and T2DM involves association analysis; however such analyses lack power to discover the mechanisms of the diseases. As an alternative, we developed novel causal inference methods for genetic studies of AD and T2DM and pipelines for systematic multi-omic casual analysis to infer multilevel omics causal networks for the discovery of common paths from genetic variants to AD and T2DM. The proposed pipelines were applied to 448 individuals from the ROSMAP Project. We identified 13 shared causal genes, 16 shared causal pathways between AD and T2DM, and 754 gene expression and 101 gene methylation nodes that were connected to both AD and T2DM in multi-omics causal networks.

SUBMITTER: Hu Z

PROVIDER: S-EPMC7058072 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Shared Causal Paths underlying Alzheimer's dementia and Type 2 Diabetes.

Hu Zixin Z Jiao Rong R Wang Panpan P Zhu Yun Y Zhao Jinying J De Jager Phil P Bennett David A DA Jin Li L Xiong Momiao M

Scientific reports 20200305 1

Although Alzheimer's disease (AD) is a central nervous system disease and type 2 diabetes MELLITUS (T2DM) is a metabolic disorder, an increasing number of genetic epidemiological studies show clear link between AD and T2DM. The current approach to uncovering the shared pathways between AD and T2DM involves association analysis; however such analyses lack power to discover the mechanisms of the diseases. As an alternative, we developed novel causal inference methods for genetic studies of AD and ...[more]

PMID: 32139775

Similar Datasets

Project description:Epidemiological evidence supports the observation that subjects with type 2 diabetes (T2D) are at higher risk to develop Alzheimer's disease (AD). However, whether and how these two conditions are causally linked is unknown. Possible mechanisms include shared genetic risk factors, which were investigated in this study based on recent genome wide association study (GWAS) findings. In order to achieve our goal, we retrieved single nucleotide polymorphisms (SNPs) associated with T2D and AD from large-scale GWAS meta-analysis consortia and tested for overlap among the T2D- and AD-associated SNPs at various p-value thresholds. We then explored the function of the shared T2D/AD GWAS SNPs by leveraging expressional quantitative trait loci, pathways, gene ontology data, and co-expression networks. We found 927 SNPs associated with both AD and T2D with p-value??0.01, an overlap significantly larger than random chance (overlapping p-value?of?6.93E-28). Among these, 395 of the shared GWAS SNPs have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D. Genes influenced by shared T2D/AD SNPs with the same risk allele were first identified using a SNP annotation variation (ANNOVAR) software, followed by using Association Protein-Protein Link Evaluator (DAPPLE) software to identify additional proteins that are known to physically interact with the ANNOVAR gene annotations. We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis. Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we found that 532 of the shared T2D/AD GWAS SNPs had divergent risk alleles in the two diseases. For individual shared T2D/AD SNPs with divergent alleles, one of the allelic forms may contribute to one of the diseases (e.g., T2D), but not necessarily to the other (e.g., AD), or vice versa. Collectively, our GWAS studies tentatively support the epidemiological observation of disease concordance between T2D and AD. Moreover, the studies provide the much needed information for the design of future novel therapeutic approaches, for a subpopulation of T2D subjects with genetic disposition to AD, that could benefit T2D and reduce the risk for subsequent development of AD.

Dataset Information

Shared Causal Paths underlying Alzheimer's dementia and Type 2 Diabetes.

Publications

Shared Causal Paths underlying Alzheimer's dementia and Type 2 Diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure