Hannon Eilis, Dempster Emma, Viana Joana, Burrage Joe, Smith Adam R, Macdonald Ruby, St Clair David, Mustard Colette, Breen Gerome, Therman Sebastian, Kaprio Jaakko, Toulopoulou Timothea, Hulshoff Pol Hilleke E, Bohlken Marc M, Kahn Rene S, Nenadic Igor, Hultman Christina M, Murray Robin M, Collier David A, Bass Nick, Gurling Hugh, McQuillin Andrew, Schalkwyk Leonard, Mill Jonathan
University of Exeter Medical School, University of Exeter, Exeter, UK.
The Institute of Medical Sciences, Aberdeen University, Aberdeen, UK.
Genome Biol. 2016 Aug 30;17(1):176. doi: 10.1186/s13059-016-1041-x.
Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated.
We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease.
This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
精神分裂症是一种高度可遗传的神经精神疾病，其特征为发作性精神病和认知功能改变。尽管在识别与精神分裂症相关的基因变异方面取得了成功，但疾病发病机制中涉及的因果基因及其功能如何调控仍存在不确定性。
我们进行了一项多阶段全表观基因组关联研究，对来自三个独立样本队列的总共1714名个体的全基因组DNA甲基化模式进行了量化。我们在三个队列中均鉴定出多个与精神分裂症持续相关的差异甲基化位点和区域；这些效应独立于吸烟等重要混杂因素。我们还表明，全基因组多个位点的表观遗传变异促成了精神分裂症的多基因性质。最后，我们展示了DNA甲基化数量性状位点与贝叶斯共定位分析相结合如何用于注释精神分裂症研究提名的扩展基因组区域，并识别因果参与疾病的潜在调控变异。
本研究代表了对精神分裂症遗传和表观遗传变异的首次系统综合分析，引入了一种可用于指导其他复杂性状和疾病全表观基因组关联研究分析的方法。我们证明了使用多基因风险评分来识别与病因变异相关的分子变异，以及使用DNA甲基化数量性状位点来细化与精神分裂症风险变异相关的功能和调控变异的实用性。最后，我们为精神分裂症的遗传关联与DNA甲基化差异的共定位提供了有力证据。
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