Elucidating the Role of Vitamin D in Depression

Abstract

Depression is a debilitating and prevalent mental disorder that creates huge societal and economic burden. Vitamin D has been implicated in several mental disorders, but existing studies on the role of circulating vitamin D (25-hydroxyvitamin D [25(OH)D]) in depression have yielded inconsistent findings. Given that vitamin D levels are readily modifiable through dietary supplementation and/or lifestyle changes, understanding the relationship between vitamin D and depression could lead to cost-effective public health strategies for preventing depression. In this dissertation, we aimed to elucidate this relationship by leveraging data from large genome-wide association studies (GWAS), longitudinal registry, and epidemiologic cohorts. In Chapter 1, we explored the association between 25(OH)D levels and the risk of incident major depressive disorder (MDD) in a general healthcare population (n=233,970). Low 25(OH)D levels were associated with an increased risk for 5-year MDD. Our study also revealed that these associations were stronger among older adults and white or Asian adults. In Chapter 2, we performed a two-sample bidirectional Mendelian randomization analysis, using summary-level data from the largest GWAS studies of 25(OH)D and depression to date, to evaluate the causal relationship between 25(OH)D and depression. There was no causal association between average lifelong 25(OH)D levels and depression, although the possibility of weaker causal effects or threshold effects remains. In Chapter 3, we examined the association between maternal vitamin D status during pregnancy and offspring depression during childhood and adolescence, and further assessed whether polygenic risk for depression (PRS) modified the association. There was no evidence for a strong association between maternal vitamin D status and offspring depression during either childhood or adolescence. Additionally, there were no interactions between PRS and maternal 25(OH)D on offspring depression. These findings suggest that vitamin D deficiency is associated with an increased risk for depression, although small changes in 25(OH)D are not causally related to depression. There was little evidence for an association between prenatal 25(OH)D exposures and early life depression. Further work is needed to understand threshold effects of 25(OH)D on health outcomes and whether there are critical windows of vulnerability to vitamin D exposure.