Cross-tissue meta-analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
medRxiv(2022)
摘要
We performed a meta-analysis of two large independent blood-based Alzheimer’s disease (AD) epigenome-wide association studies, the ADNI and AIBL studies, and identified 5 CpGs, mapped to the SPIDR, CDH6 genes, and intergenic regions, that were significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four additional methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. Our integrative analysis revealed expressions levels of 13 genes and 10 pathways were significantly associated with the AD-associated methylation differences in both brain and blood, many are involved in the immune responses in AD, such as the CD79A, LY86, SP100, CD163, CD200 , and MS4A1 genes and the neutrophil degranulation, antigen processing and presentation, interferon signaling pathways. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model included age, sex, cell types and methylation risk score based on prioritized CpGs from cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 - 0.770, P- value = 2.78 × 10−5). Our study provides a valuable resource for future mechanistic and biomarker studies in AD.
### Competing Interest Statement
The authors have declared no competing interest.
### Funding Statement
This research was supported by US National Institutes of Health grants R21AG060459 (L.W), R01AG061127 (L.W.), R01AG062634 (E.R.M, L.W.), and 1R01AG060472 (E.R.M).
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The study used ONLY openly available human data that were originally located at: adni.loni.usc.edu, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153712, and https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144858
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
All data produced are available online at adni.loni.usc.edu, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153712, and https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144858
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关键词
alzheimers,cross-tissue,meta-analysis,epigenome-wide
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