Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy.
Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy.
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DOI：
10.1186/s13059-017-1286-z
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发表时间：
2017-09-14
期刊：
影响因子：
12.3
通讯作者：
Hubner N
中科院分区：
文献类型：
--
作者：
Heinig M;Adriaens ME;Schafer S;van Deutekom HWM;Lodder EM;Ware JS;Schneider V;Felkin LE;Creemers EE;Meder B;Katus HA;Rühle F;Stoll M;Cambien F;Villard E;Charron P;Varro A;Bishopric NH;George AL Jr;Dos Remedios C;Moreno-Moral A;Pesce F;Bauerfeind A;Rüschendorf F;Rintisch C;Petretto E;Barton PJ;Cook SA;Pinto YM;Bezzina CR;Hubner N
遗传变异是RNA转录和剪接的重要决定因素，这反过来又导致人类特征的变异，包括心血管疾病。在此，我们报告了首次使用 RNA 测序对 97 名扩张型心肌病患者和 108 名非疾病对照患者的心脏转录组变异进行深入调查。我们揭示了扩张型心肌病患者和对照之间基因表达和剪接的广泛差异，影响了已知和新型扩张型心肌病基因。此外，我们还发现遗传变异对转录调节、异构体使用和等位基因特异性表达的广泛影响。全基因组关联 SNP 的系统注释确定了 60 个心脏表型的功能候选基因，占所有已发表的心脏全基因组关联位点的 20%。关注扩张型心肌病表型，我们发现在两个独立队列中，扩张型心肌病全基因组关联信号的 eQTL 变体也有所富集。 RNA转录、剪接和等位基因特异性表达都是扩张型心肌病表型的重要决定因素，并受遗传因素控制。我们的结果代表了心血管遗传学领域的强大资源。本文的在线版本 (doi:10.1186/s13059-017-1286-z) 包含补充材料，可供授权用户使用。
Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. The online version of this article (doi:10.1186/s13059-017-1286-z) contains supplementary material, which is available to authorized users.
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影响因子：
12.3
作者：
Castel SE;Levy-Moonshine A;Mohammadi P;Banks E;Lappalainen T
通讯作者：
Lappalainen T
影响因子：
30.8
作者：
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;Raychaudhuri, Soumya;Kumar, Runjun D.;Harris, Tamara B.;Launer, Lenore J.;Shuldiner, Alan R.;Alonso, Alvaro;Bader, Joel S.;EhreT, Georg;Huang, Hailiang;Kao, W. H. Linda;Strait, James B.;Macfarlane, Peter W.;Brown, Morris;Caulfield, Mark J.;Samani, Nilesh J.;Kronenberg, Florian;Willeit, Johann;Smith, J. Gustav;Greiser, Karin H.;Schwabedissen, Henriette Meyer Zu;Werdan, Karl;Carella, Massimo;Zelante, Leopoldo;Heckbert, Susan R.;Psaty, Bruce M.;Rotter, Jerome I.;Kolcic, Ivana;Poagek, Ozren;Wright, Alan F.;Griffin, Maura;Daly, Mark J.;Arnar, David O.;Holm, Hilma;Thorsteinsdottir, Unnur;Denny, Joshua C.;Roden, Dan M.;Zuvich, Rebecca L.;Emilsson, Valur;Plump, Andrew S.;Larson, Martin G.;O'Donnell, Christopher J.;Yin, Xiaoyan;Bobboll, Marco;D'Adamo, Adamo P.;Iorio, Annamaria;Sinagra, Gianfranco;Carracedo, Angel;Cummings, Steven R.;Nalls, Michael A.;Jula, Antti;Kontula, Kimmo K.;Marjamaa, Annukka;Oikarinen, Lasse;Perola, Markus;Porthan, Kimmo;Erbe, Raimund;Hoffmann, Per;Jockel, Karl-Heinz;Kalsch, Hagen;Nothen, Markus M.;Den Hoed, Marcel;Loos, Ruth J. F.;Thelle, Dag S.;Gieger, Christian;Meitinger, Thomas;Perz, Siegfried;Peters, Annette;Pruchal, Hanna;Sinner, Moritz F.;Waldenberger, Melanie;De Boer, Rudolf A.;Franke, Lude;Van der Vleuten, Pieter A.;Beckmann, Britt Maria;Martens, Eimo;Bardail, Abdennasser;Hofman, Nynke;Wilde, Arthur A. M.;Behr, Elijah R.;Dalageorgou, Chrysoula;Giudicessi, John R.;Medeiros-Domingo, Argelia;Barc, Julien;Kyndt, Florence;Probst, Vincent;Ghidoni, Alice;Insolia, Roberto;Hamilton, Robert M.;Scherer, Stephen W.;Brandimarto, Jeffrey;Margulies, Kenneth;Moravec, Christine E.;Del Greco, Fabiola;Fuchsberger, Christian;O'Connell, Jeffrey R.;Lee, Wai K.;Watt, Graham C. M.;Campbell, Harry;Wild, Sarah H.;El Mokhtari, Nour E.;Frey, Norbert;Asselbergs, Folkert W.;Leach, Irene Mateo;Navis, Gerjan;Van den Berg, Maarten P.;Van Veldhuisen, Dirk J.;Kellis, Manolis;Krijthe, Bouwe P.;Franco, Oscar H.;Hofman, Albert;Kors, Jan A.;Uitterlinden, Andre G.;Witteman, Jacqueline C. M.;Kedenko, Lyudmyla;Lamina, Claudia;Oostra, Ben A.;Abecasis, Goncalo R.;Lakatta, Edward G.;Mulas, Antonella;Orru, Marco;Schlessinger, David;Uda, Manuela;Markus, Marcello R. P.;Volker, Uwe;Snieder, Harold;Spector, Timothy D.;Arnlov, Johan;Lind, Lars;Sundstrom, Johan;Syvanen, Ann-Christine;Kivimaki, Mika;Kahonen, Mika;Mononen, Nina;Raitakari, I. T.;Viikari, Jorma S.;Adamkova, Vera;Kiech, Stefan;Brion, Maria;Nicolaides, Andrew N.;Paulweber, Bernhard;Haerting, Johannes;Dominiczak, Anna F.;Nyberg, Fredrik;Whincup, Peter H.;Hingorani, Aroon D.;Schott, Jean-Jacques;Bezzina, Connie R.;Ingelsson, Erik;Ferrucci, Luigi;Gaspariniin, Paolo;Wilson, James F.;Rudan, Igor;Franke, Andre;Miihleisen, Thomas W.;Pramstaller, Peter P.;Lehtimaki, Terho J.;Paterson, Andrew D.;Parsa, Afshin;Liu, Yongmei;Van Duijn, Cornelia M.;Siscovick, David S.;Gudnason, Vilmundur;Jamshidi, Yalda;Salomaa, Veikko;Felix, Stephan B.;Sanna, Serena;Ritchie, Marylyn D.;Stricker, Bruno H.;Stefansson, Karl;Boyer, Laurie A.;Cappola, Thomas P.;Olsen, Jesper V.;Lage, Kasper;Schwartz, Peter J.;Kaab, Stefan;Chakravarti, Aravinda;Ackerman, Michael J.;Pfeufer, Arne;De Bakker, Paul I. W.;Newton-Cheh, Christopher
通讯作者：
Newton-Cheh, Christopher
影响因子：
7
作者：
Battle A;Mostafavi S;Zhu X;Potash JB;Weissman MM;McCormick C;Haudenschild CD;Beckman KB;Shi J;Mei R;Urban AE;Montgomery SB;Levinson DF;Koller D
通讯作者：
Koller D
影响因子：
5.3
作者：
Conrad, M;Jakupoglu, C;Brielmeier, M
通讯作者：
Brielmeier, M
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium