Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer\u2019s disease

Mikko Konki,Asta Laiho,Noora M Scheinin,Miina Ollikainen,Riikka J Lund,Nancy L Pedersen,Noora Lindgren,Harri Lähdesmäki,Jaakko Kaprio,Maia Malonzo,Johannes Smolander,Tapio Lönnberg,Ida K Karlsson,Laura L Elo,Juha O Rinne,Matias Röyttä,Bishwa Ghimire

doi:10.1186/s13148-019-0729-7

Abstract

BackgroundAlzheimer’s disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs.ResultsComparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer’s disease and becomes differentially methylated after disease onset.ConclusionsDNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer’s disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.

Highlights

Alzheimer’s disease (AD) is an aging-associated neurodegenerative disorder and the most common cause of dementia
To measure the genetic risk load for AD in the Finnish study subjects, we analyzed the apolipoprotein E (APOE) genotypes and 21 loci previously associated with AD as a risk or protective variants (Table 2, Additional file 1) [4, 6]
Standardized Genetic risk score (GRS) were calculated for the study groups based on the 21 loci previously associated with AD (Table 2)

Summary

Introduction

Alzheimer’s disease (AD) is an aging-associated neurodegenerative disorder and the most common cause of dementia. In the early-onset form of AD, which accounts for approximately 2–10% of the cases, the symptoms can start already before age of 30 years. The majority of AD cases are of the late-onset form, which typically manifests after 65 years of age [1, 4]. Genetic association with apolipoprotein E (APOE) epsilon 4 (ε4) allele is common in both early- and late-onset form. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs

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