Abstract
BACKGROUND: Vitamin B12 deficiency can lead to pernicious anemia and has been associated with various neuropsychiatric diseases and cognitive decline. However, it is unclear whether increasing serum vitamin B12 levels can help to prevent the onset of psychiatric disorders and cognitive impairment in the general population. METHODS: Leveraging large-scale genome-wide association studies (GWASs), we conducted Mendelian randomization (MR) and sensitivity analyses to estimate the potential effects of serum vitamin B12 levels on eight psychiatric disorders, educational attainment and cognitive performance. We conducted additional MR analyses utilizing within-sibship studies to mitigate potential residual confounding effects. RESULTS: As a positive control, we confirm that a one standard deviation increase in genetically increased vitamin B12 levels is strongly protective against pernicious anemia (odds ratio, OR = 0.24; 95% CI: 0.15-0.40; p-value = 2.1×10(-8)). In contrast, MR estimates of vitamin B12 effects on all eight psychiatric disorders, educational attainment and cognitive performance largely overlap with the null. For example, a one standard deviation increase in genetically predicted vitamin B12 levels is associated with an OR of 1.02 for depression (95% CI: 1.00 - 1.04; p-value = 0.11), a 0.0077 standard deviation increase in educational attainment (95% CI: -0.010 - 0.025; p-value = 0.39) and a 0.013 standard deviation increase in cognitive performance (95% CI: -0.0088 - 0.035; p-value = 0.24). No significant associations are identified in sensitivity analyses excluding pleiotropic genetic instruments or MR analyses based on within-sibship studies. CONCLUSIONS: Our findings suggest that increasing overall vitamin B12 levels may not meaningfully protect against the investigated psychiatric disorders or cognitive impairment in the general population.