Common Variants Coregulate Expression of GBA and Modifier Genes to Delay Parkinson's Disease Onset

Abstract

A BS TRACT: Background: GBA mutations are numerically the most significant genetic risk factor for Parkinson's disease (PD), yet these mutations have low penetrance, suggesting additional mechanisms. Objectives: The objective of this study was to determine if the penetrance of GBA in PD can be explained by regulatory effects on GBA and modifier genes. Methods: Genetic variants associated with the regulation of GBA were identified by screening 128 common single nucleotide polymorphisms (SNPs) in the GBA locus for spatial cis-expression quantitative trail locus (supported by chromatin interactions). Results: We identified common noncoding SNPs within GBA that (1) regulate GBA expression in peripheral tissues, some of which display α-synuclein pathology and (2) coregulate potential modifier genes in the central nervous system and/or peripheral tissues. Haplotypes based on 3 of these SNPs delay disease onset by 5 years. In addition, SNPs on 6 separate chromosomes coregulate GBA expression specifically in either the substantia nigra or cortex, and their combined effect potentially modulates motor and cognitive symptoms, respectively. Conclusions: This work provides a new perspective on the haplotype-specific effects of GBA and the genetic etiology of PD, expanding the role of GBA from the gene encoding the β-glucocerebrosidase (GCase) to that of a central regulator and modifier of PD onset, with GBA expression itself subject to distant regulation. Some idiopathic patients might possess insufficient GBA-encoded GCase activity in the substantia nigra as the result of distant regulatory variants and therefore might benefit from GBA-targeting therapeutics. The SNPs' regulatory impacts provide a plausible explanation for the variable phenotypes also observed in GBA-centric Gaucher's disease and dementia with Lewy bodies.

Establishing gene regulatory networks from Parkinson’s disease risk loci

“…The 117 trans-interchromosomal-eQTL regulated genes were significantly (p < 0.01, Kruskal-Wallis test) more intolerant to loss-of-function mutations (LOEUF 0.42 [median]; a low LOEUF score is indicative of evolutionary constraint) than those regulated by cis-or trans-intrachromosomal acting eQTLs (LOEUF 0.83 and 0.85 respectively [median]; Figure 3; Supplementary table 7). This result is consistent with earlier observations that trans-eQTLs are enriched in regulating constrained genes with low LOEUF scores 19 .…”

“…Both alpha-synuclein (αSyn) protein pathology and modulation of PD-related genes have been identified in peripheral tissues (e.g. the gastrointestinal tract and heart) of PD patients 12,[14][15][16][17][18][19] . The contribution of peripheral tissue in the origins of PD warrants further research, and thus the consideration of how PD-SNPs mediate risk should not be confined to tissues of the CNS.…”

“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted April 9, 2021. ; https://doi.org/10.1101/2021.04.08.439080 doi: bioRxiv preprint 1Mb, or on different chromosomes) mechanisms (Figure 1) 19,21,22 . These cis-and trans-acting elements can regulate the transcription of one or more genes, in a tissue specific manner, and are commonly detected in the form of expression quantitative trait loci (eQTL) 23 .…”

Advancing Personalized Medicine in Common Forms of Parkinson’s Disease through Genetics: Current Therapeutics and the Future of Individualized Management

“…Finally, for common variants with low individual effect identified in previous GWAS studies, the criteria recommend calculating the PRS for a large sample series with genetic data and classifying patients according to the risk score distribution in the sample. A recent study has identified common non-coding SNPs within GBA regulating GBA expression in peripheral tissues [ 86 ]. Interestingly, the authors report that non-coding SNPs within GBA also coregulate potential modifier genes in the central nervous system and/or peripheral tissues, delaying disease onset by 5 years.…”

The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

“…Notably, the phenotypic disparity among patients with GD 51 or PD 52 with the same GBA1 genotype might indicate the existence of environmental or genetic modifiers. 53,54 These modifiers could be lysosomal genes, for example, CTSB (cathepsin B) 55 or GBA2 (discussed later). Moreover, mutations in LRRK2 (leucine-rich repeat kinase 2), which participates in lysosomal function and inflammatory response, seem to alleviate GBA1 mutations effects in human induced pluripotent stem cell (iPSC)-derived neurons 56 or astrocytes.…”