Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden.
Department of Clinical Sciences/Psychiatry, Umeå University, Umeå, Sweden.
Clin Epigenetics. 2023 Jan 4;15(1):1. doi: 10.1186/s13148-022-01394-5.
Depression is a multifactorial disorder representing a significant public health burden. Previous studies have linked multiple single nucleotide polymorphisms with depressive phenotypes and suicidal behavior. MAD1L1 is a mitosis metaphase checkpoint protein that has been linked to depression in GWAS. Using a longitudinal EWAS approach in an adolescent cohort at two time points (n = 216 and n = 154), we identified differentially methylated sites that were associated with depression-related genetic variants in MAD1L1. Three methylation loci (cg02825527, cg18302629, and cg19624444) were consistently hypomethylated in the minor allele carriers, being cross-dependent on several SNPs. We further investigated whether DNA methylation at these CpGs is associated with depressive psychiatric phenotypes in independent cohorts. The first site (cg02825527) was hypomethylated in blood (exp(β) = 84.521, p value ~ 0.003) in participants with severe suicide attempts (n = 88). The same locus showed increased methylation in glial cells (exp(β) = 0.041, p value ~ 0.004) in the validation cohort, involving 29 depressed patients and 29 controls, and showed a trend for association with suicide (n = 40, p value ~ 0.089) and trend for association with depression treatment (n = 377, p value ~ 0.075). The second CpG (cg18302629) was significantly hypomethylated in depressed participants (exp(β) = 56.374, p value ~ 0.023) in glial cells, but did not show associations in the discovery cohorts. The last methylation site (cg19624444) was hypomethylated in the whole blood of severe suicide attempters; however, this association was at the borderline for statistical significance (p value ~ 0.061). This locus, however, showed a strong association with depression treatment in the validation cohort (exp(β) = 2.237, p value ~ 0.003) with 377 participants. The direction of associations between psychiatric phenotypes appeared to be different in the whole blood in comparison with brain samples for cg02825527 and cg19624444. The association analysis between methylation at cg18302629 and cg19624444 and MAD1L1 transcript levels in CD cells shows a potential link between methylation at these CpGs and MAD1L1 expression. This study suggests evidence that methylation at MAD1L1 is important for psychiatric health as supported by several independent cohorts.
抑郁症是一种多因素障碍，代表着重大的公共健康负担。先前的研究已经将多个单核苷酸多态性与抑郁表型和自杀行为联系起来。 MAD1L1 是一种有丝分裂中期检查点蛋白，在 GWAS 中与抑郁症有关。我们使用青少年队列的纵向 EWAS 方法在两个时间点（n=216 和 n=154），鉴定了与 MAD1L1 中与抑郁相关的遗传变异相关的差异甲基化位点。三个甲基化部位（cg02825527、cg18302629 和 cg19624444）在次要等位基因携带者中持续低甲基化，与多个 SNP 交叉依赖。我们进一步研究了这些 CpG 位点的 DNA 甲基化是否与独立队列中的抑郁精神表型有关。第一个位点（cg02825527）在血液中（β 值为 84.521，p 值0.003）在有严重自杀企图的参与者（n=88）中低甲基化。同一部位在验证队列中（涉及 29 名抑郁患者和 29 名对照）的神经胶质细胞中显示出更高的甲基化（β 值=0.041，p 值0.004），并显示出与自杀（n=40，p 值0.089）和与抑郁治疗（n=377，p 值0.075）的关联趋势。第二个 CpG（cg18302629）在抑郁参与者（β 值=56.374，p 值0.023）的神经胶质细胞中显著低甲基化，但在发现队列中没有关联。最后一个甲基化位点（cg19624444）在严重自杀企图者的全血中低甲基化；然而，这种关联在统计学上具有边缘意义（p 值0.061）。然而，该位点在包含 377 名参与者的验证队列中与抑郁治疗有很强的关联（β 值=2.237，p 值~0.003）。与 cg02825527 和 cg19624444 相比，全血中的精神表型与脑组织样本之间的关联方向似乎不同。cd 细胞中 cg18302629 和 cg19624444 处的甲基化与 MAD1L1 转录水平之间的关联分析表明，这些 CpG 处的甲基化与 MAD1L1 表达之间存在潜在联系。这项研究提供了一些独立队列的支持证据，表明 MAD1L1 处的甲基化对精神健康很重要。
