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Genetics of late-onset Alzheimer's disease: update from the alzgene database and analysis of shared pathways.

ABSTRACT: The genetics of late-onset Alzheimer's disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. This review focused on such genes and analyzed shared biological pathways. Genetic markers were selected from a web-based collection (Alzgene). For each SNP in the database, it was possible to perform a meta-analysis. The quality of studies was assessed using criteria such as size of research samples, heterogeneity across studies, and protection from publication bias. This produced a list of 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. A systematic analysis of gene ontology terms associated with each marker showed that most genes were implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles. Moreover, the impact of these genes on complement cascade and cytokine production highlights the role of inflammatory response in AD pathogenesis. Gene-gene and gene-environment interactions are prominent issues in AD genetics, but they are not specifically featured in the Alzgene database.

SUBMITTER: Olgiati P

PROVIDER: S-EPMC3235576 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Genetics of late-onset Alzheimer's disease: update from the alzgene database and analysis of shared pathways.

Olgiati Paolo P Politis Antonis M AM Papadimitriou George N GN De Ronchi Diana D Serretti Alessandro A

International journal of Alzheimer's disease 20111210

The genetics of late-onset Alzheimer's disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. This review focused on such genes and analyzed shared biological pathways. Genetic markers were selected from a web-based collection (Alzgene). For each SNP in the database, it was possible to perform a meta-analysis. The quality of s ...[more]

PMID: 22191060

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Project description:Late-onset Alzheimer's disease (AD) is associated with sleep-related phenotypes (SRPs). The fact that whether they share a common genetic etiology remains largely unknown. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross-phenotype association study (CPASSOC), transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD (N = 455,258) and summary-level data for seven SRPs (sample size ranges from 359,916 to 1,331,010). AD shared a strong genetic basis with insomnia (r g = 0.20; p = 9.70 × 10-5), snoring (r g = 0.13; p = 2.45 × 10-3), and sleep duration (r g = -0.11; p = 1.18 × 10-3). The CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. Functional analysis and the TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues and highlighted the regulatory roles of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance, and positive regulation of T-cell-mediated cytotoxicity pathways. Protein-protein interaction analysis identified three potential drug target genes (APOE, MARK4, and HLA-DRA) that interacted with known FDA-approved drug target genes. The CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3, and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. MR showed insomnia had a causal effect on AD (ORIVW = 1.02, P IVW = 6.7 × 10-6), and multivariate MR suggested a potential role of sleep duration and major depression in this association. Our findings provide strong evidence of shared genetics and causation between AD and sleep abnormalities and advance our understanding of the genetic overlap between them. Identifying shared drug targets and molecular pathways can be beneficial for treating AD and sleep disorders more efficiently.

Dataset Information

Genetics of late-onset Alzheimer's disease: update from the alzgene database and analysis of shared pathways.

Publications

Genetics of late-onset Alzheimer's disease: update from the alzgene database and analysis of shared pathways.

Similar Datasets

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