Shared Pathogenic Pathways Between REM Sleep Behavior Disorder and Neurodegenerative and Psychiatric Disorders

Area of Science:

• Genetics
• Neuroscience
• Sleep Medicine

Background:

• Isolated/idiopathic REM Sleep Behavior Disorder (iRBD) often precedes synucleinopathies.
• Emerging evidence suggests links between iRBD and other neurological/psychiatric conditions.

Purpose of the Study:

• To investigate shared genetic risks between iRBD and neurodegenerative/psychiatric disorders using polygenic risk scores (PRS) and rare variant analyses.
• To identify specific biological pathways and genes implicated in these associations.

Main Methods:

• Pathway-based PRS were constructed using GWAS data for neurodegenerative and psychiatric traits.
• Rare variant burden tests were conducted in iRBD cases and controls.
• Analyses included data from the International RBD Study Group and UK Biobank.

Main Results:

• Multiple pathways showed shared polygenic risk between iRBD and both neurodegenerative (e.g., Lewy body diseases) and psychiatric disorders (e.g., PTSD).
• The serotonin transport and chaperone-mediated autophagy pathways exhibited the strongest associations with iRBD.
• Five genes (GBA1, PLEKHM1, LRP2, P2RX1, HAP1) were associated with iRBD via rare variant analysis, with some replicated in Parkinson's disease and dementia with Lewy bodies.

Conclusions:

• These findings highlight a shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits.
• The results offer insights for early iRBD identification and understanding its underlying mechanisms.