Background: Orthostatic hypotension (OH) is not rare in patients with Parkinson's disease (PD). To date, there have been few studies on the association of genetic variants with OH.

Objective: We aimed to evaluate the association of LRRK2 and GBA variants with OH in a large PD cohort.

Methods: This study utilized data from the PPMI database, including 863 participants who were divided into the sporadic PD patients (sPD, n = 357), GBA variant carriers (GBA-PD, n = 137), LRRK2 variant carriers (LRRK2-PD, n = 158) and healthy controls (HC, n = 211). LRRK2-PD patients were additionally categorized into G2019S (n = 141) and R1441G (n = 16). GBA-PD patients were categorized into three subgroups by the genomic categorization.

Results: No significant difference was found in the incidence of OH among the four groups at baseline. Lower University of Pennsylvania Scent Identification Test (UPSIT) scores, higher Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ) score and the risk GBA mutations were significantly associated with OH cross-sectionally. Higher Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total and part II scores, higher Epworth Sleepiness Scale (ESS) scores, higher RBDSQ scores and higher Scales for Outcomes in Parkinson's Disease-Autonomic Questionnaire (SCOPA-AUT) scores were strongly linked with OH progression over time. LRRK2 mutations especially LRRK2 G2019S mutation were significantly associated with the lower risk of OH progression.

Conclusions: LRRK2-PD, particularly the LRRK2-G2019S-PD, were found to have a lower risk of OH. In contrast, the role of GBA mutations in OH appears more complex, with no further evidence to suggest that GBA is associated with the progression of OH in PD.