Relationships between 25-Hydroxyvitamin D and Alpha- synucleinopathies: A Mendelian Randomization Study

BackgroundAlpha-synucleinopathies, including Parkinsons disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative diseases characterized by abnormal aggregation of alpha-synuclein. Isolated REM sleep behavior disorder (iRBD) is a prodromal stage of these disorders. While 25-hydroxyvitamin D (25[OH]D) has been linked to PD in previous studies, its causal role remains unclear, and its relationship with iRBD, MSA, and DLB is rarely explored. ObjectivesThis study used Mendelian randomization (MR) to investigate the causal relationship between 25(OH)D and iRBD, PD, MSA, and DLB. MethodsGWAS data for 25(OH)D were sourced from the UK Biobank, and outcome data for PD were obtained from the latest FinnGen R12 database. Data for iRBD, PD onset age, PD clinical progression, MSA, and DLB were derived from a broader European population. The study had two steps: univariable MR (UVMR) using genome-wide IV selection as the primary analysis, with replication analyses using biological function-based IV selection and sunlight exposure and vitamin D supplementation-related factors as exposures. Multivariable MR (MVMR) was then conducted to adjust for 13 covariates, testing the robustness of findings. Results25(OH)D showed a significant protective effect on MSA across all UVMR (both primary and replication) and MVMR analyses. It also exhibited a nominal protective effect on PD in the Finnish population in primary UVMR analysis, but this was not replicated. No associations were found between 25(OH)D and iRBD, PD onset age, PD clinical progression, or DLB. Power analyses indicated insufficient sensitivity to detect weak effects of 25(OH)D on iRBD and DLB. ConclusionsMR analysis supports a protective role of 25(OH)D against MSA. While nominally protective for PD in the Finnish population, the effect was not robust. Weak effects on iRBD and DLB cannot be excluded.