ArticleBMC medical genomics2019
Identification of exon skipping events associated with Alzheimer's disease in the human hippocampus.
Article in BMC medical genomics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 36 citations in OpenAlex.
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- Integrating amyloid and tau imaging with proteomics and genomics in Alzheimer's disease.Cell reports. Medicine · 2024Review
- Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases.Brain sciences · 2023Review
- Alternative splicing in neurodegenerative disease and the promise of RNA therapies.Nature reviews. Neuroscience · 2023Review
- Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD.International neurourology journal · 2022Article
- Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 ofInternational journal of molecular sciences · 2021Article
- RNA Dynamics in Alzheimer's Disease.Molecules (Basel, Switzerland) · 2021Review
- SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.Molecular neurodegeneration · 2021Article
- Alternative splicing in Alzheimer's disease.Aging clinical and experimental research · 2021Review
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- Transcriptomics in Alzheimer's Disease: Aspects and Challenges.International journal of molecular sciences · 2020Review
- ExonSkipDB: functional annotation of exon skipping event in human.Nucleic acids research · 2020Article
- Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors.BMC medical genomics · 2019Article
- The International Conference on Intelligent Biology and Medicine (ICIBM) 2018: genomics meets medicine.BMC medical genomics · 2019Article
- mRNA isoform balance in neuronal development and disease.Wiley interdisciplinary reviews. RNAReview
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundAt least 90% of human genes are alternatively spliced. Alternative splicing has an important function regulating gene expression and miss-splicing can contribute to risk for human diseases, including Alzheimer's disease (AD).
methodsWe developed a splicing decision model as a molecular mechanism to identify functional exon skipping events and genetic variation affecting alternative splicing on a genome-wide scale by integrating genomics, transcriptomics, and neuroimaging data in a systems biology approach. In this study, we analyzed RNA-Seq data of hippocampus brain tissue from Alzheimer's disease (AD; n = 24) and cognitively normal elderly controls (CN; n = 50) and identified three exon skipping events in two genes (RELN and NOS1) as significantly associated with AD (corrected p-value < 0.05 and fold change > 1.5). Next, we identified single-nucleotide polymorphisms (SNPs) affecting exon skipping events using the splicing decision model and then performed an association analysis of SNPs potentially affecting three exon skipping events with a global cortical measure of amyloid-β deposition measured by [
resultsTwo exons in RELN and one exon in NOS1 showed significantly lower expression levels in the AD participants compared to CN participants, suggesting that the exons tend to be skipped more in AD. We also showed the loss of the core protein structure due to the skipped exons using the protein 3D structure analysis. The targeted SNP-based association analysis identified one intronic SNP (rs362771) adjacent to the skipped exon 24 in RELN as significantly associated with cortical amyloid-β levels (corrected p-value < 0.05). This SNP is within the splicing regulatory element, i.e., intronic splicing enhancer. The minor allele of rs362771 conferred decreases in cortical amyloid-β levels in the right temporal and bilateral parietal lobes.
conclusionsOur results suggest that exon skipping events and splicing-affecting SNPs in the human hippocampus may contribute to AD pathogenesis. Integration of multiple omics and neuroimaging data provides insights into possible mechanisms underlying AD pathophysiology through exon skipping and may help identify novel therapeutic targets.
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