Introduction: Epidemiological studies suggest that patients with Parkinson ′s 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. Methods: 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 (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. Results: Our 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. Conclusion: Overall, our analyses indicate lack of genetic link between B12 levels or metabolism and PD.

PH has had research support from Parkinson Canada, Parkinson Quebec, Fonds de Recherche Quebec - Sante, the Natural Sciences and Engineering Research Council of Canada, the Weston Brain Institute, the Michael J Fox Foundation for Parkinson′s Research, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the New Frontiers in Research Fund and Healthy Brains for Healthy Lives. PH has received payments from Abbvie, adMare BioInnovations, ConSynance Therapeutics, Neurodiem, Sanford Burnham Prebys, Sunovion, ConSynance Therapeutics and Througline Strategy and is a Scientific Advisor to Talon Pharmaceuticals. Z.G.O received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Simcere, Guidepoint, Lighthouse and Deerfield. Other authors declare no conflicts of interest.

This study was financially supported by grants from The Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives initiative (HBHL), Parkinson Canada

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Ethics committee of McGill University gave ethical approval for this work.

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All supplementary materials, including additional tables and figures, are available in the Supplementary Materials section. The data used in the preparation of this article were obtained from the AMP PD Knowledge Platform (https://www.amp-pd.org) and the UKBB via Neurohub (https://www.mcgill.ca/hbhl/neurohub). The full GWAS summary statistics for the 23andMe inc., discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit research.23andme.com/collaborate/ for more information and to apply to access the data. All code used in the analysis is available on our GitHub repository, which can be accessed at https://github.com/senkkon/B12-level-and-Parkinson-s-disease.

https://github.com/senkkon/B12-level-and-Parkinson-s-disease