Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains
Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains
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DOI：
10.1186/s13041-019-0429-4
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发表时间：
2019-01-28
期刊：
影响因子：
3.6
通讯作者：
Mill, Jonathan
中科院分区：
文献类型：
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作者：
Hannon, Eilis;Marzi, Sarah J.;Mill, Jonathan
全基因组关联研究 (GWAS) 中与复杂表型相关的大多数变异并不直接索引影响蛋白质结构的编码变化。相反，它们被假设会影响基因调控，与疾病相关的常见变异在调控域中丰富，包括增强子和开放染色质区域。因此，人们有兴趣使用表观基因组注释数据来识别所涉及的具体调控机制并确定风险变异的优先顺序。我们使用染色质免疫沉淀和高度并行测序 (ChIP-seq) 技术，对内嗅皮层样本中基因组的赖氨酸 H3K27 乙酰化 (H3K27ac) 进行了定量，H3K27ac 是活性增强子和启动子的有力标记，与基因表达和转录因子结合密切相关。 H3K27ac 峰使用所有样本组合的高质量读数进行调用，并使用 LD 评分回归以及公开可用的 7 种精神和神经退行性状特征的 GWAS 结果构成分区遗传力分析的基础。与包含跨多种细胞类型和组织的其他活性调节和功能元件的基因组区域相比，所有七个大脑性状的遗传力在这些 H3K27ac 峰中显着富集（富集范围为 1.09-2.13）。最强的富集是肌萎缩侧索硬化症 (ALS)（富集 = 2.19；95% CI = 2.12-2.27）、自闭症（富集 = 2.11；95% CI = 2.05-2.16）和重度抑郁症（富集 = 2.04；95% CI = 1.92-2.16）。尽管我们发现皮质 H3K27ac 域的体重指数（富集 = 1.16；95% CI = 1.13-1.19）、曾经吸烟（富集 = 2.07；95% CI = 2.04-2.10）、HDL（富集 = 1.53；95% CI = 2.04-2.10）、HDL（富集 = 1.53；95% CI = 1.45-1.62）和甘油三酯（富集度 = 1.33；95% CI = 1.24-1.42）。这些结果表明，大脑疾病的风险等位基因优先位于皮质的调节/增强功能区域，进一步支持了这些表型的遗传变异影响大脑基因调节的假设。
Most variants associated with complex phenotypes in genome-wide association studies (GWAS) do not directly index coding changes affecting protein structure. Instead they are hypothesized to influence gene regulation, with common variants associated with disease being enriched in regulatory domains including enhancers and regions of open chromatin. There is interest, therefore, in using epigenomic annotation data to identify the specific regulatory mechanisms involved and prioritize risk variants. We quantified lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - across the genome in entorhinal cortex samples using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). H3K27ac peaks were called using high quality reads combined across all samples and formed the basis of partitioned heritability analysis using LD score regression along with publicly-available GWAS results for seven psychiatric and neurodegenerative traits. Heritability for all seven brain traits was significantly enriched in these H3K27ac peaks (enrichment ranging from 1.09-2.13) compared to regions of the genome containing other active regulatory and functional elements across multiple cell types and tissues. The strongest enrichments were for amyotrophic lateral sclerosis (ALS) (enrichment = 2.19; 95% CI = 2.12-2.27), autism (enrichment = 2.11; 95% CI = 2.05-2.16) and major depressive disorder (enrichment = 2.04; 95% CI = 1.92-2.16). Much lower enrichments were observed for 14 non-brain disorders, although we identified enrichment in cortical H3K27ac domains for body mass index (enrichment = 1.16; 95% CI = 1.13-1.19), ever smoked (enrichment = 2.07; 95% CI = 2.04-2.10), HDL (enrichment = 1.53; 95% CI = 1.45-1.62) and trigylcerides (enrichment = 1.33; 95% CI = 1.24-1.42). These results indicate that risk alleles for brain disorders are preferentially located in regions of regulatory/enhancer function in the cortex, further supporting the hypothesis that genetic variants for these phenotypes influence gene regulation in the brain.