GWAS by Subtraction to Disentangle RBD Genetic Background from α-Synucleinopathies

Area of Science:

• Neuroscience
• Genetics
• Sleep Medicine

Background:

• Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia during REM sleep.
• Idiopathic RBD (iRBD) is a strong prodromal marker for α-synucleinopathies, with a high conversion rate to neurodegenerative conditions.
• RBD converters often exhibit a more severe clinical trajectory.

Purpose of the Study:

• To investigate the genetic architecture of iRBD and its relationship with α-synucleinopathies.
• To determine if iRBD is a distinct genetic entity or an early sign of neurodegeneration.

Main Methods:

• Genomic Structural Equation Modeling (GenomicSEM) was employed.
• A GWAS-by-subtraction approach was utilized to differentiate genetic factors of iRBD from shared liabilities in α-synucleinopathies.

Main Results:

• The SNCA locus was identified as a key genetic regulator of iRBD susceptibility.
• iRBD demonstrated a partially distinct genetic signature but retained genomic overlap with neurodegenerative traits.
• This suggests iRBD's genetic architecture lies on a continuum of α-synucleinopathy risk.

Conclusions:

• iRBD's genetic underpinnings are partially distinct yet linked to broader α-synucleinopathy risk.
• Neuroanatomical correlates may indicate early trajectories toward neurodegeneration in iRBD patients.
• Findings support developing biomarkers for disease stratification and improved early intervention strategies.