RT Journal Article
SR Electronic
T1 Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 430603
DO 10.1101/430603
A1 Stephen A. Semick
A1 Rahul A. Bharadwaj
A1 Leonardo Collado-Torres
A1 Ran Tao
A1 Joo Heon Shin
A1 Amy Deep-Soboslay
A1 James Weiss
A1 Daniel R. Weinberger
A1 Thomas M. Hyde
A1 Joel E. Kleinman
A1 Andrew E. Jaffe
A1 Venkata S. Mattay
YR 2018
UL http://biorxiv.org/content/early/2018/09/29/430603.abstract
AB Background 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 represented as variation in DNA methylation (DNAm), we surveyed 420,852 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).Results We identified 858 sites with robust differential methylation, collectively annotated to 772 possible genes (FDR<5%, within 10kb). These sites were overrepresented in AD genetic risk loci (p=0.00655), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR<5%). We analyzed corresponding RNA-seq data to prioritize 130 genes within 10kb of the differentially methylated sites, which were differentially expressed and had expression levels associated with nearby DNAm levels (p<0.05). This validated gene set includes previously reported (e.g. ANK1, DUSP22) and novel genes involved in Alzheimer’s disease, such as ANKRD30B.Conclusions These results highlight DNAm changes in Alzheimer’s disease that have gene expression correlates, 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.