Unraveling the Role of Clonal Hematopoiesis in Neurodegenerative Diseases

ABSTRACT Clonal hematopoiesis (CH) has been linked to an increased risk of cancer and cardiovascular diseases. However, its potential implications in various age-related conditions, particularly neurodegenerative diseases, remain insufficiently explored. Recent research has highlighted the protective effect of clonal hematopoiesis of

indeterminate potential (CHIP) against Alzheimer's disease (AD), emphasizing the need for further investigation into CH's role across a spectrum of neurodegenerative diseases. Yet, the involvement of CH in other neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and

amyotrophic lateral sclerosis/frontotemporal lobar degeneration (ALS/FTD), has not been comprehensively investigated. Additionally, the distinct implications of other types of CH, including autosomal mosaic chromosomal alteration (mCA) and loss of the Y chromosome (LOY), on these diseases have yet to be

thoroughly examined. To fill this knowledge gap, this project will unravel the disentanglement of commonalities and disparities in associations between different CH types and neurodegenerative diseases by leverage a large amount of high-throughput sequencing data of AD, PD, DLB, and ALT/FTD. Moreover, this project will gain

insight into the underlying mechanisms of its potential varying effects of CH across the diseases by utilizing extensive functional genomics data. To this end, this project has three specific aims. In aim 1, we will uncover the associations of different CH types with neurodegenerative diseases by leveraging whole-genome sequencing

data from multiple cohorts. We will also perform Mendelian randomization to support causal associations between CH and neurodegenerative diseases. In aim 2, we will characterize inter-individual transcriptomic variability in individuals with and without CH across central nervous system tissues and myeloid cells by

leveraging previously published data, including bulk, sorted, and single-nuclei RNA-seq (snRNA-seq), as well as assay for transposase-accessible chromatin using sequencing (ATAC-seq), from disease cohorts. We will also perform cell type-specific transcriptome and chromatin accessibility characterization by detecting cells with

autosomal mCA and LOY from snRNA-seq/ ATAC-seq. In aim 3, we will employ two innovative experimental approaches: (1) snRNA-seq paired with genotyping of transcriptome (GoT) and (2) iPSC-derived human microglia-like cells (iMGL) to delve into the cell type-specific functional impacts of CHIP. Aim 3 will significantly

complement Aim2 since cell type-specific characterization of CHIP is challenging unlike autosomal mCA and LOY. Our preliminary results suggest varying effects of CHIP and LOY on the risk of different neurodegenerative diseases and functional impact of LOY, especially highlighted in microglia. These findings validate and motivate

our work plan, driving us to pursue further studies in this project. The comprehensive understanding of CH's role in neurodegenerative diseases achieved through this project will make significant contributions to the discovery of novel treatment options and the discovery of biomarkers for predicting the risk or progression of these diseases.