Systematic localization of common disease-associated variation in regulatory DNA.
Systematic localization of common disease-associated variation in regulatory DNA.
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DOI：
10.1126/science.1222794
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发表时间：
2012-09-07
期刊：
影响因子：
--
通讯作者：
Stamatoyannopoulos JA
中科院分区：
文献类型：
--
作者：
Maurano MT;Humbert R;Rynes E;Thurman RE;Haugen E;Wang H;Reynolds AP;Sandstrom R;Qu H;Brody J;Shafer A;Neri F;Lee K;Kutyavin T;Stehling-Sun S;Johnson AK;Canfield TK;Giste E;Diegel M;Bates D;Hansen RS;Neph S;Sabo PJ;Heimfeld S;Raubitschek A;Ziegler S;Cotsapas C;Sotoodehnia N;Glass I;Sunyaev SR;Kaul R;Stamatoyannopoulos JA
全基因组关联研究（GWAS）已经确定了许多与常见疾病和性状相关的非编码变异。我们发现这些变异集中在由DNA酶I超敏感位点（DHSs）标记的调控DNA中。88%的此类DHSs在胎儿发育期间具有活性，并且在与孕期暴露相关的表型中富集。我们确定了数百个DHSs的远距离基因靶点，这可能解释表型关联。与疾病相关的变异系统性地扰乱转录因子识别序列，频繁改变等位基因染色质状态，并形成调控网络。我们还证明了在DHSs内与疾病弱相关变异的组织选择性富集，以及在不了解生理机制的情况下，从头确定了克罗恩病、多发性硬化症和一种心电图性状的致病细胞类型。我们的研究结果表明，调控DNA变异普遍参与常见人类疾病，并为多种疾病提供了致病方面的见解。
Genome-wide association studies (GWAS) have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by DNase I hypersensitive sites (DHSs). 88% of such DHSs are active during fetal development, and are enriched for gestational exposure-related phenotypes. We identify distant gene targets for hundreds of DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrate tissue-selective enrichment of more weakly disease-associated variants within DHSs, and the de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease, and provide pathogenic insights into diverse disorders.
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影响因子：
4.5
作者：
Maurano MT;Wang H;Kutyavin T;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
John S;Sabo PJ;Thurman RE;Sung MH;Biddie SC;Johnson TA;Hager GL;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
DOI：
10.1073/pnas.112212199
发表时间：
2002-05-28
影响因子：
11.1
作者：
Lettice, LA;Horikoshi, T;Noji, S
通讯作者：
Noji, S