Differences in Sex-Specific Frequency of Glucocerebrosidase Variant Carriers and Familial Parkinsonism

Abstract

Background: Although men and women with the LRRK2 G2019S variant appear to be equally likely to have Parkinson's disease (PD), the sex-distribution among glucocerebrosidase (GBA) variant carriers with PD, including limited to specific variant severities of GBA, is not well understood. Further, the sex-specific genetic contribution to PD without a known genetic variant is controversial.

Objectives: To better understand sex differences in genetic contribution to PD, especially sex-specific frequencies among GBA variant carriers with PD (GBA PD) and LRRK2-G2019S variant carriers with PD (LRRK2 PD).

Methods: We assess differences in the sex-specific frequency in GBA PD, including in subsets of GBA variant severity, LRRK2 PD, and idiopathic PD in an Ashkenazi Jewish cohort with PD. Further, we expand prior work evaluating differences in family history of parkinsonism.

Results: Both idiopathic PD (267/420 men, 63.6%) (P < 0.001) and GBA PD overall (64/107, 59.8%) (P = 0.042) were more likely to be men, whereas no difference was seen in LRRK2 PD (50/99, 50.5%) and LRRK2/GBA PD (5/10, 50%). However, among GBA PD probands, severe variant carriers were more likely to be women (15/19 women, 79.0%) (P = 0.005), whereas mild variant carriers (44/70 men, 62.9%) (P = 0.039) and risk-variant carriers (15/17 men, 88.2%) (P = 0.001) were more likely to be men.

Conclusions: Our study demonstrates that the male-sex predominance present in GBA PD overall was not consistent across GBA variant severities, and a female-sex predominance was present among severe GBA variant carriers. Therefore, research and trial designs for PD should consider sex-specific differences, including across GBA variant severities. © 2022 International Parkinson and Movement Disorder Society.

Keywords: GBA; LRRK2; Parkinson's; family history; sex.

Figure 1:. Sex Distribution of PD overall and in IPD, LRRK2 and GBA, including by GBA variant. 1A. Comparison of the frequency of LRRK2 and GBA variants (overall) among men and women.

Note the greater proportion of women vs. men with LRRK2 PD (20% vs. 10.8%), similar proportion of GBA PD in both (17.6% vs. 17.3%), and subsequent smaller proportion of idiopathic PD comprising women vs men (62.4% vs. 72.0%) (p=0.057). 1B. Distribution of sex by PD groups. Note the overall greater percentage of men with GBA PD vs. women with GBA-PD (p=0.042), unlike LRRK2 PD (p=0.920), and similar to IPD (p<0.001) 1C. Sex frequency in GBA-PD separated by variant severity, as defined by severe, mild or risk-variant. GBA variants include the major variants (both severe and mild variants), which, when bi-allelic decrease activity of the glucocerebrosidase enzyme and cause Gaucher disease (GD), but when monoallelic increase the risk of synucleinopathies including PD, PD with dementia (PD-D), and dementia with Lewy bodies (DLB); and risk-variants, which when biallelic, do not cause Gaucher disease, but are associated with increased risk of PD and DLB.^,, Similar to 1B where GBA variants overall are associated with greater risk in men, there is significant increase in men with mild variants and risk-variants. In stark contrast, however, there is greater frequency of severe variants in women (p=0.001).

Figure 2.. Proportion of participants, overall and by PD group, with a family history of PD, stratified by sex.

As the black signifies individuals with parkinsonism in a first-degree relative, the grey area nonetheless includes a subset that likely have a major genetic contribution that is yet to be determined. As anticipated, because of lower penetrance in GBA PD compared to LRRK2 PD, the proportion with first degree family member with parkinsonism is greater in the LRRK2 PD (38.4%) than GBA PD (18.7%) (p=0.002). As a smaller proportion of men have a first-degree family history of parkinsonism, there is a larger contribution of other factors including additional genetic, epigenetic, environmental, hormonal and structurally different factors.^,, We cannot exclude that there is also an undetermined “protective factor” portion that is also responsible for the smaller percentage of non-first-degree family member cases in the women. We postulate that the differential lipid response to inflammation that may be responsible for sex differences in GBA variant PD may play a role in idiopathic PD as well. ^–