Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits

被引：36

作者：

Benaglio, Paola ^{[1
]}

D'Antonio-Chronowska, Agnieszka ^{[2
]}

Ma, Wubin ^{[3
]}

Yang, Feng ^{[3
]}

Greenwald, William W. Young ^{[4
]}

Donovan, Margaret K. R. ^{[4
,5
]}

DeBoever, Christopher ^{[4
]}

Li, He ^{[2
]}

Drees, Frauke ^{[2
]}

Singhal, Sanghamitra ^{[1
]}

Matsui, Hiroko ^{[2
]}

van Setten, Jessica ^{[6
]}

Sotoodehnia, Nona ^{[7
,8
]}

Gaulton, Kyle J. ^{[1
]}

Smith, Erin N. ^{[1
]}

D'Antonio, Matteo ^{[2
]}

Rosenfeld, Michael G. ^{[3
]}

Frazer, Kelly A. ^{[1
,2
]}

机构：

[1] Univ Calif San Diego, Dept Pediat, Rady Childrens Hosp, Div Genome Informat Sci, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Med, Howard Hughes Med Inst, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Bioinformat & Syst Biol, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Biomed Informat, La Jolla, CA 92093 USA

[6] Univ Utrecht, Univ Med Ctr Utrecht, Dept Cardiol, Utrecht, Netherlands

[7] Univ Washington, Dept Med, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA USA

[8] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Div Cardiol, Seattle, WA 98195 USA

来源：

NATURE GENETICS | 2019年 / 51卷 / 10期

基金：

美国国家科学基金会; 瑞士国家科学基金会;

关键词：

GENOME-WIDE ASSOCIATION; PR INTERVAL; DNA-BINDING; HEART-RATE; FUNCTIONAL VARIATION; CARDIAC CONDUCTION; COMMON VARIANTS; QRS DURATION; LOCI; IDENTIFICATION;

D O I：

10.1038/s41588-019-0499-3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified similar to 2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes.

引用

页码：1506 / +

页数：15

共 85 条

[1] Protein-DNA binding in the absence of specific base-pair recognition [J].

Afek, Ariel ;

Schipper, Joshua L. ;

Horton, John ;

Gordan, Raluca ;

Lukatsky, David B. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (48) :17140-17145

[2] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[3] Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis [J].

Ang, Yen-Sin ;

Rivas, Renee N. ;

Ribeiro, Alexandre J. S. ;

Srivas, Rohith ;

Rivera, Janell ;

Stone, Nicole R. ;

Pratt, Karishma ;

Mohamed, Tamer M. A. ;

Fu, Ji-Dong ;

Spencer, C. Ian ;

Tippens, Nathaniel D. ;

Li, Molong ;

Narasimha, Anil ;

Radzinsky, Ethan ;

Moon-Grady, Anita J. ;

Yu, Haiyuan ;

Pruitt, Beth L. ;

Snyder, Michael P. ;

Srivastava, Deepak .

CELL, 2016, 167 (07) :1734-+

[4]

[Anonymous], 2015, Nature, DOI DOI 10.1038/NATURE15393

[5] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[6] Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization [J].

Arking, Dan E. ;

Pulit, Sara L. ;

Crotti, Lia ;

Van der Harst, Pim ;

Munroe, Patricia B. ;

Koopmann, Tamara T. ;

Sotoodehnia, Nona ;

Rossin, Elizabeth J. ;

Morley, Michael ;

Wang, Xinchen ;

Johnson, Andrew D. ;

Lundby, Alicia ;

Gudbjartsson, Daniel F. ;

Noseworthy, Peter A. ;

Eijgelsheim, Mark ;

Bradford, Yuki ;

Tarasov, Kirill V. ;

Dorr, Marcus ;

Miiller-Nurasyid, Martina ;

Lahtinen, Annukka M. ;

Nolte, Ilja M. ;

Smith, Albert Vernon ;

Bis, Joshua C. ;

Isaacs, Aaron ;

Newhouse, Stephen J. ;

Evans, Daniel S. ;

Post, Wendy S. ;

Waggott, Daryl ;

Lyytikainen, Leo-Pekka ;

Hicks, Andrew A. ;

Eisele, Lewin ;

Ellinghaus, David ;

Hayward, Caroline ;

Navarro, Pau ;

Ulivi, Sheila ;

Tanaka, Toshiko ;

Tester, David J. ;

Chatel, Stephanie ;

Gustafsson, Stefan ;

Kumari, Meena ;

Morris, Richard W. ;

Naluai, Asa T. ;

Padmanabhan, Sandosh ;

Kluttig, Alexander ;

Strohmer, Bernhard ;

Panayiotou, Andrie G. ;

Torres, Maria ;

Knoflach, Michael ;

Hubacek, Jaroslav A. ;

Slowikowski, Kamil .

NATURE GENETICS, 2014, 46 (08) :826-836

[7] Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors [J].

Ban, Hiroshi ;

Nishishita, Naoki ;

Fusaki, Noemi ;

Tabata, Toshiaki ;

Saeki, Koichi ;

Shikamura, Masayuki ;

Takada, Nozomi ;

Inoue, Makoto ;

Hasegawa, Mamoru ;

Kawamata, Shin ;

Nishikawa, Shin-Ichi .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (34) :14234-14239

[8] Impact of regulatory variation across human iPSCs and differentiated cells [J].

Banovich, Nicholas E. ;

Li, Yang I. ;

Raj, Anil ;

Ward, Michelle C. ;

Greenside, Peyton ;

Calderon, Diego ;

Tung, Po Yuan ;

Burnett, Jonathan E. ;

Myrthil, Marsha ;

Thomas, Samantha M. ;

Burrows, Courtney K. ;

Romero, Irene Gallego ;

Pavlovic, Bryan J. ;

Kundaje, Anshul ;

Pritchard, Jonathan K. ;

Gilad, Yoav .

GENOME RESEARCH, 2018, 28 (01) :122-131

[9] Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death [J].

Bezzina, Connie R. ;

Barc, Julien ;

Mizusawa, Yuka ;

Remme, Carol Ann ;

Gourraud, Jean-Baptiste ;

Simonet, Floriane ;

Verkerk, Arie O. ;

Schwartz, Peter J. ;

Crotti, Lia ;

Dagradi, Federica ;

Guicheney, Pascale ;

Fressart, Veronique ;

Leenhardt, Antoine ;

Antzelevitch, Charles ;

Bartkowiak, Susan ;

Schulze-Bahr, Eric ;

Zumhagen, Sven ;

Behr, Elijah R. ;

Bastiaenen, Rachel ;

Tfelt-Hansen, Jacob ;

Olesen, Morten Salling ;

Kaeaeb, Stefan ;

Beckmann, Britt M. ;

Weeke, Peter ;

Watanabe, Hiroshi ;

Endo, Naoto ;

Minamino, Tohru ;

Horie, Minoru ;

Ohno, Seiko ;

Hasegawa, Kanae ;

Makita, Naomasa ;

Nogami, Akihiko ;

Shimizu, Wataru ;

Aiba, Takeshi ;

Froguel, Philippe ;

Balkau, Beverley ;

Lantieri, Olivier ;

Torchio, Margherita ;

Wiese, Cornelia ;

Weber, David ;

Wolswinkel, Rianne ;

Coronel, Ruben ;

Boukens, Bas J. ;

Bezieau, Stephane ;

Charpentier, Eric ;

Chatel, Stephanie ;

Despres, Aurore ;

Gros, Francoise ;

Kyndt, Florence ;

Lecointe, Simon .

NATURE GENETICS, 2013, 45 (09) :1044-+

[10]

Buenrostro JD, 2013, NAT METHODS, V10, P1213, DOI [10.1038/NMETH.2688, 10.1038/nmeth.2688]

← 1 2 3 4 5 6 7 8 9 →