| Autor: |
Seonggyun Han, Jason E. Miller, Seyoun Byun, Dokyoon Kim, Shannon L. Risacher, Andrew J. Saykin, Younghee Lee, Kwangsik Nho, for Alzheimer’s Disease Neuroimaging Initiative |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
BMC Medical Genomics, Vol 12, Iss S1, Pp 51-61 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
1755-8794 |
| DOI: |
10.1186/s12920-018-0453-8 |
| Popis: |
Abstract Background At 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). Methods We 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 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 [18F] Florbetapir position emission tomography (PET) scan as an AD-related quantitative phenotype. A whole-brain voxel-based analysis was also performed. Results Two 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 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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