Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease
Semick SA, Bharadwaj RA, Collado-Torres L, Tao R, Shin JH, Deep-Soboslay A, Weiss JR, Weinberger DR et al.. Acta neuropathologica, 2019-02-02
Topic: Amyloid, tau and blood-test diagnosis
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 identified 858 sites with robust differential 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 differentially methylated sites. These 130 genes were differentially 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 differences 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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APA 7th
Semick, S. A., Bharadwaj, R. A., Collado-Torres, L., Tao, R., Shin, J. H., Deep-Soboslay, A., et al. (2019). Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease. Acta neuropathologica. https://doi.org/10.1007/s00401-019-01966-5
Vancouver
Semick SA, Bharadwaj RA, Collado-Torres L, Tao R, Shin JH, Deep-Soboslay A, et al. Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease. Acta neuropathologica. 2019. doi:10.1007/s00401-019-01966-5. PMID: 30712078.
BibTeX
@article{semick2019-30712078,
author = {Semick, S. A. and Bharadwaj, R. A. and Collado-Torres, L. and Tao, R. and Shin, J. H. and Deep-Soboslay, A. and Weiss, JR. and Weinberger, D. R. and others},
title = {{Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease}},
journal = {Acta neuropathologica},
year = {2019},
doi = {10.1007/s00401-019-01966-5},
pmid = {30712078},
url = {https://doi.org/10.1007/s00401-019-01966-5}
}
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Key findings
- 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).
- These 130 genes were differentially expressed between AD cases and controls and their expression was associated with nearby DNAm (p < 0.05).
- These results highlight DNAm differences in Alzheimer's disease that have gene expression correlates, further implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD.
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Study details
- Participants49
- Evidence strengthLow
How this study scored 48/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 28 of the 58 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2019 — within 10 year(s) of the newest study here |
| Sample size | 1 / 4 | 49 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30712078) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 28 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 28 of the 58 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
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