Identification of genetic elements in metabolism by high-throughput mouse phenotyping

作者：Jan Rozman, Birgit Rathkolb, Manuela A. Oestereicher, Christine Schütt, Aakash Chavan Ravindranath, Stefanie Leuchtenberger, Sapna Sharma, Martin Kistler, Monja Willershäuser, Robert Brommage, Terrence F. Meehan, Jeremy Mason, Hamed Haselimashhadi, Juan Antonio Aguilar‐Pimentel, Lore Becker, Irina Treise, Kristin Moreth, Lillian Garrett, Sabine M. Hölter, Annemarie Zimprich, Susan Marschall, Oana V. Amarie, Julia Calzada-Wack, Frauke Neff, Laura Brachthäuser, Christoph Lengger, Claudia Stoeger, Lilly Zapf, Yi-Li Cho, Patricia da Silva‐Buttkus, Markus Kraiger, Philipp Mayer‐Kuckuk, Karen Kristine Gampe, Moya Wu, Nathalie Conte, Jonathan Warren, Chao-Kung Chen, Ilinca Tudose, Mike Relac, Peter Matthews, Heather Cater, Helen P. M. Natukunda, James Cleak, Lydia Teboul, Sharon Clementson-Mobbs, Zsombor Szoke-Kovacs, Alison P. Walling, Sara Johnson, Gemma Codner, Tanja Fiegel, Natalie Ring, Henrik Westerberg, Simon Greenaway, Duncan Sneddon, Hugh W. Morgan, Jorik Loeffler, Michelle Stewart, Ramiro Ramírez‐Solis, Allan Bradley, William C. Skarnes, Karen P. Steel, Simon A. Maguire, Joshua Dench, David Lafont, Valerie E. Vancollie, Selina Pearson, Amy S. Gates, Mark Sanderson, Carl Shannon, Lauren F. E. Anthony, Maksymilian T. Sumowski, Robbie S. B. McLaren, Brendan Doe, Hannah Wardle‐Jones, Mark Griffiths, Antonella Galli, Agnieszka Świątkowska, Christopher Isherwood, Anneliese O. Speak, Emma L. Cambridge, Heather Wilson, Susana Caetano, Anna Karin B. Maguire, David J. Adams, Joanna Bottomley, Edward J. Ryder, Diane Gleeson, Laurent Pouilly, Stéphane Rousseau, Aurélie Auburtin, Patrick T. Reilly, Abdel Ayadi, Mohammed Selloum, Joshua A. Wood, Dave Clary, Peter J. Havel, Todd Tolentino, Heather Tolentino, Mike Schuchbauer, Sheryl Pedroia, Amanda Trainor, Esi Djan, Milton Pham, Alison Huynh, Vincent de Vera, John Seavitt, Juan Gallegos, Arturo Garza, Elise Mangin, Joel Senderstrom, Iride Lazo, Kate Mowrey, Ritu Bohat, Rodney C. Samaco, Surabi Veeraragavan, Christine Beeton, Sowmya Kalaga, Lois Kelsey, Igor Vukobradovic, Zorana Berberovic, Celeste Owen, Dawei Qu, Ruolin Guo, Susan Newbigging, Lily Morikawa, Napoleon Law, Xueyuan Shang, Patricia Feugas, Yanchun Wang, Mohammad Eskandarian, Yingchun Zhu, Patricia Penton, Valerie Laurin, Shannon Clarke, Qing Lan, Gillian Sleep, Amie Creighton, Elsa Jacob, Ozge Danisment, Marina Gertsenstein, Monica Pereira, S. MacMaster, Sandra Tondat, Tracy Carroll, Jorge Cabezas, Jane Hunter, Greg Clark, Mohammed Bubshait, David Miller, Khondoker Sohel, Hibret A. Adissu, Milan Ganguly, Alexandr Bezginov, Francesco Chiani, Chiara Di Pietro, Gianfranco Di Segni, Olga Ermakova, Filomena Ferrara, Paolo Fruscoloni, Alessia Gambadoro, Serena Gastaldi, Elisabetta Golini, Gina La Sala, Silvia Mandillo, Daniela Marazziti, Marzia Massimi, Rafaele Matteoni, Tiziana Orsini, Miriam Pasquini, Marcello Raspa, Aline Rauch, Gianfranco Rossi, Nicoletta Rossi, Sabrina Putti, Ferdinando Scavizzi, Giuseppe D. Tocchini-Valentini, Shigeharu Wakana, Tomohiro Suzuki, Masaru Tamura, Hideki Kaneda, Tamio Furuse, Kimio Kobayashi, Ikuo Miura, Ikuko Yamada, Yuichi Obata, Atsushi Yoshiki, Shinya Ayabe, J. Nicole Chambers, Karel Chalupský, Claudia Seisenberger, Antje Bürger, Joachim Beig, Ralf Kühn, Andreas Hörlein, Joel Schick, Oskar Oritz, Florian Giesert, Jochen Graw, Markus Ollert, Carsten B. Schmidt‐Weber, Tobias Stoeger, Ali Önder Yildirim, Oliver Eickelberg, Thomas Klopstock, Dirk H. Busch, Raffi Bekeredjian, Andreas Zimmer, Jules O. Jacobsen, Damian Smedley, Mary E. Dickinson, Frank Benso, Iva Morse, Hyoung-Chin Kim, Ho Lee, Soo Young Cho, Tertius Hough, Ann‐Marie Mallon, Sara Wells, Luís Santos, Christopher J. Lelliott, Jacqueline K. White, Tania Sorg, Marie‐France Champy, Lynette Bower, Corey Reynolds, Ann M. Flenniken, Stephen A. Murray, Lauryl M. J. Nutter, Karen L. Svenson, David West, Glauco P. Tocchini‐Valentini, Arthur L. Beaudet, Fátima Bosch, Robert Braun, Michael S. Dobbie, Xiang Gao, Yann Hérault, Ala Moshiri, Bret A. Moore, K. C. Kent Lloyd, Colin McKerlie, Hiroshi Masuya, Nobuhiko Tanaka, Paul Flicek, Helen Parkinson, Radislav Sedláček, Je Kyung Seong, Chi‐Kuang Leo Wang, Mark W. Moore, Steve D. M. Brown, Matthias H. Tschöp, Wolfgang Wurst, Martin Klingenspor, Eckhard Wolf, Johannes Beckers, Fausto Machicao, Andreas Peter, Harald Staiger, Hans‐Ulrich Häring, Harald Grallert, Mónica Campillos, Holger Maier, Helmut Fuchs, Valerie Gailus-Durner, Thomas Werner, Martin Hrabě de Angelis · 发表于：Nature Communications · 年份：2018 · DOI：10.1038/s41467-017-01995-2 · 被引用次数：72 · 研究领域：Metabolomics and Mass Spectrometry Studies、Nutrition, Genetics, and Disease、Adipose Tissue and Metabolism

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.