Vitamin D: marker, cause or consequence of depression? An exploration using genomics

Background: Observational studies suggest an association between circulating vitamin D and depression. Trials testing the effect of vitamin D supplementation on depression reported inconclusive findings. It remains unknown whether the vitamin D-depression association stems from shared etiology or from a direct causal relationship. We explored the nature of the association between 25-hydroxyvitamin D (25-OH-D) and major depressive disorder (MDD) exploiting data and statistical tools from genomics. Methods: Results from the two largest GWAS on 25-OH-D (79,366 samples) and major depressive disorder (MDD; 135,458 cases and 344,901 controls) were applied to individual-level data (>2,000 subjects with measures of genotype, circulating 25-OH-D and DSM-IV lifetime MDD) and summary-level data analyses. A genetic association between 25-OH-D and MDD was tested by polygenic risk scores (PRS) and by estimating genetic correlation between traits. Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between 25-OH-D and depression. Results: In individual-level data, the 25-OH-D PRS was associated (p=1.4e-20) with 25-OH-D level, but not with lifetime MDD. Conversely, the MDD PRS was associated with MDD (p=2.3e-5), but not with 25-OH-D. In summary-level data analyses, the rg between the traits was low and not significant (-0.06, p=0.11). 2SMR analyses provided no evidence of a significant causal role of 25-OH-D for MD and vice versa. Conclusions: The use of genomics tools indicated that shared etiology or direct causality between vitamin D concentrations and depression is unlikely: vitamin D may represent a marker rather than a cause, or consequence, of depression.