Common Variants Coregulate Expression of GBA and Modifier Genes to Delay Parkinson's Disease Onset
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 alpha-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 beta-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. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC on behalf of International Parkinson and Movement Disorder Society.
|ISBN||1531-8257 (Electronic) 0885-3185 (Linking)|
|Authors||Schierding, W.; Farrow, S.; Fadason, T.; Graham, O. E. E.; Pitcher, T. L.; Qubisi, S.; Davidson, A. J.; Perry, J. K.; Anderson, T. J.; Kennedy, M. A.; Cooper, A.; O'Sullivan, J. M.|
|Responsible Garvan Author||A/Prof Antony Cooper|
|Publisher Name||MOVEMENT DISORDERS|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/32557794|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/15455|