Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., AIM2, C16orf80, DGUOK, and ST14) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is the major cause of dementia and is projected to affect more than 13 million people in the United States by 2050, imposing huge health and economic burdens [1,2]
Many genetic variants mapped to several chromosomal regions and genes have far been associated with AD by genome-wide association studies (GWAS) [4,5]; the vast majority of AD cases cannot be etiologically attributed to these variants [2,6]
Top methylation quantitative trait locus (mQTL) corresponding to these probes were nominally significant (6.45E-06 ≤ PGWAS) in our genome-wide meta-analyses [27,28], except for the cg06750524 probe corresponding to the Apolipoprotein E (APOE) gene whose top mQTLs had 2.15E-83 ≤ PGWAS ≤ 8.19E-30 under the five analysis plans of interest
Summary
Alzheimer’s disease (AD) is the major cause of dementia and is projected to affect more than 13 million people in the United States by 2050, imposing huge health and economic burdens [1,2]. Epigenetic modifications of gene expression in interaction with non-genetic factors are hypothesized to contribute to AD development [6,9], in light of the heterogeneous clinical manifestations of AD observed among patients with similar or identical genetic backgrounds [10]. Previous studies have provided many lines of evidence of associations between AD and gene-specific epigenetic modifications They mainly investigated the DNA methylation and histone modification differences between AD cases and unaffected controls using candidate gene or genome-wide analysis approaches (e.g., pyrosequencing and array hybridization) which revealed AD-associated epigenetic modifications in some well-known AD genes, such as amyloid-β precursor protein (APP), Microtubule Associated Protein Tau (MAPT) [14], and Apolipoprotein E (APOE) [15], as well as in other genes [12]. APOE methylation was not statistically different between cases and controls in samples obtained from their cerebellum [15]
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