Investigating the genetic relationship between vitamin B12 deficiency and Parkinson's disease

IntroductionEpidemiological studies suggest that patients with Parkinsons disease (PD) may have lower levels of vitamin B12 compared to healthy controls, and it was proposed that PD patients could benefit from vitamin B12 supplementation. Functional studies have shown that B12 could modify LRRK2 activity and may directly interact with alpha-synuclein. This study aimed 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. MethodsWe 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 (SKAT-O) in 4,815 PD patients and 65,607 controls from two independent cohorts. We constructed pathway-specific polygenic risk scores (PRS) for genes essential to B12 metabolism and for genes identified in previous genome-wide association studies (GWAS) 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. ResultsOur analysis showed no associations between common variants of genes crucial in B12 metabolism and PD. Pathway PRS identified nominal association between B12-related genes and PD (OR = 1.061, 95% CI: 1.004-1.121, p = 0.038), which did not survive Bonferroni correction. In the rare variants analysis, we identified a significant association between variants with high CADD scores in the CUBN gene (P=6.07E-05; Pfdr=0.005) in the AMP-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. Additionally, no genetic correlation was observed between vitamin B12 and PD risk or age-at-onset GWASs. ConclusionOverall, our analyses indicate lack of genetic link between B12 levels or metabolism and PD.