Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
Biol Psychiatry. 2023 Oct 15;94(8):630-639. doi: 10.1016/j.biopsych.2023.01.027. Epub 2023 Feb 9.
Metabolic differences have been reported between individuals with and without major depressive disorder (MDD), but their consistency and causal relevance have been unclear.
We conducted a metabolome-wide association study of MDD with 249 metabolomic measures available in the UK Biobank (n = 29,757). We then applied two-sample bidirectional Mendelian randomization and colocalization analysis to identify potentially causal relationships between each metabolite and MDD.
A total of 191 metabolites tested were significantly associated with MDD (false discovery rate-corrected p < .05), which decreased to 129 after adjustment for likely confounders. Lower abundance of omega-3 fatty acid measures and a higher omega-6 to omega-3 ratio showed potentially causal effects on liability to MDD. There was no evidence of a causal effect of MDD on metabolite levels. Furthermore, genetic signals associated with docosahexaenoic acid colocalized with loci associated with MDD within the fatty acid desaturase gene cluster. Post hoc Mendelian randomization of gene-transcript abundance within the fatty acid desaturase cluster demonstrated a potentially causal association with MDD. In contrast, colocalization analysis did not suggest a single causal variant for both transcript abundance and MDD liability, but rather the likely existence of two variants in linkage disequilibrium with one another.
Our findings suggest that decreased docosahexaenoic acid and increased omega-6 to omega-3 fatty acids ratio may be causally related to MDD. These findings provide further support for the causal involvement of fatty acids in MDD.
已有研究报道，患有和不患有重度抑郁症（MDD）的个体之间存在代谢差异，但这些差异的一致性和因果关系尚不清楚。
我们对 UK Biobank 中的 29757 名个体进行了 MDD 的代谢组学全基因组关联研究（n=29757），共涉及 249 项代谢组学指标。然后，我们应用两样本双向孟德尔随机化和共定位分析来确定每种代谢物与 MDD 之间潜在的因果关系。
共检测到 191 种代谢物与 MDD 显著相关（经错误发现率校正的 P<0.05），在调整了可能的混杂因素后，这一数字减少到 129 种。ω-3 脂肪酸指标丰度降低，ω-6 与 ω-3 的比值升高，与 MDD 的易感性呈潜在因果关系。没有证据表明 MDD 对代谢物水平有因果影响。此外，与二十二碳六烯酸相关的遗传信号与脂肪酸去饱和酶基因簇中与 MDD 相关的基因座存在共定位。脂肪酸去饱和酶簇内基因-转录本丰度的事后孟德尔随机化分析表明，其与 MDD 之间存在潜在的因果关系。相比之下，共定位分析并没有提示单一致病变异与转录本丰度和 MDD 易感性都有关，而是很可能存在两个彼此处于连锁不平衡状态的变异。
我们的研究结果表明，二十二碳六烯酸减少和 ω-6 与 ω-3 脂肪酸比值增加可能与 MDD 存在因果关系。这些发现为脂肪酸在 MDD 中的因果作用提供了进一步的证据。
