DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.
DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.
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作者：
Hannon E;Dempster EL;Mansell G;Burrage J;Bass N;Bohlken MM;Corvin A;Curtis CJ;Dempster D;Di Forti M;Dinan TG;Donohoe G;Gaughran F;Gill M;Gillespie A;Gunasinghe C;Hulshoff HE;Hultman CM;Johansson V;Kahn RS;Kaprio J;Kenis G;Kowalec K;MacCabe J;McDonald C;McQuillin A;Morris DW;Murphy KC;Mustard CJ;Nenadic I;O'Donovan MC;Quattrone D;Richards AL;Rutten BP;St Clair D;Therman S;Toulopoulou T;Van Os J;Waddington JL;Wellcome Trust Case Control Consortium (WTCCC);CRESTAR consortium;Sullivan P;Vassos E;Breen G;Collier DA;Murray RM;Schalkwyk LS;Mill J
我们对来自7个独立队列的4483名参与者的血液DNA甲基化谱进行了系统分析，确定了与精神病，精神分裂症和难治性精神分裂症相关的差异甲基化位置（DMPs）。精神病病例的特点是血细胞比例的测量结果存在显著差异，并且来自DNA甲基化数据的吸烟暴露增加，其中最大的差异见于难治性精神分裂症患者。我们实施了一个严格的管道来荟萃分析整个数据集的表观全基因组关联研究（EWAS）结果，确定了95个与精神病相关的DMP和1048个与精神分裂症相关的DMP，并有证据表明共定位于疾病遗传关联研究提名的区域。许多精神分裂症相关的DNA甲基化差异仅存在于难治性精神分裂症患者中，可能反映了非典型抗精神病药物氯氮平的暴露。我们的研究结果强调了如何利用DNA甲基化数据来识别生理（例如，差异细胞计数）和环境（例如，吸烟）与精神病相关的因素和难治性精神分裂症的分子生物标志物。
We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.