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Alzheimer disease (AD) specific transcription, DNA methylation and splicing in twenty AD associated loci.

ABSTRACT: Genome-wide association studies have identified twenty loci associated with late-onset Alzheimer disease (LOAD). We examined each of the twenty loci, specifically the ±50kb region surrounding the most strongly associated variant, for changes in gene(s) transcription specific to LOAD. Post-mortem human brain samples were examined for expression, methylation, and splicing differences. LOAD specific differences were detected by comparing LOAD to normal and "disease" controls. Eight loci, prominently ABCA7, contain LOAD specific differences. Significant changes in the CELF1 and ZCWPW1 loci occurred in genes not located nearest the associated variant, suggesting that these genes should be investigated further as LOAD candidates.

SUBMITTER: Humphries C

PROVIDER: S-EPMC4540636 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Alzheimer disease (AD) specific transcription, DNA methylation and splicing in twenty AD associated loci.

Humphries Crystal C Kohli Martin A MA Whitehead Patrice P Mash Deborah C DC Pericak-Vance Margaret A MA Gilbert John J

Molecular and cellular neurosciences 20150521

Genome-wide association studies have identified twenty loci associated with late-onset Alzheimer disease (LOAD). We examined each of the twenty loci, specifically the ±50kb region surrounding the most strongly associated variant, for changes in gene(s) transcription specific to LOAD. Post-mortem human brain samples were examined for expression, methylation, and splicing differences. LOAD specific differences were detected by comparing LOAD to normal and "disease" controls. Eight loci, prominentl ...[more]

PMID: 26004081

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Project description:PurposeAlzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is heterogeneity in features across brain regions between AD patients, leading to different severity and progression rates; however, brain region-specific AS mechanisms still remain unclear. Therefore, we aimed to systemically investigate AS in multiple brain regions of AD patients and how they affect clinical features.MethodsWe analyzed RNA sequencing (RNA-Seq) data obtained from brain regions (frontal and temporal) of AD patients. Reads were mapped to the hg19 reference genome using the STAR aligner, and exon skipping (ES) rates were estimated as percent spliced in (PSI) by rMATs. We focused on AD-risk genes discovered by genome-wide association studies, and accordingly evaluated associations between PSI of skipped exons in AD-risk genes and Braak stage and plaque density mean (PM) for each brain region. We also integrated whole-genome sequencing data of the ascertained samples with RNA-Seq data to identify genetic regulators of feature-associated ES.ResultsWe identified 26 and 41 ES associated with Braak stage in frontal and temporal regions, respectively, and 10 and 50 ES associated with PM. Among those, 10 were frontal-specific (CLU and NTRK2), 65 temporal-specific (HIF1A and TRPC4AP), and 26 shared ES (APP) that accompanied functional Gene Ontology terms, including axonogenesis in shared-ES genes. We further identified genetic regulators that account for 44 ES (44% of the total). Finally, we present as a case study the systematic regulation of an ES in APP, which is important in AD pathogenesis.ConclusionThis study provides new insights into brain region-dependent AS regulation of the architecture of AD-risk genes that contributes to AD pathologies, ultimately allowing identification of a treatment target and region-specific biomarkers for AD.

Dataset Information

Alzheimer disease (AD) specific transcription, DNA methylation and splicing in twenty AD associated loci.

Publications

Alzheimer disease (AD) specific transcription, DNA methylation and splicing in twenty AD associated loci.

Similar Datasets

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