Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.
Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.
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DOI：
10.1038/nn.4182
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发表时间：
2016-01
影响因子：
25
通讯作者：
Mill J
中科院分区：
文献类型：
--
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
我们在大量（n=166）跨越受孕后56-166天的人胎儿脑样品中表征了DNA甲基化数量性状基因座（mQTL），鉴定了> 16，000个胎儿脑mQTL。胎脑mQTL主要是顺式作用的，富含调节染色质结构域和转录因子结合位点，并显示出与遗传变异体的显著重叠，这些遗传变异体也与脑中的基因表达相关。使用来自成人大脑三个不同区域（前额叶皮层、纹状体和小脑）的组织，我们发现大多数胎儿大脑mQTL在发育上是稳定的，尽管一个子集的特征是胎儿特异性效应。我们发现，胎儿脑mQTL是丰富的风险基因座之间确定在最近的大规模全基因组关联研究（GWAS）的精神分裂症，一个严重的精神疾病与假设的神经发育组成部分。最后，我们展示了如何mQTL可以被用来细化GWAS基因座，通过识别离散位点的变量胎儿脑甲基化与精神分裂症的风险变异。
We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n=166) of human fetal brain samples spanning 56–166 days post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs are primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and show significant overlap with genetic variants also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum) we show that most fetal brain mQTLs are developmentally stable, although a subset is characterized by fetal-specific effects. We show that fetal brain mQTLs are enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we demonstrate how mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.