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. 2022 Nov 26;14(23):5031.
doi: 10.3390/nu14235031.

Associations of Genetically Predicted Vitamin B12 Status across the Phenome

Marie-Joe Dib  1   2 , Kourosh R Ahmadi  3 , Loukas Zagkos  1 , Dipender Gill  1 , Brooke Morris  4 , Paul Elliott  1   2   5 , Abbas Dehghan  1   2   5 , Ioanna Tzoulaki  1   2   6
Affiliations

Associations of Genetically Predicted Vitamin B12 Status across the Phenome

Marie-Joe Dib et al. Nutrients. .

Abstract

Variation in vitamin B12 levels has been associated with a range of diseases across the life-course, the causal nature of which remains elusive. We aimed to interrogate genetically predicted vitamin B12 status in relation to a plethora of clinical outcomes available in the UK Biobank. Genome-wide association study (GWAS) summary data obtained from a Danish and Icelandic cohort of 45,576 individuals were used to identify 8 genetic variants associated with vitamin B12 levels, serving as genetic instruments for vitamin B12 status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B12 status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B12 status. We used external GWAS summary statistics for replication of significant findings. Correction for multiple testing was taken into consideration using a 5% false discovery rate (FDR) threshold. MR analysis identified an association between higher genetically predicted vitamin B12 status and lower risk of vitamin B deficiency (including all B vitamin deficiencies), serving as a positive control outcome. We further identified associations between higher genetically predicted vitamin B12 status and a reduced risk of megaloblastic anaemia (OR = 0.35, 95% CI: 0.20-0.50) and pernicious anaemia (0.29, 0.19-0.45), which was supported in replication analyses. Our study highlights that higher genetically predicted vitamin B12 status is potentially protective of risk of vitamin B12 deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B12 status in disease diagnosis, progression and management remains to be investigated.

Keywords: Mendelian randomisation; deficiency; epidemiology; pernicious anaemia; vitamin B12.

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Conflict of interest statement

D.G. is employed part-time by Novo Nordisk, unrelated to the submitted work. The remaining authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Manhattan plot depicting associations between a genetic risk score of vitamin B12 status and 945 health outcomes in the UK Biobank.
Figure 2
Figure 2
Forest plots for the Mendelian randomisation effect of genetically predicted vitamin B12 levels on megaloblastic and pernicious anaemia. Blue, red and yellow squares and lines depict odds ratios and 95% confidence intervals for inverse-variance weighted (IVW), weighted median (WM) and Egger MR analyses, respectively.
See this image and copyright information in PMC

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