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

ABSTRACT: 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 ?-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 ?-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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Schierding W

PROVIDER: S-EPMC7496525 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Schierding William W Farrow Sophie S Fadason Tayaza T Graham Oscar E E OEE Pitcher Toni L TL Qubisi Sara S Davidson Alan J AJ Perry Jo K JK Anderson Tim J TJ Kennedy Martin A MA Cooper Antony A O'Sullivan Justin M JM

Movement disorders : official journal of the Movement Disorder Society 20200618 8

<h4>Background</h4>GBA mutations are numerically the most significant genetic risk factor for Parkinson's disease (PD), yet these mutations have low penetrance, suggesting additional mechanisms.<h4>Objectives</h4>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.<h4>Methods</h4>Genetic variants associated with the regulation of GBA were identified by screening 128 common single nucleotide polymorphisms (SN ...[more]

PMID: 32557794

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Project description:Background: Numerous studies have indicated that there is a possible relationship between GBA variants and Parkinson's disease (PD), however, most of them focused on a few variants such as L444P, N370S. We performed a comprehensive pooled analysis to clarify the relationship between variations of GBA and the risk of PD in different racial groups. Methods: Standard meta-analysis was conducted, including generating inclusion and exclusion criteria, searching literature, extracting and analyzing data. Results: Fifty studies containing 20,267 PD patients and 24,807 controls were included. We found that variants 84insGG, IVS2+1G>A, R120W, H255Q, E326K, T369M, N370S, D409H, L444P, R496H and RecNciI increased the risk of PD in total populations (OR: 1.78-10.49; p: <0.00001, 0.00005, 0.0008, 0.005, <0.00001, 0.004, <0.00001, 0.0003, <0.00001, <0.0001, 0.0001). In subgroup analysis by ethnicity, in AJ populations, variants 84insGG, R496H, N370S increased the risk of PD (OR: 9.26-3.51; p: <0.00001, <0.0001, <0.00001). In total non-AJ populations, variants L444P, R120W, IVS2+1G>A, H255Q, N370S, D409H, RecNciI, E326K, T369M increased the risk of PD (OR: 8.66-1.89; p: <0.00001, 0.0008, 0.02, 0.005, <0.00001, 0.001, 0.0001, <0.00001, 0.002). Among the non-AJ populations, pooled analysis from five different groups were done separately. Variants L444P, N370S, H255Q, D409H, RecNciI, E326K increased risk of PD (OR: 6.52-1.84; p: <0.00001, <0.00001, 0.005, 0.005, 0.04, <0.00001) in European/West Asians while R120W and RecNciI in East Asians (OR: 14.93, 3.56; p: 0.001, 0.003). L444P increased the risk of PD in Hispanics, East Asians and Mixed populations (OR: 15.44, 12.43, 7.33; p: 0.00004, <0.00001, 0.009). Lacking of enough original studies, we failed to conduct quantitative analysis in Africa. Conclusions: Obvious racial differences were found for GBA variants in PD. 84insGG and R496H exclusively increased PD risks in AJ populations, so did L444P, R120W, IVS2+1G>A, H255Q, D409H, RecNciI, E326K, T369M in non-AJ populations. N370S increased the risk of PD in both ethnics. In non-AJ subgroup populations, N370S, H255Q, D409H, E326K exclusively increased PD risks in European/West Asians, as were R120W in East Asians. L444P increased the risk of PD in all groups in non-AJ ethnicity. These results will contribute to the future genetic screening of GBA gene in PD.

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

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

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