Cell-type specific alteration of DNA methylation in Alzheimer’s Disease Público

Abstract

Alzheimer’s disease (AD) is one of the chronic neurodegenerative disorders that causing great social burden. Hoping to identify novel biological signals in AD, we conduct in-depth analyses of brain DNA methylation data from ROS/MAP cohort, with consideration of cellular heterogeneity in brain tissues. We apply a reference-based method EpiDISH to estimate cell-type proportions, and a new method TOAST to detect cell-specific differential DNA methylation (csDM). The estimated portions show modest correlations with a number of clinical outcomes, including Braak stage, CERAD score, sex, overall amyloid level, age of death, and cognitive values. The csDM analysis does not find any cell-type specific differentially methylated loci with statistical significance after multiple testing correction. However, a more powerful joint test procedure identifies 1454 significant loci from the joint signals of glia and neuron. We systematically investigate the biological implication of the loci. From gene ontology (GO) enrichment analysis, we find that the transplanting mesenchymal stem cell (MSC) can be seen as potential way to stop AD, because these cells can express feature of the neural cell and have similarity with ependymal cells. It is inspiring because intracerebral transplantation of MSCs has been identified improvement in AD mice. This project provides a unique view to AD epigenetic research from cell-type specific analysis. Future studies could address the transplantation of MSCs method in AD area to validate new treatment and understand biological progress associated with AD, and to discover diagnostic biomarkers and therapeutic targets.

Table of Contents

INTRODUCTION ...........................................................................................................1

METHOD .......................................................................................................................6

Description of ROS/MAP data ........................................................................................6

Reference DNA methylation data ..................................................................................7

Solving for proportions using EpiDISH .........................................................................8

Cell-type specific DM (csDM) test using TOAST ...........................................................9

Pathway and Gene Ontologies Analysis ......................................................................11

RESULTS .....................................................................................................................13

Data Description .........................................................................................................13

Cell Proportion:...........................................................................................................15

DMCs of glia, neuron, and joint analysis ....................................................................19

Pathway Analysis and Go Analysis .............................................................................20

Comparison with existing results................................................................................21

DISCUSSION ..............................................................................................................23

CONCLUSION.............................................................................................................25

REFERENCE................................................................................................................26

About this Master's Thesis

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School	Rollins School of Public Health
Department	Biostatistics
Subfield / Discipline	Biostatistics - MPH & MSPH
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Biology, Genetics
Palabra Clave	DNA methylation Alzheimer's Disease Cell-type specific
Committee Chair / Thesis Advisor	Hao Wu, Emory University
Committee Members	Suprateek Kundu, Emory University

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