Investigating the Genetic Relationship Between Vitamin B12 Metabolism and Parkinson Disease

Epidemiologic studies suggest that patients with Parkinson disease (PD) may have lower levels of vitamin B12 compared with healthy controls, and it was proposed that patients with PD could benefit from vitamin B12 supplementation. Functional studies have shown that B12 could modify LRRK2 activity and may directly interact with alpha-synuclein. The aim of this study was to investigate the role of common and rare variants in genes related to B12 metabolism and assess the potential causal relationships between B12 levels and PD risk, age at onset, and motor/cognitive progression.

We investigated the association between common and rare variants in genes involved in vitamin B12 metabolism. Rare variants (minor allele frequency <0.01) were analyzed using the optimal sequence kernel association test in 4,815 patients with PD and 65,607 controls from 2 independent cohorts. We constructed pathway-specific polygenic risk scores (PRSs) for genes essential to B12 metabolism and for genes identified in previous genome-wide association studies (GWASs) on B12 metabolism. Mendelian randomization and genetic correlation analyses were applied to explore the relationship between vitamin B12 levels and PD risk, age at onset, and disease progression.

Our analysis showed no associations between common variants of genes crucial in B12 metabolism and PD. Pathway PRSs identified nominal association between B12-related genes and PD (odds ratio [OR] = 1.061, 95% CI 1.004-1.121, p = 0.038), which did not survive Bonferroni correction. In the rare-variant analysis, we identified a significant association between variants with high Combined Annotation Dependent Depletion scores in the CUBN gene (p = 6.07E-05; Pfdr = 0.005) in the Accelerating Medicines Partnership-PD cohort, driven by the benign variant p.G3114S (OR = 3.3; p = 3.56E-05); however, this was not validated in the meta-analysis. We did not identify a potentially causal relationship between vitamin B12 levels and the risk, age at onset, or progression of PD. In addition, no genetic correlation was observed between vitamin B12 and PD risk or age-at-onset GWASs.

Overall, our analyses indicate lack of genetic link between B12 levels or metabolism and PD.