Objective: The aim of this study was to investigate the genetic association and causal link between vitamin B12 and the risk and progression of Parkinson’s disease (PD).

Background: The human body cannot synthesize vitamin B12 and relies on external sources. However, there are genes implicated in its metabolism, including MTRR, MTR, CUBN, MMACHC, FUT2 and TCN2. Several studies have shown that patients with PD tend to have lower levels of vitamin B12 compared to healthy controls and suggested that supplementation with vitamin B12 could potentially reduce the risk of PD. The role of vitamin B12 in the pathogenesis of PD has been linked to several mechanisms, including the modulation of LRRK2 activity and direct interactions with alpha-synuclein. Yet, no genetic studies have conclusively linked B12 levels and PD or identified genetic factors leading to lower B12 in PD patients.

Method: We investigated the potential association between genes involved in vitamin B12 metabolism and PD by examining rare variants (minor allele frequency < 1%) using SKAT-O in two independent cohorts (PD: 4,815; controls: 65,607). We applied Mendelian randomization and analyzed genetic correlations to explore the relationship between vitamin B12 levels and PD risk, age-at-onset, and disease progression, using genome-wide association studies including European ancestry participants without sample overlap.

Results: In our study, we discovered a significant association between rare variants with high CADD scores in the CUBN (p=0.0002) and TCN2 (p=0.0087) genes, with the risk of PD in the meta-analysis of two independent cohorts. However, the specific variant p.G3114S, which primarily contributed to the association for rare CUBN variants in the AMP-PD cohort (OR=3.3; p=3.56E-05), did not show significance in the UKBB cohort (OR=1.12; p=0.22). Furthermore, when we excluded this variant and conducted the burden analysis again, CUBN no longer showed any significant association. Notably, the high CADD score variants in TCN2 were exclusive to the UKBB cohort.

We did not find a causal effect of vitamin B12 level on the risk or progression of PD (OR=1.03 (0.92-1.16), p=0.1). We also did not find any genetic correlation between the two traits (rg=-0.05, p=0.69).

Conclusion: Our analysis suggests a possible association between rare B12 metabolism gene variants and PD; however, no causal link or genetic correlation was confirmed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-genetic-relationship-between-vitamin-b12-deficiency-and-parkinsons-disease/