Abstract
Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired 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. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) 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. In individual-level data analyses, 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 analyses, 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). Applying genomics tools indicated 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.
Highlights
In recent years a growing interest has emerged in the potential value of nutritional supplementation in mood disorders
In the present study, we examined the nature of the association of 25-OH-D and n3-PUFA with major depressive disorder (MDD) using the latest data and analytical tools developed in genomics
We found no significant evidence of shared genetic risk or direct causality between vitamin D or n3-PUFA and MDD; unresolved confounding[13] should be considered at this stage, the most likely explanation for the association reported by observational studies
Summary
In recent years a growing interest has emerged in the potential value of nutritional supplementation in mood disorders. Large-scale randomized controlled trials such as MoodFOOD1 (N ~ 1000) or VITAL-DEP2 (N ~ 25 000) have been established to test the effect of supplementation in the prevention of depression. The rationale for these interventions was inspired from epidemiological evidence of an inverse association between depression and circulating concentrations of compounds that could be supplemented, such as vitamin D and omega-3 polyunsaturated fatty acids (n3-PUFA). Previous clinical studies attempted to translate this observational evidence in interventions: meta-analyses[9,10,11,12] pooling results from trials testing
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