Cell Type-Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder.
Cell Type-Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder.
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DOI：
10.1016/j.biopsych.2019.10.014
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发表时间：
2020-03-01
影响因子：
10.6
通讯作者：
van den Oord, Edwin J. C. G.
中科院分区：
文献类型：
--
作者：
Chan, Robin F.;Turecki, Gustavo;Shabalin, Andrey A.;Guintivano, Jerry;Zhao, Min;Xie, Lin Y.;van Grootheest, Gerard;Kaminsky, Zachary A.;Dean, Brian;Penninx, Brenda W. J. H.;Aberg, Karolina A.;van den Oord, Edwin J. C. G.
我们试图描述与重性抑郁症（MDD）相关的脑和血液中甲基化的变化。由于大块组织的分析可能会模糊相关信号并妨碍对结果的生物学解释，因此在细胞类型特异性水平上研究了这些变化。在MDD病例和对照组的3个人死后脑样本（n = 206）和1个血液样本（N = 1132）中，我们使用表观基因组去卷积在神经元/神经胶质亚群（脑数据）和粒细胞/T细胞/B细胞/单核细胞亚群（血液数据）中进行细胞类型特异性全甲基化相关研究。来自第四次死后脑收集（n = 58）的分选的神经元/神经胶质用于验证目的。细胞类型特异性甲基化全关联研究确定了神经元/神经胶质细胞中的多个发现，这些发现在大脑集合中检测到，并且在物理分选的细胞核中可重复。血液样本中的细胞类型特异性分析确定了T细胞、单核细胞和全血中的甲基化组范围内的显著相关性，这复制了过去MDD甲基化研究的结果。通路分析涉及MDD中的p75神经营养因子受体/神经生长因子信号传导和先天免疫toll样受体信号传导。神经元、神经胶质、大脑、T细胞、单核细胞和全血中的最高结果富集了由MDD和其他精神疾病的全基因组关联研究支持的基因。我们在细胞类型特异性水平上复制并鉴定了人脑和血液样本中新的MDD甲基化相关性。我们的研究结果为免疫系统如何与大脑相互作用以影响MDD易感性提供了机制性见解。重要的是，我们的研究结果涉及人类样本中与MDD的关联，涉及许多密切相关的生物学途径。这些与疾病相关的位点和途径代表了MDD有希望的新治疗靶点。
We sought to characterize methylation changes in brain and blood associated with major depressive disorder (MDD). As analyses of bulk tissue may obscure association signals and hamper the biological interpretation of findings, these changes were studied on a cell type–specific level. In 3 collections of human postmortem brain (n = 206) and 1 collection of blood samples (N = 1132) of MDD cases and controls, we used epigenomic deconvolution to perform cell type–specific methylome-wide association studies within subpopulations of neurons/glia for the brain data and granulocytes/T cells/B cells/monocytes for the blood data. Sorted neurons/glia from a fourth postmortem brain collection (n = 58) were used for validation purposes. Cell type–specific methylome-wide association studies identified multiple findings in neurons/glia that were detected across brain collections and were reproducible in physically sorted nuclei. Cell type–specific analyses in blood samples identified methylome-wide significant associations in T cells, monocytes, and whole blood that replicated findings from a past methylation study of MDD. Pathway analyses implicated p75 neurotrophin receptor/nerve growth factor signaling and innate immune toll-like receptor signaling in MDD. Top results in neurons, glia, bulk brain, T cells, monocytes, and whole blood were enriched for genes supported by genome-wide association studies for MDD and other psychiatric disorders. We both replicated and identified novel MDD–methylation associations in human brain and blood samples at a cell type–specific level. Our results provide mechanistic insights into how the immune system may interact with the brain to affect MDD susceptibility. Importantly, our findings involved associations with MDD in human samples that implicated many closely related biological pathways. These disease-linked sites and pathways represent promising new therapeutic targets for MDD.
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DOI：
10.1176/appi.ajp.2018.17060595
发表时间：
2018-08-01
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Han LKM;Aghajani M;Clark SL;Chan RF;Hattab MW;Shabalin AA;Zhao M;Kumar G;Xie LY;Jansen R;Milaneschi Y;Dean B;Aberg KA;van den Oord EJCG;Penninx BWJH
通讯作者：
Penninx BWJH
影响因子：
25
作者：
Hannon E;Spiers H;Viana J;Pidsley R;Burrage J;Murphy TM;Troakes C;Turecki G;O'Donovan MC;Schalkwyk LC;Bray NJ;Mill J
通讯作者：
Mill J
影响因子：
15.1
作者：
Garcia-Rizo, Clemente;Fernandez-Egea, Emilio;Kirkpatrick, Brian
通讯作者：
Kirkpatrick, Brian
影响因子：
3.5
作者：
Crawford, Bethany;Craig, Zoe;Murphy, Therese M.
通讯作者：
Murphy, Therese M.
影响因子：
3.7
作者：
Aberg, Karolina A.;Chan, Robin F.;van den Oord, Edwin J. C. G.
通讯作者：
van den Oord, Edwin J. C. G.