Background: Depression is a disabling and highly prevalent condition where genetic and epigenetic differences, such as DNA methylation (DNAm), contribute to prediction of disease liability. Method: We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N=8,898, mean age=49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined=2,049, mean age=79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N=423, mean age=17.1 years). Result: Wide-spread associations were found between PRS constructed using genetic risk variants for depression and DNAm in cytosine- guanine dinucleotide (CpG) probes that localised to genes involved in immune responses and neural development (NCpG=599, pBonferroni<0.05, p<6.5e-8). The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r=0.83) and in adolescents (r=0.76). Additional analysis on the methylome-wide associations was conducted for each lead genetic risk variant. Over 40% of the independent genetic risk variants showed associations with CpG probe DNAm located in both the same (cis) and distal probes (trans) to the genetic loci (pBonferroni<0.045). Subsequent Mendelian randomisation analysis showed that DNAm and depression are mutually causal (pFDR<0.039), and there is a greater number of causal effects found from DNAm to depression (DNAm to depression: pFDR ranged from 0.045 to 2.06e-120; depression to DNAm: pFDR ranged from 0.046 to 2.1e-23). Conclusion: Polygenic risk scores for depression, especially those constructed from genome-wide significant genetic risk variants, showed epigenome-wide methylation association differences in the methylome associated with immune responses and brain development. We also found evidence from Mendelian randomisation evidence that DNAm may be causal to depression, as well as a causal consequence of depression.

中文翻译：

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抑郁症遗传风险的全 DNA 甲基化关联研究涉及抗原加工和免疫反应

背景：抑郁症是一种致残且高度流行的疾病，其中遗传和表观遗传差异，如 DNA 甲基化 (DNAm)，有助于预测疾病倾向。方法：我们通过在苏格兰一代（N = 8,898，平均年龄 = 49.8 岁）中进行全甲基化组关联研究 (MWAS) 并在洛锡安出生队列中进行复制，研究了抑郁症的多基因风险评分 (PRS) 与 DNAm 之间的关联。 1921 年和 1936 年以及雅芳父母和儿童纵向研究 (ALSPAC) 中的成人（N 组合 = 2,049，平均年龄分别为 79.1、69.6 和 47.2 岁）。我们还在 ALSPAC 儿童（N = 423，平均年龄 = 17.1 岁）中进行了复制 MWAS。结果：发现使用抑郁症遗传风险变异构建的 PRS 与胞嘧啶鸟嘌呤二核苷酸 (CpG) 探针中的 DNAm 之间存在广泛关联，这些探针定位于参与免疫反应和神经发育的基因（NCpG=599，pBonferroni<0.05，p<6.5e -8). 显着关联的效应大小在成人 (r=0.83) 和青少年 (r=0.76) 的发现和复制样本之间高度相关。对每个先导遗传风险变异进行了全甲基化关联的额外分析。超过 40% 的独立遗传风险变异显示与位于相同 (cis) 和远端探针 (trans) 的 CpG 探针 DNAm 与遗传基因座 (pBonferroni<0.045) 相关。随后的孟德尔随机化分析表明，DNAm 和抑郁症是相互因果关系的（pFDR<0.039），并且从 DNAm 到抑郁症发现了更多的因果效应（DNAm 到抑郁症：pFDR 范围从 0.045 到 2.06e-120；抑郁症到 DNAm：pFDR 范围从 0.046 到 2.1e-23）。结论：抑郁症的多基因风险评分，尤其是那些由全基因组显着遗传风险变异构建的评分，显示出与免疫反应和大脑发育相关的甲基化组的表观基因组范围的甲基化关联差异。我们还发现来自孟德尔随机化证据的证据表明 DNAm 可能是抑郁症的因果关系，也是抑郁症的因果关系。尤其是由全基因组显着遗传风险变异构建的那些，在与免疫反应和大脑发育相关的甲基化组中显示出表观基因组范围内的甲基化关联差异。我们还发现来自孟德尔随机化证据的证据表明 DNAm 可能是抑郁症的因果关系，也是抑郁症的因果关系。尤其是由全基因组显着遗传风险变异构建的那些，在与免疫反应和大脑发育相关的甲基化组中显示出表观基因组范围内的甲基化关联差异。我们还发现来自孟德尔随机化证据的证据表明 DNAm 可能是抑郁症的因果关系，也是抑郁症的因果关系。