Associations of Genetically Predicted Vitamin B(12) Status across the Phenome

Variation in vitamin B(12) 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 B(12) 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 B(12) levels, serving as genetic instruments for vitamin B(12) status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B(12) status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B(12) 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 B(12) 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 B(12) 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 B(12) status is potentially protective of risk of vitamin B(12) deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B(12) status in disease diagnosis, progression and management remains to be investigated.