Journal Article

Functional genomics elucidates regulatory mechanisms of Parkinson’s disease-associated variants

Li, Ming, Liu, Jiewei, Xiao, Xiao, Huo, Yongxia, Yao, Yong-Gang, Luo, Xiong-Jian, Chen, Rui, Li, Shiwu, Li, Xiaoyan

2022

Overview

Background Genome-wide association studies (GWASs) have identified multiple risk loci for Parkinson’s disease (PD). However, identifying the functional (or potential causal) variants in the reported risk loci and elucidating their roles in PD pathogenesis remain major challenges. To identify the potential causal (or functional) variants in the reported PD risk loci and to elucidate their regulatory mechanisms, we report a functional genomics study of PD. Methods We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) (from neuronal cells and human brain tissues) data and GWAS-identified single-nucleotide polymorphisms (SNPs) in PD risk loci. We then conducted a series of experiments and analyses to validate the regulatory effects of these (i.e., functional) SNPs, including reporter gene assays, allele-specific expression (ASE), transcription factor (TF) knockdown, CRISPR-Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Results We identified 44 SNPs (from 11 risk loci) affecting the binding of 12 TFs and we validated the regulatory effects of 15 TF binding-disrupting SNPs. In addition, we also identified the potential target genes regulated by these TF binding-disrupting SNPs through eQTL analysis. Finally, we showed that 4 eQTL genes of these TF binding-disrupting SNPs were dysregulated in PD cases compared with controls. Conclusion Our study systematically reveals the gene regulatory mechanisms of PD risk variants (including widespread disruption of CTCF binding), generates the landscape of potential PD causal variants, and pinpoints promising candidate genes for further functional characterization and drug development.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Binding / Biomedicine / Brain / Chromatin / CRISPR / Development and progression / Disruption / Drug development / Functional genomics / Gene expression / Gene mapping / Genes / Genetic aspects / Genetic Predisposition to Disease - genetics / Genome editing / Genome-wide association studies / Genome-wide association studies (GWASs) / Genome-Wide Association Study / Genomes / Genomics / Health aspects / Humans / Immunoprecipitation / Medicine / Medicine & Public Health / Movement disorders / Neurodegenerative diseases / Nucleotides / Parkinson Disease - genetics / Parkinson's disease / Parkinson’s disease (PD) / Pathogenesis / Pipelines / Polymorphism, Single Nucleotide - genetics / Quantitative trait loci / Regulatory mechanisms / Regulatory mechanisms (biology) / Reporter gene / Research Article / Risk / Risk factors / Sequences / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Single-nucleotide polymorphisms (SNPs) / Software / Transcription factor (TF) binding