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| Status |
Public on Jan 31, 2019 |
| Title |
Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
Late-onset Alzheimer’s disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identiied 858 sites with robust diferential methylation collectively annotated to 772 possible genes (FDR < 5%, within 10 kb). These sites were overrepresented in AD genetic risk loci (p = 0.00655) and were enriched for changes during normal aging (p < 2.2 × 10−16), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR < 5%). To functionally validate these associations, we generated and analyzed corresponding transcriptome data to prioritize 130 genes within 10 kb of the diferentially methylated sites. These 130 genes were diferentially expressed between AD cases and controls and their expression was associated with nearby DNAm (p < 0.05). This integrated analysis implicates novel genes in Alzheimer’s disease, such as ANKRD30B. These results highlight DNAm diferences in Alzheimer’s disease that have gene expression correlates, further implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.
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| Overall design |
We measured DNA methylation (DNAm) levels from dorsolateral prefrontal cortex (DLPFC), hippocampus (HIPPO), entorhinal cortex (ERC), and cerebellum (CRB) of postmortem brain donors diagnosed with Alzheimer's disease (N=24) and neurotypical controls (N=49). For additional demographic information, please refer to Table S1 of the corresponding publication.
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| Contributor(s) |
Semick SA, Jaffe AE |
| Citation(s) |
30712078, 35585924 |
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| Submission date |
Jan 30, 2019 |
| Last update date |
May 26, 2022 |
| Contact name |
Stephen A Semick |
| Organization name |
University of Maryland School of Medicine
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| Street address |
655 W Baltimore St S
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21201 |
| Country |
USA |
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| Platforms (1) |
| GPL13534 |
Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482) |
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| Samples (269)
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| Relations |
| BioProject |
PRJNA517907 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE125895_RAW.tar |
2.3 Gb |
(http)(custom) |
TAR (of IDAT) |
| GSE125895_matrix_processed.csv.gz |
903.3 Mb |
(ftp)(http) |
CSV |
| GSE125895_matrix_signal_intensities.csv.gz |
668.4 Mb |
(ftp)(http) |
CSV |
| Processed data are available on Series record |
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