Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, United Kingdom.
MRC Human Genetics Unit, The Institute of Genetics and Cancer, The University of Edinburgh, United Kingdom.
EBioMedicine. 2022 May;79:104000. doi: 10.1016/j.ebiom.2022.104000. Epub 2022 Apr 29.
DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions.
Here, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPAC, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432).
Each trait MS was significantly associated with its corresponding phenotype in GS (β=0.089-1.457) and in ALSPAC (β=0.078-2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (β=0.053-0.145). After accounting for relevant lifestyle factors, MS for educational attainment (β=0.094) and alcohol consumption (MS<0.01-0.5; β=-0.069-0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes.
We showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (p<0.05), but not when smoking, alcohol consumption, and BMI were also included as covariates. MDD results did not replicate in the smaller, female-only independent ALSPAC cohort (N=565; N=9,502), potentially due to demographic differences or low statistical power, but effect sizes were consistent with the direction reported in GS. DNAm scores for modifiable MDD risk factors may contribute to disease vulnerability and, in some cases, explain additional variance to their observed phenotypes.
Wellcome Trust.
DNA 甲基化（DNAm）与随时间变化的环境因素有关，这些因素导致了重度抑郁症（MDD）的发病风险。我们试图验证生活方式和生化因素的 DNAm 特征是否与 MDD 相关，以揭示 MDD 风险的动态生物标志物，这些标志物可能可以通过生活方式干预来改善。
在这里，我们使用之前在大规模甲基化全基因组关联研究中报道的 CpG 位点，在苏格兰一代研究（GS）（N=9502）和复制队列阿伯丁儿童纵向研究（ALSPAC）（N=565）中，为生活方式（BMI、吸烟、饮酒和教育程度）和生化因素（高密度脂蛋白（HDL）和总胆固醇）计算了多个 p 值阈值的甲基化评分（MS）。我们还比较了它们对 MDD 的预测准确性，与 GS 中独立的 GS 子样本（N=4432）中的 MDD MS 进行了比较。
在 GS 中，每个特征 MS 与相应表型呈显著相关（β=0.089-1.457），在 ALSPAC 中也呈显著相关（β=0.078-2.533）。在 GS 中，每个 MS 与 MDD 相关，在调整相应表型后，也具有显著相关性（β=0.053-0.145）。在考虑了相关的生活方式因素后，教育程度（β=0.094）和饮酒（MS<0.01-0.5；β=-0.069-0.083）的 MS 在 GS 中仍与 MDD 显著相关。在独立的 GS 子样本中，吸烟（AUC=0.569）和教育程度（AUC=0.585）MS 比 MDD MS（AUC=0.553）能够更好地区分 MDD 与对照组。尽管在调整相应的 MS 表型后，所有特征的效应方向一致，但在 ALSPAC 中，涉及 MDD 的分析并未复制，尽管在调整吸烟、饮酒和 BMI 作为协变量时，结果仍然显著。
我们表明，生活方式和生化 MS 与 MDD 相关，即使在调整了相应的表型后，也具有统计学意义（p<0.05），但当将吸烟、饮酒和 BMI 也作为协变量时，则不具有统计学意义。在规模较小、仅为女性的独立 ALSPAC 队列（N=565；N=9502）中，MDD 结果并未复制，这可能是由于人口统计学差异或统计能力较低，但效应大小与在 GS 中报告的方向一致。可改变的 MDD 风险因素的 DNAm 评分可能有助于疾病易感性，并且在某些情况下，可能会解释其观察到的表型的额外差异。
惠康信托基金会。
