A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison-猫眼课题宝

DOI：

10.1101/2023.10.27.23297630

发表时间：

2023-10

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其他

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作者：

Xueyi Shen;M. Barbu;D. Caramaschi;R. Arathimos;D. Czamara;F. David;Anna Dearman;Evelyn Dilkes;Marisol Herrera-Rivero;F. Huider;L. Kühn;Kuan-Chen Lu;T. Palviainen;A. Schowe;Gemma L Shireby;Antoine Weihs;Chloe C. Y. Wong;E. Davyson;Hannah Casey;Mark J Adams;Antje-Kathrin Allgaier;Michael Barber;Joe Burrage;A. Caspi;Ricardo Costeira;Erin C. Dunn;L. Feldmann;J. Frank;F. Freisleder;D. Gadd;E. Greimel;E. Hannon;Sarah E Harris;G. Homuth;D. M. Howard;S. Iurato;T. Korhonen;Tzu-Pin Lu;N. G. Martin;Jade Martins;E. Mcdermott;S. Meinert;P. Navarro;M. Ollikainen;Verena Pehl;C. Piechaczek;A. D. Scherff;F. Stein;F. Streit;A. Teumer;H. Völzke;J. Dongen;R. Walker;Natan Yusupov;L. Arseneault;Jordana T. Bell;Klaus Berger;E. Binder;D. Boomsma;Simon R Cox;U. Dannlowski;K. Evans;Helen L. Fisher;A. Forstner;Hans‐Jörgen Grabe;J. Kaprio;T. Kircher;Johannes Kopf-Beck;M. Kumari;Po-Hsiu Kuo;Qingqin S. Li;T. Moffitt;Hugh Mulcahy;Therese M. Murphy;Gerd Schulte-Körne;J. Mill;C. Lewis;Optima Working Group;Pgc Mdd;N. Wray;Andrew M. McIntosh

重度抑郁症 (MD) 是全球疾病负担的主要原因，实验和基于人群的研究均表明 DNA 甲基化 (DNAm) 的差异可能与该疾病有关。然而，之前的 DNAm 研究迄今为止尚未得到广泛重复，这表明需要进行更大规模的荟萃分析研究。在本研究中，精神病基因组学联盟重度抑郁症工作组对 24,754 名欧洲血统参与者（5,443 名 MD 病例）和一个东亚样本（243 例，1846 名对照）的 18 项研究进行了终生 MD 的全甲基化关联分析 (MWAS) 荟萃分析。我们确定了 15 个与终生 MD 相关的 CpG 位点，具有全甲基化显着性 (p < 6.42e-8)。欧洲血统的顶级 CpG 效应大小与独立东亚 MWAS 的效应大小呈正相关（对于重要 CpG 位点，r = 0.482 和 p = 0.068；对于前 100 个 CpG 位点，r = 0.261 和 p = 0.009）。在样本外分类分析中，使用 MWAS 摘要统计数据创建的甲基化评分 (MS) 与 MD 状态显着相关（β = 0.122，p = 0.005，AUC = 0.53）。 MS 还与五种炎症标志物相关，其中与肿瘤坏死因子 Beta 的关联性最强（β=-0.154，p=1.5e-5）。孟德尔随机化 (MR) 分析表明，23 个 CpG 位点可能与 MD 存在因果关系，其中 6 个位点在独立的 mQTL 数据集中重复（Wald 比率检验，绝对 {beta} 范围为 0.056 至 0.932，p 范围为 7e-3 至 4.58e-6）。位于主要组织相容性复合体 (MHC) 区域的 CpG 位点显示了 MR 分析与 MD 相关的最有力证据。我们的研究提供了 DNA 甲基化变异与 MD 相关的证据，并进一步提供了支持免疫系统参与的证据。不同祖先的更大样本量可能会揭示可复制的关联，以改善机械推论，并有可能为分子靶标识别提供信息。

Major Depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation (DNAm) may be associated with the condition. However, previous DNAm studies have not so far been widely replicated, suggesting a need for larger meta-analysis studies. In the present study, the Psychiatric Genomics Consortium Major Depressive Disorder working group conducted a meta-analysis of methylome-wide association analysis (MWAS) for life-time MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1846 controls). We identified fifteen CpG sites associated with lifetime MD with methylome-wide significance (p < 6.42e-8). Top CpG effect sizes in European ancestries were positively correlated with those from an independent East Asian MWAS (r = 0.482 and p = 0.068 for significant CpG sites, r = 0.261 and p = 0.009 for the top 100 CpG sites). Methylation score (MS) created using the MWAS summary statistics was significantly associated with MD status in an out-of-sample classification analysis (beta = 0.122, p = 0.005, AUC = 0.53). MS was also associated with five inflammatory markers, with the strongest association found with Tumor Necrosis Factor Beta (beta=-0.154, p=1.5e-5). Mendelian randomisation (MR) analysis demonstrated that 23 CpG sites were potentially causally associated with MD and six of those were replicated in an independent mQTL dataset (Wald's ratio test, absolute {beta} ranged from 0.056 to 0.932, p ranged from 7e-3 to 4.58e-6). CpG sites located in the Major Histocompatibility complex (MHC) region showed the strongest evidence from MR analysis of being associated with MD. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system. Larger sample sizes in diverse ancestries are likely to reveal replicable associations to improve mechanistic inferences with the potential to inform molecular target identification.

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

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