In:
Alzheimer's & Dementia, Wiley, Vol. 16, No. S2 ( 2020-12)
Abstract:
In addition to the APOE locus, there has been considerable success in identifying genetic variants associated with an increased risk of developing Alzheimer’s disease (AD). However, there remains considerable uncertainty about the causal genes involved in AD neuropathology and the way in which these loci are functionally regulated by AD risk variants. As the majority of genetic variants are hypothesised to act via disruptions to gene regulation, there is increasing interest in the role of the epigenome, which encompasses a diverse number of chemical modifications to DNA and nucleosomal histone proteins that directly influence gene expression. Methods We have profiled DNA methylation in 1,284 brain samples from up to two regions (prefrontal cortex and occipital cortex) from 656 individuals in the Brains for Dementia Research (BDR) cohort. After stringent quality control, we performed epigenome‐wide association studies of four quantitative measures of neuropathology, Braak stage, Thal amyloid stage, Lewy Body stage and Cerad stage. Using matched genetic data available for these samples, performed a genome‐wide association study of methylomic variation to identify DNAm quantitative trait loci (mQTLs). These mQTL were then were integrated with results from AD GWAS, using summary data‐based Mendelian randomisation, to identify loci where DNA methylation is associated with AD. Finally, we generated polygenic risk scores for these samples and performed an epigenome‐wide study of genetic risk for AD. Results We identified multiple differentially methylated positions (DMPs) associated with neuropathology and AD polygenic risk score, replicating previous findings at known loci and implicating genes linked to known neuropathological pathways. Integrating our database of mQTLs with summary data from a recent AD GWAS, we report pleiotropic associations between AD and DNA methylation at several sites in the genome, including associations annotated to genes implicated in AD (e.g. SLC39A13, SPI1, MS4A6A, and BCL3). Conclusions We identified epigenetic differences associated with detailed measures of neuropathology providing insights on the molecular processes that underlie the disease progression. Furthermore, we characterised the complex relationship between genetic and epigenetic variation, identifying molecular consequences of high genetic risk for AD and prioritising candidate genes for functional follow up.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2201940-6
Permalink