Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
NIHR Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK.
Transl Psychiatry. 2021 Nov 4;11(1):561. doi: 10.1038/s41398-021-01674-3.
Observational evidence has implicated vitamin D levels as a risk factor in major depressive disorder (MDD). Confounding or reverse causation may be driving these observed associations, with studies using genetics indicating little evidence of an effect. However, genetic studies have relied on broad definitions of depression. The genetic architecture of different depression subtypes may vary since MDD is a highly heterogenous condition, implying potentially diverging requirements in therapeutic approaches. We explored the associations between vitamin D and two subtypes of MDD, for which evidence of a causal link could have the greatest clinical benefits: treatment-resistant depression (TRD) and atypical depression (AD). We used a dual approach, combining observational data with genetic evidence from polygenic risk scores (PRS) and two-sample Mendelian randomization (MR), in the UK Biobank. There was some evidence of a weak association between vitamin D and both incident TRD (Ncases = 830) and AD (Ncases = 2366) in observational analyses, which largely attenuated when adjusting for confounders. Genetic evidence from PRS and two-sample MR, did not support a causal link between vitamin D and either TRD (Ncases = 1891, OR = 1.01 [95%CI 0.78, 1.31]) or AD (Ncases = 2101, OR = 1.04 [95%CI 0.80, 1.36]). Our comprehensive investigations indicated some evidence of an association between vitamin D and TRD/AD observationally, but little evidence of association when using PRS and MR, mirroring findings of genetic studies of vitamin D on broad depression phenotypes. Results do not support further clinical trials of vitamin D in these MDD subtypes but do not rule out that small effects may exist that require larger samples to detect.
观察性证据表明，维生素 D 水平是重度抑郁症（MDD）的一个风险因素。混杂因素或反向因果关系可能导致了这些观察到的关联，而使用遗传学的研究表明，这种影响的证据很少。然而，遗传研究依赖于抑郁症的广泛定义。不同抑郁症亚型的遗传结构可能有所不同，因为 MDD 是一种高度异质的疾病，这意味着治疗方法可能存在潜在的差异。我们探讨了维生素 D 与 MDD 两种亚型之间的关联，对于这些亚型，因果关系的证据可能具有最大的临床获益：治疗抵抗性抑郁症（TRD）和非典型抑郁症（AD）。我们在英国生物库中采用了一种双重方法，将观察性数据与多基因风险评分（PRS）和两样本孟德尔随机化（MR）的遗传证据相结合。在观察性分析中，维生素 D 与新发 TRD（Ncases=830）和 AD（Ncases=2366）之间存在一些弱关联的证据，这些关联在调整混杂因素后基本减弱。PRS 和两样本 MR 的遗传证据并不支持维生素 D 与 TRD（Ncases=1891，OR=1.01 [95%CI 0.78, 1.31]）或 AD（Ncases=2101，OR=1.04 [95%CI 0.80, 1.36]）之间存在因果关系。我们的综合研究表明，维生素 D 与 TRD/AD 之间存在一些观察性关联的证据，但使用 PRS 和 MR 时，关联的证据很少，这与维生素 D 对广泛的抑郁症表型的遗传研究结果一致。结果不支持在这些 MDD 亚型中进一步进行维生素 D 的临床试验，但不能排除存在需要更大样本量才能检测到的小效应的可能性。
