Aberrant DNA Methylation Associated with Repetitive Head Impact Exposure and Chronic Traumatic Encephalopathy

Abstract
Every year, over 200 million people are exposed to repetitive head impacts (RHI) through contact sports, military
service, and domestic violence. RHI-exposure confers risk for developing multiple progressive
neurodegenerations, including chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. The
diagnosis of CTE is defined by hyperphosphorylated tau in neurons surrounding blood vessels at the depths of
the cortical sulci that typically begins in the dorsolateral frontal cortex (DLFC). Currently, CTE can only be
diagnosed at autopsy, and there are no established biomarkers or disease modifying treatments. The
development of CTE is associated with increasing years of contact sports participation and with age. Therefore,
examination of a community population with small amounts of RHI exposure as well as a group enriched for RHI
exposure and CTE may allow for the discovery of changes associated with RHI and CTE pathology development.
Epigenome-wide association studies offer a unique opportunity for identification of novel genetic alterations
associated with RHI-exposure and CTE. The most extensively studied epigenetic modification is DNA
methylation, in which a methyl group is added onto a DNA sequence most commonly at a cytosine that is followed
by a guanine, known as a CpG site. This proposal will utilize postmortem human brain tissue from two distinct
brain banks: a community-based bank and a brain bank for those with a history of RHI, with the world's largest
collection of autopsy-confirmed CTE cases. We hypothesize that RHI-exposure and CTE will have unique DNA
methylation signatures resulting in alterations to gene and protein expression. Our preliminary studies identified
13 genes that contained or were nearby multiple aberrantly methylated CpG sites (n=465) that reached genome
wide significance for their association with years of contact sports play (proxy used for RHI-exposure) in
postmortem human brain tissue. Pathway analyses reveal that the genes containing or close by the aberrantly
methylated CpGs are involved in neurogenesis, synaptic organization, and cell signaling. Based on these
promising preliminary results, we aim to (1) determine the association of RHI-exposure with aberrant DNA
methylation and the downstream alterations on gene and protein expression and (2) to identify distinct DNA
methylation signatures in CTE and the downstream alterations in gene and protein expression, and their
association to tau accumulation. By elucidating unique epigenetic signatures linked to low level RHI-exposure
and to CTE neuropathology, this research will enhance our understanding of the underlying alterations occurring
in RHI-exposure and CTE, which may aid in efforts for biomarkers and rational drug design.

Grant Number: 5F31NS141294-02
NIH Institute/Center: NIH
Principal Investigator: Kerry Breen