Demographic characteristics
This study encompassed a total of 4034 patients and 2931 healthy participants. Among the patients, 1777 (44.1%) individuals were diagnosed with early-onset PD (EOPD, AAO ≤ 50 years); parallelly, 1652 healthy participants matched for age and sex were included. Additionally, there were 2257 (55.9%) participants with late-onset PD (LOPD, AAO > 50 years), accompanied by 1279 age and sex matched control participants. Detailed demographic information for this cohort is presented in Supplementary Table 1. Notably, none of the participants had been previously identified as carriers of pathogenic or likely pathogenic variants associated with PD-causing genes3,18.
Spectrum and frequency of GBA1 variants
In this study, 104 variants were identified, comprising 84 missense, 6 splicing, 8 frameshift, and 6 stop-gain variants. Among these, 96 variants had been previously reported, while the remaining 8 were novel. Among PD patients, 92 variants were detected, encompassing 72 missense, 6 splicing, 8 frameshift, and 6 stop-gain variants. Notably, 10 variants were shared between PD patients and control, whereas, 12 variants were exclusive to the control group.
The GBA1 variants were classified into four different types based on their deduced and observed phenotypic effects on GD or PD. Of all the variants found in PD patients, 34 were classified as severe, 7 as mild, 2 as risk, and 49 as unknown. Of all the variants found in control, four were classified as severe, two as mild, one as risk, and the other 15 were unknown (Fig. 1).
Schematic drawing of the gene and the protein domains, and diagram of reported and newly discovered GBA1 variants. Note: Different colors indicate different types of GBA1 variants. Red indicates reported severe variants, Pink indicates novel severe variants, which means variants are loss of function variants or variants were reported in Gaucher’s patients and were defined severe but were unreported in PD, Yellow indicates mild variants, Blue indicates risk variants, Black indicates reported variants of unknown significance, and green indicates novel missense variants. PD Parkinson’s Disease.
Furthermore, we observed that, apart from p.L483P and p.R202Q, which were low-frequency variants with a minor allele frequency (MAF) ranging from 0.01 to 0.05, the remaining variants were deemed rare according to the criterion of MAF being <0.01. After comparing the frequency of GBA1 variants between these two groups, we found that GBA1 variants detected in patients with PD significantly differed from those observed in control. Among the 4034 patients with PD, 301 (7.46%) carried GBA1 variants, while 53 (1.81%) out of 2931 control carried GBA1 variants (P < 0.001, odds ratio [OR] = 4.38, 95% confidence interval [CI]: 3.26–5.89) (Fig. 2).
a Number of patients and control with different types of GBA1 variants. b Frequency of different types of GBA1 variants in patients and control. PD Parkinson’s disease; N-PD patients without GBA1 variants; GBA1-PD patients with GBA1 variants; N-HC control without GBA1 variants; GBA1-HC control with GBA1 variants; Severe known to cause GD type II or III; Mild known to cause GD type I; Risk variants that are associated with risk for PD but do not cause GD; Unknown reported variants of unknown significance or unreported missense variants; GD Gaucher’s disease.
Regarding the types of GBA1 variants, we identified 176 patients (4.36%) carrying severe variants, a prevalence significantly higher than that among control (0.27%) (P < 0.001, OR = 16.67, 95% CI: 8.19–33.91). Mild variants were present in 34 patients (0.84%), while only in four control participants (0.14%) (P < 0.001, OR = 6.22, 95% CI: 2.21–17.55). However, the analysis showed no significant difference in the occurrence of risk variants between patients (0.07%) and control (0.03%) (P = 0.643, OR = 2.18, 95% CI: 0.23–20.97). For unknown variants, they were identified in 88 patients (2.18%) and 40 control participants (1.36%), demonstrating a statistically significant difference (P = 0.016, OR = 1.61, 95% CI: 1.11–2.35) (Fig. 2, Supplementary Table 2).
When selecting variants with at least ten patients to systematically interrogate the association of single-nucleotide variants (SNVs), we observed significant differences for the p.L483P variant detected in PD patients compared to that in control (2.35% vs. 0.14%, P < 0.001, OR = 17.65, 95% CI: 6.48–48.05). Furthermore, our study showed that p.G241R and p.S310G variants contribute to an increased risk of PD. Specifically, p.G241R was present in 10 patients (0.25%) but none in control (P = 0.007, OR = 15.3, 95% CI: 1.25–261.1). Similarly, p.S310G was found in twenty patients (0.5%) and only three control participants (0.1%) (P = 0.005, OR = 4.86, 95% CI: 1.52–28.04). Conversely, the analysis did not reveal significant difference for the second most common variant in our cohort, the p.R202Q variant, with frequencies of 0.55% in patients and 0.72% in control (Table 1, Supplementary Table 3).
Furthermore, we investigated the frequency of GBA1 variants in EOPD and LOPD patients. In EOPD patients, 185 (10.41%) carried GBA1 variants, significantly higher than in LOPD patients, in which only 116 (5.14%) carried GBA1 variants. A total of 122 (6.87%) EOPD patients and 54 (2.39%) LOPD patients carried severe variants. However, the analysis showed no significant differences for mild, risk, and unknown variants between the two groups. Performing the SNV association, we found that the proportion of EOPD patients with the p.L483P variant was significantly higher than that of LOPD patients. Seventy-four (4.16%) EOPD patients carried p.L483P, while 21 (0.93%) LOPD patients carried p.L483P.
Genotype-Phenotype
We found that patients with non-synonymous GBA1 variants had an earlier AAO (mean: 50 years, standard deviation (SD): 9.64 years) compared to non-carriers (mean: 54.15 years, SD: 11.01 years), along with a higher Hoehn and Yahr (H-Y) stage (mean: 2.12, SD: 0.76) in contrast to non-carriers (mean: 1.98, SD: 0.76) (Table 2). Furthermore, the postural instability gait difficulty (PIGD) motor subtype was predominant in both groups, but the proportion of PIGD in patients with GBA1 variants was higher than that in non-carriers (69.93% vs. 57.36%), indicating increased rigidity and less tremor. In the realm of non-motor symptoms, patients with GBA1 variants demonstrated lower Hyposmia Rating Scale (HRS) scores related to olfactory function than those without GBA1 variants (18.19 vs. 19.55), and olfactory loss was more prevalent among patients with GBA1 variants than non-carriers (54.48% vs. 40.95%). Regarding sleep disturbances, patients with GBA1 variants exhibited a higher rate of probable rapid-eye-movement sleep behavior disorder (pRBD) than those without GBA1 variants, while no significant differences were observed in excessive daytime sleepiness (EDS) and overall sleep quality. In addition, patients with non-synonymous GBA1 variants displayed higher rates of constipation and depression than non-carriers. Regarding motor complications, patients with GBA1 variants had higher freezing of gait (FOG) rate than non-carriers (Fig. 3, Table 2).
a Mean score of motor symptoms in N-PD, GBA1-PD, and L483P-PD. b AAO of N-PD, GBA1-PD, and L483P-PD. c Frequency (%) of family history and motor and non-motor symptoms in N-PD, GBA1-PD, and L483P-PD. * Significantly different between N-PD and GBA1-PD groups. † Significantly different between N-PD and L483P-PD groups. PD Parkinson’s disease; N-PD patients without GBA1 variant; GBA1-PD patients with GBA1 variants; L483P-PD patients with GBA1 p.L483P variant; AAO age at onset; UPDRS Unified Parkinson’s Disease Rating Scale; EDS excessive daytime sleepiness; pRBD probable rapid-eye-movement sleep behavior disorder; TD tremor-dominant; PIGD postural instability and gait difficulty; FOG Freezing of Gait.
Since the most important variant we found was p.L483P, we specifically analyzed the clinical characteristics of patients with p.L483P. Compared with non-carriers, cases with p.L483P had an earlier AAO and a higher H-Y stage. Compared with non-carriers, olfactory loss and pRBD were more prevalent in those with p.L483P (Fig. 3, Table 2).
Additionally, we analyzed the clinical characteristics of both EOPD and LOPD cases with GBA1 variants. When comparing EOPD cases with and without GBA1 variants, we found no significant differences between the two groups in age and AAO. However, patients with GBA1 variants displayed a higher H-Y stage. Moreover, compared to non-carriers, patients with GBA1 variants exhibited a higher prevalence of olfactory loss, pRBD, and constipation. While when comparing LOPD cases with and without GBA1 variants, those with GBA1 variants exhibited an earlier AAO. Furthermore, GBA1 variants carriers within the LOPD group displayed a higher occurrence of olfactory loss, depression, pRBD and constipation (Supplementary Table 4).
Finally, we compared the clinical characteristics of different types of GBA1 variants including Severe-PD and Mild-PD. Notably, Severe-PD cases displayed an earlier AAO and higher levodopa equivalent daily dose (LEDD) compared to Mild-PD cases. However, we did not identify significant differences in other clinical characteristics (Supplementary Table 5).