Integrated Genetic Analysis of Racial Differences of Common GBA Variants in Parkinson's Disease: A Meta-Analysis

Yuan Zhang, Li Shu, Qiying Sun, Xun Zhou, Hongxu Pan, Jifeng Guo, Beisha Tang, Yuan Zhang, Li Shu, Qiying Sun, Xun Zhou, Hongxu Pan, Jifeng Guo, Beisha Tang

Abstract

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.

Keywords: AJ; GBA; Parkinson's disease; meta-analysis; non-AJ.

Figures

Figure 1
Figure 1
Flow chart of publications included process.
Figure 2
Figure 2
A total of 18 GBA variants were included and conducted in the meta-analysis. (A) 18 GBA variants related to PD were included for meta-analysis according to our inclusion and exclusion criteria. (B) 11 of 18 variants were found to increase the risk for PD. And the MAFs of the 11 risk variants were largely ethnicity dependent.
Figure 3
Figure 3
Schematic representation of the GBA gene and protein with the 11 risk variants. All variants are named following the common nomenclature which begins 39 codons downstream from the first ATG, excluding the 39-residue signal peptide. GBA has 11 exons and the protein has three domains, signal peptide, glyco_hydro_30, and glycol_hydro_30C. Numbers below the protein line indicate the boundaries of each domain.

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