Associations of Genetically Predicted Vitamin B12 Status across the Phenome

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.

Ancient DNA suggests anaemia and low bone mineral density as the cause for porotic hyperostosis in ancient individuals

“…This could have triggered changes in vitamin B12 metabolism. Here, I used a genetic score with four SNPs 37 related to vitamin B12 metabolism that can be recovered in the database of ancient samples used here (see Supplementary Table 4 ).…”

Ancient DNA confirms anaemia as the cause for Porotic Hyperostosis in ancient Neolithics together with a genetic architecture for low bone mineral density

“…This situation should have triggered changes in vitamin B12 metabolism. Here I used a genetic score with 4 SNPs (32) related to vitamin B12 metabolism that can be recovered in the database of ancient samples used here (see Supplementary Table 4).…”

Estimating effects of serum vitamin B12 levels on psychiatric disorders and cognitive impairment: a Mendelian randomization study

“…However, no explicit associations have been identified between vitamin B12 levels and coronary artery disease, type 2 diabetes, measures of obesity, or Alzheimer’s disease 19, 20 . Recently, a phenome-wide study based on the UK Biobank confirmed the association between increased vitamin B12 levels and reduced odds of pernicious anemia 21 . However, it remains unclear whether the genetically predicted vitamin B12 levels are associated with psychiatric disorders and cognitive impairment, due to limited statistical power in previous studies.…”