Mendelian Randomization Analysis of the Brain, Cerebrospinal Fluid, and Plasma Proteome Identifies a Potential...

Isolated REM sleep behavior disorder (iRBD) is among the strongest clinical markers of prodromal α-synucleinopathies. Pinpointing causal proteins may open the door to early diagnosis and disease-modifying therapies.

We performed a proteome-wide Mendelian randomization (MR) using protein QTLs from brain, cerebrospinal fluid, and plasma, with GWAS data from 1,061 iRBD cases and 8,386 controls. The findings were validated in an independent cohort of 35,559 individuals from Iceland, utilizing plasma proteome data. To assess the directionality and robustness of the association, we additionally performed Steiger filtering and Bayesian colocalization analyses. PheWAS was applied to explore pleiotropy and safety.

Among hundreds of proteins screened, only plasma SPOCK3 (SPARC/Osteonectin, Cwcv and Kazal-like Domains Proteoglycan 3) showed a significant causal link to iRBD (OR = 2.07, 95% CI = 1.50-2.84, P = 7.45 × 10⁻⁶). No brain or CSF proteins met significance. In the independent cohort, MR confirmed the association between SPOCK3 and iRBD risk (OR = 1.39, 95% CI: 1.03-1.88, P = 0.029). Steiger filtering supported the inferred causal direction (P < 0.05), and colocalization analysis revealed a high posterior probability of a shared causal variant between SPOCK3 levels and iRBD risk (PPH4 = 0.96). PheWAS revealed no major off-target associations.

Plasma SPOCK3 emerges as a candidate peripheral biomarker for iRBD. While Mendelian randomization supports a potential causal association, the underlying mechanisms-such as extracellular matrix involvement-require further experimental validation.