Systematic Localization of Common Disease-Associated Variation in Regulatory DNA

被引：2623

作者：

Maurano, Matthew T. ^{[1
]}

Humbert, Richard ^{[1
]}

Rynes, Eric ^{[1
]}

Thurman, Robert E. ^{[1
]}

Haugen, Eric ^{[1
]}

Wang, Hao ^{[1
]}

Reynolds, Alex P. ^{[1
]}

Sandstrom, Richard ^{[1
]}

Qu, Hongzhu ^{[1
,2
]}

Brody, Jennifer ^{[3
]}

Shafer, Anthony ^{[1
]}

Neri, Fidencio ^{[1
]}

Lee, Kristen ^{[1
]}

Kutyavin, Tanya ^{[1
]}

Stehling-Sun, Sandra ^{[1
]}

Johnson, Audra K. ^{[1
]}

Canfield, Theresa K. ^{[1
]}

Giste, Erika ^{[1
]}

Diegel, Morgan ^{[1
]}

Bates, Daniel ^{[1
]}

Hansen, R. Scott ^{[4
]}

Neph, Shane ^{[1
]}

Sabo, Peter J. ^{[1
]}

Heimfeld, Shelly ^{[5
]}

Raubitschek, Antony ^{[6
]}

Ziegler, Steven ^{[6
]}

Cotsapas, Chris ^{[7
,8
]}

Sotoodehnia, Nona ^{[3
,9
]}

Glass, Ian ^{[10
]}

Sunyaev, Shamil R. ^{[11
,12
]}

Kaul, Rajinder ^{[4
]}

Stamatoyannopoulos, John A. ^{[1
,13
]}

机构：

[1] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[2] Chinese Acad Sci, Beijing Inst Genom, Lab Dis Genom & Individualized Med, Beijing 100029, Peoples R China

[3] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[4] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA

[5] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA

[6] Benaroya Res Inst, Program Immunol, Seattle, WA 98101 USA

[7] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA

[8] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA

[9] Univ Washington, Dept Med, Div Cardiol, Seattle, WA 98195 USA

[10] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA

[11] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[12] Harvard Univ, Sch Med, Boston, MA 02115 USA

[13] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA

来源：

SCIENCE | 2012年 / 337卷 / 6099期

关键词：

CROHNS-DISEASE; 22; LOCI; VARIANTS; EVOLUTION; PROMOTER; CELLS;

D O I：

10.1126/science.1222794

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing 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 demonstrated 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.

引用

页码：1190 / 1195

页数：6

共 36 条

[1] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[2] FETAL NUTRITION AND CARDIOVASCULAR-DISEASE IN ADULT LIFE [J].

BARKER, DJP ;

GLUCKMAN, PD ;

GODFREY, KM ;

HARDING, JE ;

OWENS, JA ;

ROBINSON, JS .

LANCET, 1993, 341 (8850) :938-941

[3] The NIH Roadmap Epigenomics Mapping Consortium [J].

Bernstein, Bradley E. ;

Stamatoyannopoulos, John A. ;

Costello, Joseph F. ;

Ren, Bing ;

Milosavljevic, Aleksandar ;

Meissner, Alexander ;

Kellis, Manolis ;

Marra, Marco A. ;

Beaudet, Arthur L. ;

Ecker, Joseph R. ;

Farnham, Peggy J. ;

Hirst, Martin ;

Lander, Eric S. ;

Mikkelsen, Tarjei S. ;

Thomson, James A. .

NATURE BIOTECHNOLOGY, 2010, 28 (10) :1045-1048

[4] Lack of support for association between the KIF1B rs10492972[C] variant and multiple sclerosis [J].

Booth, David R. ;

Heard, Robert N. ;

Stewart, Graeme J. ;

Cox, Mathew ;

Scott, Rodney J. ;

Lechner-Scott, Jeannette ;

Goris, An ;

Dobosi, Rita ;

Dubois, Benedicte ;

Saarela, Janna ;

Leppa, Virpi ;

Peltonen, Leena ;

Pirttila, Tuula ;

Cournu-Rebeix, Isabelle ;

Fontaine, Bertrand ;

Bergamaschi, Laura ;

D'Alfonso, Sandra ;

Leone, Maurizio ;

Lorentzen, Aslaug R. ;

Harbo, Hanne F. ;

Celius, Elisabeth G. ;

Spurkland, Anne ;

Link, Jenny ;

Kockum, Ingrid ;

Olsson, Tomas ;

Hillert, Jan ;

Ban, Maria ;

Baker, Amie ;

Kemppinen, Anu ;

Sawcer, Stephen ;

Compston, Alastair ;

Robertson, Neil P. ;

De Jager, Philip L. ;

Hafler, David A. ;

Barcellos, Lisa F. ;

Ivinson, Adrian J. ;

McCauley, Jacob L. ;

Pericak-Vance, Margaret A. ;

Oksenberg, Jorge R. ;

Hauser, Stephen L. ;

Sexton, David ;

Haines, Jonathan .

NATURE GENETICS, 2010, 42 (06) :469-470

[5] Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease [J].

Brand, S. .

GUT, 2009, 58 (08) :1152-1167

[6] A POINT MUTATION IN THE A-GAMMA-GLOBIN GENE PROMOTER IN GREEK HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN [J].

COLLINS, FS ;

METHERALL, JE ;

YAMAKAWA, M ;

PAN, J ;

WEISSMAN, SM ;

FORGET, BG .

NATURE, 1985, 313 (6000) :325-326

[7] Mapping complex disease traits with global gene expression [J].

Cookson, William ;

Liang, Liming ;

Abecasis, Goncalo ;

Moffatt, Miriam ;

Lathrop, Mark .

NATURE REVIEWS GENETICS, 2009, 10 (03) :184-194

[8] Pervasive Sharing of Genetic Effects in Autoimmune Disease [J].

Cotsapas, Chris ;

Voight, Benjamin F. ;

Rossin, Elizabeth ;

Lage, Kasper ;

Neale, Benjamin M. ;

Wallace, Chris ;

Abecasis, Goncalo R. ;

Barrett, Jeffrey C. ;

Behrens, Timothy ;

Cho, Judy ;

De Jager, Philip L. ;

Elder, James T. ;

Graham, Robert R. ;

Gregersen, Peter ;

Klareskog, Lars ;

Siminovitch, Katherine A. ;

van Heel, David A. ;

Wijmenga, Cisca ;

Worthington, Jane ;

Todd, John A. ;

Hafler, David A. ;

Rich, Stephen S. ;

Daly, Mark J. .

PLOS GENETICS, 2011, 7 (08)

[9] DNase I sensitivity QTLs are a major determinant of human expression variation [J].

Degner, Jacob F. ;

Pai, Athma A. ;

Pique-Regi, Roger ;

Veyrieras, Jean-Baptiste ;

Gaffney, Daniel J. ;

Pickrell, Joseph K. ;

De Leon, Sherryl ;

Michelini, Katelyn ;

Lewellen, Noah ;

Crawford, Gregory E. ;

Stephens, Matthew ;

Gilad, Yoav ;

Pritchard, Jonathan K. .

NATURE, 2012, 482 (7385) :390-394

[10] Mechanisms of disease: Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. [J].

Fajans, SS ;

Bell, GI ;

Polonsky, KS .

NEW ENGLAND JOURNAL OF MEDICINE, 2001, 345 (13) :971-980

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