Multitissue H3K27ac profiling of GTEx samples links epigenomic variation to disease.
Multitissue H3K27ac profiling of GTEx samples links epigenomic variation to disease.
复制标题
DOI：
10.1038/s41588-023-01509-5
复制
发表时间：
2023-10
期刊：
影响因子：
30.8
通讯作者：
Kellis, Manolis
中科院分区：
文献类型：
--
作者：
Hou, Lei;Xiong, Xushen;Park, Yongjin;Boix, Carles;James, Benjamin;Sun, Na;He, Liang;Patel, Aman;Zhang, Zhizhuo;Molinie, Benoit;Van Wittenberghe, Nicholas;Steelman, Scott;Nusbaum, Chad;Aguet, Francois;Ardlie, Kristin G.;Kellis, Manolis
与复杂性状相关的遗传变异主要是非编码的，它们对基因调控活性的影响在很大程度上仍未被描述。为了解决这个问题，我们分析了来自基因型组织表达（GTEx）的387个脑、心脏、肌肉和肺样本中组蛋白标记H3K27ac的表观基因组变异。我们用组织特异性活性模式标注了2828k个活性调控元件（AREs）。我们确定了2436个性别偏倚的AREs和5397个受遗传影响的AREs，这些AREs与组织中的130 k遗传变异（haQTLs）相关。我们整合遗传和表观基因组变异，通过揭示候选作用组织、驱动snp和受影响的AREs，为55项全基因组关联研究（GWAS）中的疾病相关位点提供机制见解。最后，我们建立了基于遗传学的非基因连接分数（gLink分数），并展示了它们优先考虑snp -非基因电路的独特能力。总的来说，我们的表观基因组数据集、计算集成和机制预测为理解人类疾病/特征（如精神分裂症）的分子基础提供了宝贵的资源和重要的见解。对387个脑、心脏、肌肉和肺样本的H3K27ac全基因组图谱的分析，以及eQTL和全基因组关联研究（GWAS）数据整合，确定了组织特异性遗传影响的活性调控区域和潜在介导疾病病因的靶基因。
Genetic variants associated with complex traits are primarily noncoding, and their effects on gene-regulatory activity remain largely uncharacterized. To address this, we profile epigenomic variation of histone mark H3K27ac across 387 brain, heart, muscle and lung samples from Genotype-Tissue Expression (GTEx). We annotate 282 k active regulatory elements (AREs) with tissue-specific activity patterns. We identify 2,436 sex-biased AREs and 5,397 genetically influenced AREs associated with 130 k genetic variants (haQTLs) across tissues. We integrate genetic and epigenomic variation to provide mechanistic insights for disease-associated loci from 55 genome-wide association studies (GWAS), by revealing candidate tissues of action, driver SNPs and impacted AREs. Lastly, we build ARE–gene linking scores based on genetics (gLink scores) and demonstrate their unique ability to prioritize SNP–ARE–gene circuits. Overall, our epigenomic datasets, computational integration and mechanistic predictions provide valuable resources and important insights for understanding the molecular basis of human diseases/traits such as schizophrenia. Analysis of H3K27ac genome-wide maps across 387 brain, heart, muscle and lung samples, along with eQTL and genome-wide association studies (GWAS) data integration, identifies tissue-specific genetically influenced active regulatory regions and target genes that potentially mediate disease etiology.
登录
查看更多内容
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
64.8
作者：
Boix CA;James BT;Park YP;Meuleman W;Kellis M
通讯作者：
Kellis M
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
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL