Abstract
Genome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses of GWAS findings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome-wide association signals in PD and open chromatin in neurons across multiple brain regions, finding a significant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identified by two de novo motif discovery methods. Analyses were performed in parallel, both finding that PD risk variants significantly overlap with open chromatin regions harboring motifs of basic Helix-Loop-Helix (bHLH) transcription factors. Our findings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting about 1% of the population above 60 years of a ge[1]
Pairwise intersections in terms of Jaccard statistics of ATAC-seq peaks representing open chromatin regions (OCRs) in the different cell types show a separation between neurons and non-neurons, with the inter-region similarity being higher between the nonneurons (Supplementary Figure S1)
PD risk variants are significantly enriched in OCRs of neurons of the superior temporal cortex (GoShifter adj. p = 0.028, GREGOR adj. p = 6.94 × 10–05)
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting about 1% of the population above 60 years of a ge[1]. PD risk variants have been integrated with gene expression data, epigenomic annotations and functionally related gene sets to identify cell types and pathways implicated in PD p athogenesis[5,6,7]. A fine-mapping study of autoimmune diseases found that predicted causal variants tend to occur near binding sites for immune related transcription factors, but only a fraction alter recognizable transcription factor binding m otifs[12]. Transcription factor binding patterns vary between cell types and may be directly assessed through chromatin immunoprecipitation sequencing (ChIP-seq)[13]. Transcription factors only occupy a small proportion of the genomic sequences matching to their consensus binding sites. Integration of genome sequence information together with cell type specific experimental data has been shown to improve the accuracy of inference of transcription factor b inding[17]
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