Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Abstract

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological pathways underlying PD using the largest currently available cohorts of genetic data and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) andthe Accelerating Medicines Partnership -Parkinson's disease initiative (AMP-PD), among other sources. We placed these insights into a cellular context. We applied large-scale pathway-specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk in a cohort of 457,110 individuals by focusing on a compilation of 2,199 publicly annotated gene sets representative of curated pathways, of which we nominate 46 pathways associated with PD risk. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data, including 4,331 individuals. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for adult dopaminergic neurons, serotonergic neurons, and radial glia. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of 1,612 PD patients, which revealed 54 connecting networks associated with PD. Our analyses highlight several promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

“…Here, we also found for the first time that patients with higher PRS from PD risk exhibit lower levels of CSF Aβ42, suggesting that similar genes or pathways predispose individuals to an accumulation of Aβ in the brain and to develop PD. This is in agreement with a recent report suggesting that the PD genes from the PRS analysis are enriched for AD genes [2].…”

Butyrate and related epigenetic changes link Parkinson’s disease to inflammatory bowel disease and depressive symptoms

“…We have also shown that the neutrophil epigenome is linked less to other SCFAs. A recent study [51] reported that neutrophil degranulation is potentially linked to PD risk. Our gene set enrichment analysis suggests that butyrate-linked epigenetic changes may impact this pathway.…”

“…4b). Pathway analysis shows that epigenetic alterations of three recently identified PD polygenic risk pathways [51] (neutrophil degranulation, metabolism of lipids, and innate immune system) in the monocyte and neutrophil epigenome were linked to butyrate levels (Fig. 4c).…”

“…Pathway analysis was performed on the common genomic regions (butyrate-associated mDNA regions, GWAS loci of PD and each of the other diseases, respectively). All of the six PD polygenic risk pathways without known PD risk loci [51] were significantly altered in ulcerative colitis, Crohn's disease, rheumatoid arthritis, and bipolar disorder (FDR q < 0.05) (Fig. 5b).…”

The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson’s disease data

“…In addition to investigating individual variant effects with colocalization and epistasis, visualizing biological networks can help with understanding complex molecular relationships and interactions. In PD research, genetic and gene expression data has been used in community network analysis to nominate pathways and genes for drug target and functional prioritization 17,18 .…”