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 < 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 [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 < 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. CONCLUSIONS:Our 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.
journal_name
BMC Med Genomicsjournal_title
BMC medical genomicsauthors
Han S,Miller JE,Byun S,Kim D,Risacher SL,Saykin AJ,Lee Y,Nho K,for Alzheimer’s Disease Neuroimaging Initiative.doi
10.1186/s12920-018-0453-8subject
Has Abstractpub_date
2019-01-31 00:00:00pages
13issue
Suppl 1issn
1755-8794pii
10.1186/s12920-018-0453-8journal_volume
12pub_type
杂志文章abstract:BACKGROUND:Glioblastoma multiforme (GBM) tends to occur between the ages of 45 and 70. This relatively early onset and its poor prognosis make the impact of GBM on public health far greater than would be suggested by its relatively low frequency. Tissue and blood samples have now been collected for a number of populati...
journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-4-63
更新日期:2011-08-09 00:00:00
abstract:BACKGROUND:Understanding how genes are expressed specifically in particular tissues is a fundamental question in developmental biology. Many tissue-specific genes are involved in the pathogenesis of complex human diseases. However, experimental identification of tissue-specific genes is time consuming and difficult. Th...
journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-6-S1-S10
更新日期:2013-01-01 00:00:00
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journal_title:BMC medical genomics
pub_type: 社论
doi:10.1186/s12920-020-00833-7
更新日期:2020-12-28 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/s12920-018-0467-2
更新日期:2019-01-31 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/s12920-017-0282-1
更新日期:2017-07-26 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2012-06-18 00:00:00
abstract:BACKGROUND:The collection of viable DNA samples is an essential element of any genetics research programme. Biological samples for DNA purification are now routinely collected in many studies with a variety of sampling methods available. Initial observation in this study suggested a reduced genotyping success rate of s...
journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-6-20
更新日期:2013-06-10 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/s12920-020-00769-y
更新日期:2020-08-26 00:00:00
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journal_title:BMC medical genomics
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更新日期:2009-07-23 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2019-05-31 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/s12920-017-0283-0
更新日期:2017-06-19 00:00:00
abstract:BACKGROUND:Reliability of real-time PCR (RT-qPCR) data is dependent on the use of appropriate reference gene(s) for normalization. To date, no validated reference genes have been reported for normalizing gene expression in human myocardium. This study aimed to identify validated reference genes for use in gene expressi...
journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-1-64
更新日期:2008-12-29 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章,评审
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更新日期:2015-07-29 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-5-9
更新日期:2012-04-03 00:00:00
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pub_type: 杂志文章
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更新日期:2010-08-20 00:00:00
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pub_type: 杂志文章
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更新日期:2015-10-14 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-3-11
更新日期:2010-04-09 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-1-3
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journal_title:BMC medical genomics
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journal_title:BMC medical genomics
pub_type: 杂志文章
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journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2018-05-02 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
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journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2014-05-30 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2016-08-26 00:00:00
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pub_type: 杂志文章
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更新日期:2020-10-22 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2020-08-26 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2017-10-11 00:00:00