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

• Published in: Movement disorders Vol. 37; no. 11; pp. 2217 - 2225
• Main Authors: Ortega, Roberto A., Bressman, Susan B., Raymond, Deborah, Ozelius, Laurie J., Katsnelson, Viktoriya, Leaver, Katherine, Swan, Matthew C., Shanker, Vicki, Miravite, Joan, Wang, Cuiling, Bennett, Steffany A.L., Saunders‐Pullman, Rachel
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-11-2022; Wiley Subscription Services, Inc
• Subjects: Basal ganglia; Brain diseases; Central nervous system diseases; family history; Female; GBA; Gender differences; Genetic diversity; Glucosylceramidase; Glucosylceramidase - genetics; Heterozygote; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; LRRK2; LRRK2 protein; Male; Movement disorders; Mutation; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson's; Parkinson's disease; sex; Sex differences; Women; Parkinson's; LRRK2; family history; GBA; sex
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.29197

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.