Aquaporin-4 polymorphisms modify the penetrance of Parkinson’s disease in leucine-rich repeat kinase 2 carriers
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Background
Pathogenic mutations in the leucine-rich repeat kinase-2 ( LRRK2 ) gene are the most common cause of familial Parkinson’s disease (PD). LRRK2 shows incomplete penetrance, yet the biological factors influencing disease expression remain unknown.
Objectives
To investigate whether genetic variants in aquaporin-4 ( AQP4 ), key in glymphatic system functioning, are associated with the penetrance of PD in LRRK2 carriers.
Methods
We analyzed baseline data from 302 LRRK2 carriers from the Parkinson’s Progression Markers Initiative. Fourteen AQP4 single nucleotide polymorphisms, previously implicated in PD, Alzheimer’s disease, or other neurodegenerative-related processes were tested for association with PD manifestation using logistic regression models adjusted for age and sex. Recessive, dominant, and additive genetic models were explored. Sensitivity analyses were conducted in G2019S carriers (n=273).
Results
One hundred twenty-seven (42%) LRRK2 carriers were asymptomatic, and 174 (58%) had PD. There were no differences between groups in age (63.5[9.5] vs. 62.2[7.5]) or number of women (52.0% vs. 55.7%). Homozygosity for the minor allele of rs9951307 was associated with reduced likelihood of PD (OR=0.28, 95% CI 0.10–0.64, p=0.005), whereas rs335930 homozygosity was associated with increased likelihood (OR=4.2, 95% CI 1.41–15.6, p=0.016). Additive models supported these associations, though rs335930 did not surpass the adjusted threshold. Results were consistent in the G2019S subgroup.
Conclusions
AQP4 polymorphisms may contribute to the variable penetrance of LRRK 2 mutations, potentially though modulation of glymphatic clearance. These findings support the glymphatic system as a relevant pathway in familial PD and highlight AQP4 as a candidate therapeutic target.
