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.

Reply to: “Differences in Sex‐Specific Frequency of Glucocerebrosidase Variant Carriers and Familial Parkinsonism”

“…Our results for a Serbian cohort of patients with PD failed to confirm sex-specific inequal frequencies of GBA variants based on their severity. Moreover, the most frequently detected mutations in our GBA-PD cohort were severe, in contrast with findings of Ortega and colleagues, 1 where the mild mutations were the most frequent.…”

“…We read with great interest the manuscript recently published by Ortega and colleagues regarding sex distribution in genetic Parkinson's disease (PD) patients. 1 In the authors' cohort, sex distribution among idiopathic PD was predominantly men and equally distributed in LRRK2-PD, as previously reported. In the GBA cohort, severe variant carriers were more likely to be women (15 of 19 women, 79.0%), whereas mild variant carriers and risk-variant carriers were more likely to be men (59 of 87 men, 67.8%).…”

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

“…However, this was not statistically significant at their sample size and would require a larger sample to demonstrate a statistically significant effect. In contrast, the report from Thaler et al 2 showed opposite sex‐specific frequencies. These interesting discrepancies underline the pressing need, highlighted by both groups and a core conclusion of our paper, to further evaluate in larger ongoing studies sex dimorphisms in genotypic‐phenotypic associations and to continue to report additional cases in a diversity of studies and ethnicities worldwide to better understand sex differences in PD.…”

“…These interesting discrepancies underline the pressing need, highlighted by both groups and a core conclusion of our paper, to further evaluate in larger ongoing studies sex dimorphisms in genotypic‐phenotypic associations and to continue to report additional cases in a diversity of studies and ethnicities worldwide to better understand sex differences in PD. The limitation of our study due to sample size was also acknowledged in our paper 3 . We suggest that all studies should include not only the number of cases of men and women, but pay careful attention to phenotype, as GBA variants contribute to both PD and dementia with Lewy bodies, therefore, case ascertainment and categorization differences may affect sex distributions and explain convergent and divergent findings.…”

“…We are also grateful for Kresojević et al 1 for highlighting the need to sequence the GBA gene as well as separately reporting sex associated with specific GBA variants. This is important as variants may not only be undergoing reclassification, but be categorized and combined differently across studies.…”