A role for vitamin D and omega-3 fatty acids in major depression? An exploration using genomics
Background: Trials testing the effect of vitamin D or omega-3 fatty acids (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were boosted by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Methods: Results from GWAS on 25-OH-D (N=79366), n3-PUFA (N=24925) and MDD (135458 cases, 344901 controls) were applied to individual-level data (>2,000 subjects with measures of genotype, DSM-IV lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. Outcome: In individual-level data, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p=1.4e-20, PRS N3-PUFA p=9.3e-6, PRS MDD p=1.4e-4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p=0.50) or n3-PUFA (p=0.16), or for a causal role of MDD on 25-OH-D (p=0.25) or n3-PUFA (p=0.66). Conclusions: Applying genomics tools indicated that that shared genetic risk or direct causality between 25-OH-D, n3-PUFA and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.
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