自闭症谱系障碍的组蛋白乙酰化组全基因组关联研究。
Histone Acetylome-wide Association Study of Autism Spectrum Disorder.
机构信息
Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
出版信息
Cell. 2016 Nov 17;167(5):1385-1397.e11. doi: 10.1016/j.cell.2016.10.031.
The association of histone modification changes with autism spectrum disorder (ASD) has not been systematically examined. We conducted a histone acetylome-wide association study (HAWAS) by performing H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem samples from ASD and matched control brains. Despite etiological heterogeneity, ≥68% of syndromic and idiopathic ASD cases shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex. Similarly, multiple genes associated with rare genetic mutations in ASD showed common "epimutations." Acetylome aberrations in ASD were not attributable to genetic differentiation at cis-SNPs and highlighted genes involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity. By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases. Due to the relative stability of histone modifications postmortem, we anticipate that the HAWAS approach will be applicable to multiple diseases.
组蛋白修饰变化与自闭症谱系障碍（ASD）的关联尚未得到系统研究。我们对 257 例 ASD 和匹配对照大脑的死后样本进行了 H3K27ac 染色质免疫沉淀测序（ChIP-seq），开展了组蛋白乙酰化组全关联研究（HAWAS）。尽管病因存在异质性，但 >5000 个前额叶和颞叶皮质的顺式调控元件中，≥68%的综合征和特发性 ASD 病例存在共同的乙酰化组特征。同样，与 ASD 罕见基因突变相关的多个基因也表现出共同的“表观突变”。ASD 中的乙酰化组异常与 cis-SNPs 的遗传分化无关，突出了涉及突触传递、离子转运、癫痫、行为异常、趋化作用、组蛋白去乙酰化和免疫的基因。通过将组蛋白乙酰化与基因型相关联，我们在人类大脑区域中发现了 >2000 个组蛋白乙酰化数量性状基因座（haQTLs），包括四个候选精神疾病的因果变异。由于组蛋白修饰在死后相对稳定，我们预计 HAWAS 方法将适用于多种疾病。
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