Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.
Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.
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DOI：
10.1038/nn.4181
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发表时间：
2016-01
影响因子：
25
通讯作者：
Kleinman JE
中科院分区：
文献类型：
--
作者：
Jaffe AE;Gao Y;Deep-Soboslay A;Tao R;Hyde TM;Weinberger DR;Kleinman JE
DNA甲基化（DNAm）在大脑发育中很重要，可能在精神分裂症中也很重要。我们对335名非精神病对照者和191名精神分裂症患者的前额叶皮质中的DNA m进行了表征，并发现了从产前到产后生活过渡期间的广泛变化。这些DNA m变化表现在转录组中，与细胞景观的变化密切相关，并且与精神分裂症的遗传风险区域重叠。四分之一已发表的GWAS提示基因座（4，208/15，930，p<10−100）表现为显著甲基化数量性状基因座（meQTL），包括59.6%的GWAS阳性精神分裂症基因座。我们确定了2,104个在精神分裂症患者和对照组之间存在差异的CpG，富含与发育和神经分化相关的基因。精神分裂症相关的CpG与产前-产后过渡相关的变化密切相关，并显示GWAS风险位点略有富集，而不对应于区分青春期和成年后生活的CpG。这些数据暗示了这种疾病的发育起源的表观遗传成分。
DNA methylation (DNAm) is important in brain development, and potentially in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia, and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape, and overlap regions of genetic risk for schizophrenia. A quarter of published GWAS-suggestive loci (4,208/15,930, p<10−100) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls, enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci, while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder.