Enrichment of schizophrenia heritability in both neuronal and glia cell regulatory elements.
Enrichment of schizophrenia heritability in both neuronal and glia cell regulatory elements.
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DOI：
10.1038/s41398-017-0053-y
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发表时间：
2018-01-10
影响因子：
6.8
通讯作者：
Hill MJ
中科院分区：
文献类型：
--
作者：
Tansey KE;Hill MJ
全基因组关联研究已经确定了超过100个强大的精神分裂症风险基因座，其中数千个变异介导遗传遗传性，其中大多数位于非编码区。分析方法表明，这种遗传性在从人类死后脑组织中鉴定的调控元件内的变体中强烈富集。然而，大量的死后脑组织具有异质的细胞组成，使得生物学解释变得困难。我们试图通过分离神经元和神经胶质信号来细化介导精神分裂症遗传性的细胞类型，所用数据来自：（1）NeuN分选的死后脑和（2）细胞培养系统。精神分裂症的遗传力分区使用连锁不平衡（LD）评分回归。来自NeuN阳性（神经元）和NeuN阴性（非神经元）细胞的H3K4me3（活性启动子的标记）标记的基因组区域内的变异解释了精神分裂症遗传率的显著性（P = 1.38 × 10−10和P = 7.97 × 10−10）。然而，位于NeuN阳性（神经元）细胞特异性的H3K4me3位点的变异体富集（P = 3.13 × 10−4），而NeuN阴性（非神经元）细胞特异性的变异体则没有富集（P = 0.470）。来自细胞培养系统的数据模拟了这种关联模式。我们发现，先前观察到的富集遗传性的变体在大脑H3K4me3网站是由神经元和非神经元脑细胞类型介导的。然而，只有神经元细胞群体表现出独特的贡献，由细胞类型特异性调控元件驱动。细胞培养系统概括了疾病相关的基因调控景观，验证它们作为未来调查精神分裂症遗传机制的工具。确定风险变异体运作的细胞类型将大大增加我们对精神分裂症病理生物学的理解，并有助于开发新的模型系统和疗法。
Genome-wide association studies have identified over 100 robust risk loci for schizophrenia with thousands of variants mediating genetic heritability, the majority of which reside in non-coding regions. Analytical approaches have shown this heritability is strongly enriched at variants within regulatory elements identified from human post-mortem brain tissue. However, bulk post-mortem brain tissue has a heterogeneous cell composition, making biological interpretations difficult. We sought to refine the cell types mediating schizophrenia heritability by separating neuronal and glial signals using data from: (1) NeuN-sorted post-mortem brain and (2) cell culture systems. Schizophrenia heritability was partitioned using linkage disequilbrium (LD) score regression. Variants within genomic regions marked by H3K4me3 (marker of active promoters) from NeuN-positive (neuronal) and NeuN-negative (non-neuronal) cells explained a significant amount of schizophrenia heritability (P = 1.38 × 10−10 and P = 7.97 × 10−10). However, variants located in H3K4me3 sites specific to NeuN-positive (neuronal) cells were enriched (P = 3.13 × 10−4), while those specific to NeuN-negative (non-neuronal) cells were not (P = 0.470). Data from cell culture systems mimicked this pattern of association. We show the previously observed enrichment of heritability from variants at brain H3K4me3 sites is mediated by both neuronal and non-neuronal brain cell types. However, only neuronal cell populations showed a unique contribution driven by cell-type specific regulatory elements. Cell culture systems recapitulate disease relevant gene-regulatory landscapes, validating them as a tool for future investigation of genetic mechanisms underlying schizophrenia. Identifying the cell types in which risk variants operate will greatly increase our understanding of schizophrenia pathobiology and aid in the development of novel model systems and therapies.
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DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
11
作者：
Richards AL;Jones L;Moskvina V;Kirov G;Gejman PV;Levinson DF;Sanders AR;Molecular Genetics of Schizophrenia Collaboration (MGS);International Schizophrenia Consortium (ISC);Purcell S;Visscher PM;Craddock N;Owen MJ;Holmans P;O'Donovan MC
通讯作者：
O'Donovan MC
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL