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

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.