University of Exeter Medical School, RILD Building, Royal Devon & Exeter Hospital, University of Exeter, Barrack Rd, Exeter, EX2 5DW, UK.
Blizard Institute, Queen Mary University of London, London, E1 2AD, UK.
Mol Brain. 2019 Jan 28;12(1):7. doi: 10.1186/s13041-019-0429-4.
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.
大多数与全基因组关联研究（GWAS）中复杂表型相关的变体并不直接影响蛋白质结构的编码变化。相反，它们被假设影响基因调控，与疾病相关的常见变体在包括增强子和开放染色质区域在内的调控域中富集。因此，人们对使用表观基因组注释数据来识别特定的调控机制并确定风险变体感兴趣。我们使用染色质免疫沉淀 followed by highly parallel sequencing (ChIP-seq) 在额皮质样本中定量测定了组蛋白 H3K27 乙酰化 (H3K27ac) - 一种活跃的增强子和启动子的稳健标记，与基因表达和转录因子结合强烈相关。使用高质量的读数在所有样本中进行组合来调用 H3K27ac 峰，并使用 LD 得分回归与七个精神和神经退行性疾病的公开 GWAS 结果一起形成分区遗传力分析的基础。与包含多种细胞类型和组织中其他活跃调节和功能元素的基因组区域相比，所有七个大脑特征的遗传力在这些 H3K27ac 峰中显著富集（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）。对于 14 种非脑部疾病，观察到的富集程度要低得多，尽管我们确定了皮质 H3K27ac 结构域中体重指数（富集=1.16；95%CI=1.13-1.19）、曾经吸烟（富集=2.07；95%CI=2.04-2.10）、高密度脂蛋白（HDL）（富集=1.53；95%CI=1.45-1.62）和甘油三酯（富集=1.33；95%CI=1.24-1.42）的富集。这些结果表明，大脑疾病的风险等位基因优先位于皮质中调节/增强子功能的区域，进一步支持这些表型的遗传变异影响大脑基因调控的假设。
