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Whole-methylome sequencing to identify unique epigenetic profiles in Lewy body dementias (R03)

Debby Tsuang, MD
PI:
Debby Tsuang, MD
University of Washington

Summary

Lewy body dementia (LBD) is a prevalent and debilitating neurodegenerative disorder with no cure currently available. Existing tools to distinguish LBD subtypes are imprecise and this imprecision poses challenges for timely diagnosis and for research. The goal of this study is to identify unique epigenetic signatures (patterns of gene activation) in LBD that will facilitate diagnosis and treatment.

Study Information

Title: Whole-methylome sequencing to identify unique epigenetic profiles in Lewy body dementias
PI Name: Debby Tsuang
Repository: Parkinson's Disease Biomarker Program
Status: Controlled Access
Funding Source: NIH-NINDS
Abstract: Lewy body dementia (LBD) is a prevalent disorder that is characterized by impaired attention and executive function, visual hallucinations, parkinsonian features, sleep difficulty, and worse functional and survival outcomes than Alzheimer's disease (AD) or Parkinson's disease (PD). The two clinical entities of LBD, Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are heterogeneous. Although they share a common neuropathological finding, namely Lewy pathology, they have variable disease courses and treatment strategies. Yet current diagnostic procedures to distinguish these subtypes are imprecise and thus pose an important challenge for timely clinical diagnosis and for research. We will therefore leverage existing resources (e.g., postmortem brain tissue, DNA samples, genotypes, and methylome data) to advance the discovery of unique peripheral biomarkers for DLB and PDD. Epigenetic modifications have been identified as capable of altering transcriptional activity across multiple genes and biological pathways. A state-of-the-art technological method known as whole- genome bisulfite sequencing (WGBS) has been used to construct methylome maps for human cells and provides unbiased interrogation of the approximately 3 million quantifiable CpG sites. The detection of disease-dependent DNA methylation patterns that are concordant between peripheral blood leukocytes (PBLs) and postmortem brain (PMB) tissue in PD suggests that methylation profiles may serve as a readily accessible biomarker for LBD. However, previous studies did not include genome-wide interrogation. We thus propose the following 3 aims to identify unique epigenetic profiles in LBD. Aim 1. Generate whole-methylome from the PMBs and PBLs of LBD subjects using WGBS. We will perform whole-methylome sequencing in frontal cortical and PBL samples selected from a well- characterized national LBD consortium and the University of Washington Neuropathology Core. Aim 2. Define differentially methylated regions (DMRs) that are specifically associated with LBD. We will detect concordant methylation profiles in LBD, thereby identifying potential peripheral biomarkers that serve as a good proxy for methylation alterations in the brain. Aim 3. Validate DMRs identified in Aim 2 in additional PBL samples using targeted bisulfite sequencing. We will verify our findings in samples selected from the National Alzheimer's Coordinating Center and the PDBP. We hypothesize that we will identify concordant methylation alterations in brain and blood in LBD, and we expect that a subset of these DMRs will be verified in additional PBLs. These findings will thereby constitute novel sources for biomarker discovery and development in accessible tissue. PUBLIC HEALTH RELEVANCE: Lewy body dementia (LBD) is a prevalent and debilitating neurodegenerative disorder. Currently, there is no cure for this disorder. Existing diagnostic procedures to distinguish LBD subtypes are imprecise and thus pose an important challenge for timely clinical diagnosis and for research. This proposal seeks to identify unique epigenetic profiles in LBD. These findings will thereby constitute novel sources for biomarker discovery and development in accessible tissue. As such, findings will have significant public health relevance as we address a prevalent disorder in the aging population
Study ID: PDBP-STUDY0000266
Data Type: Genomics
Study Type: Natural History
Grant ID: R03 NS103950
Study Started On: 2017-09-28
Study Completed On: 2020-09-29
Estimated number of Subjects: 95

Abstract

LBD is a prevalent disorder that is characterized by impaired attention and executive function, visual hallucinations, parkinsonian features, sleep difficulty, and worse functional and survival outcomes than Alzheimer’s disease (AD) or Parkinson’s disease (PD). The two clinical entities of LBD, Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are heterogeneous. Although they share a common neuropathological finding, namely Lewy pathology, they have variable disease courses and treatment strategies. Yet current diagnostic procedures to distinguish these subtypes are imprecise and this imprecision poses an important challenge for timely clinical diagnosis and for research. We will therefore leverage existing resources (e.g., postmortem brain tissue, DNA samples, genotypes, and methylome data) to advance the discovery of unique peripheral biomarkers for DLB and PDD. Epigenetic modifications have been shown to be capable of altering transcriptional activity across multiple genes and biological pathways. A state-of-the-art technological method known as a whole-genome methylation genotyping array has been used to construct methylome maps for human cells and to provide unbiased interrogation of the approximately 3 million quantifiable CpG sites. The detection of disease-dependent DNA methylation patterns that are unique in the postmortem brain (PMB) tissue of PD suggests that methylation profiles may serve as a readily accessible biomarker for LBD. However, previous methylation studies did not include genome-wide interrogation of methylation sites. We thus propose the following 3 aims to identify unique epigenetic profiles in LBD.

      • Aim 1. Generate whole-methylome genotypes from the PMBs of LBD subjects using a state-of-the-art genotyping array. We will perform whole-methylome genotyping in frontal cortical samples selected from a well-characterized national LBD consortium and the University of Washington Neuropathology Core.
      • Aim 2. Identify differentially methylated regions (DMRs) in PMBs from Aim 1 that are specifically associated with LBD, including its DLB and PDD subtypes. We will detect unique methylation profiles in LBD, thereby identifying potential methylation alterations in the brain.
      •  Aim 3. Replicate DMRs identified in Aim 2 in PMB samples selected from the Alzheimer’s Disease Research Centers and Neurobiobank. We hypothesize that we will identify unique methylation patterns in the brains of subjects with LBD, and we expect that a subset of these DMRs will be verified in additional samples. These findings will thereby constitute novel sources for biomarker discovery and development in accessible tissue.

Goals

  • Conduct whole-methylome genotyping in PMBs from the following groups: pure DLB (n=19), DLB + concomitant AD (n=19), PDD (n=19), AD (n=19), and control (n=19) subjects. We will use the illumina methylation genotyping array, which will interrogate over 85,000 methylation sites throughout the entire genome.
  • Identify methylated regions and methylation patterns that differ between each subject group.
  • Replicate these patterns in additional samples.
  • Pursue future studies, including RNA sequencing in the same samples to investigate whether validated DMRs are associated with changes in gene expression.