TY - JOUR
T1 - Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease
AU - Semick, Stephen A.
AU - Bharadwaj, Rahul A.
AU - Collado-Torres, Leonardo
AU - Tao, Ran
AU - Shin, Joo Heon
AU - Deep-Soboslay, Amy
AU - Weiss, James R.
AU - Weinberger, Daniel R.
AU - Hyde, Thomas M.
AU - Kleinman, Joel E.
AU - Jaffe, Andrew E.
AU - Mattay, Venkata
N1 - Funding Information:
Funding This work was supported by the funding from Lieber Institute for Brain Development and the Maltz Research Laboratories.
Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - DNA methylation
KW - Human brain genomics
KW - Postmortem human brain tissue
KW - RNA sequencing
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U2 - 10.1007/s00401-019-01966-5
DO - 10.1007/s00401-019-01966-5
M3 - Article
C2 - 30712078
AN - SCOPUS:85061024232
VL - 137
SP - 557
EP - 569
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 4
ER -