LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder

Area of Science:

• Neuroscience
• Genetics

Background:

• Rapid eye movement (REM)-sleep behavior disorder (RBD) is a predictor of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy-bodies (DLB), and multiple system atrophy (MSA).
• The genetic overlap between RBD and PD/DLB is partial, and the specific role of Leucine-rich repeat kinase 2 (LRRK2) variants in RBD risk remains unclear.

Purpose of the Study:

• To investigate the association between LRRK2 variants and the risk of developing RBD.
• To determine if known PD-associated LRRK2 mutations contribute to RBD risk.

Main Methods:

• Sequencing of the full coding sequence, exon-intron boundaries, and untranslated regions of LRRK2 in 350 RBD patients and 869 controls using targeted next-generation sequencing.
• Application of regression and burden models to analyze the relationship between LRRK2 variants and RBD.

Main Results:

• No PD-causing pathogenic mutations were found in RBD patients.
• The LRRK2 p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR=0.66).
• A common variant, p.S1647T, showed a nominal association with increased RBD risk (OR=1.28).

Conclusions:

• Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype exhibit a decreased risk of developing RBD.
• Pathogenic mutations in LRRK2 likely have minimal to no role in the development of RBD.
• Further research is required to validate these findings and elucidate the protective mechanisms.