Abstract
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.
| Original language | English |
|---|---|
| Article number | 288 |
| Journal | Nature Communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2018 |
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In: Nature Communications, Vol. 9, No. 1, 288, 01.12.2018.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Identification of genetic elements in metabolism by high-throughput mouse phenotyping
AU - Rozman, Jan
AU - Rathkolb, Birgit
AU - Oestereicher, Manuela A.
AU - Schütt, Christine
AU - Ravindranath, Aakash Chavan
AU - Leuchtenberger, Stefanie
AU - Sharma, Sapna
AU - Kistler, Martin
AU - Willershäuser, Monja
AU - Brommage, Robert
AU - Meehan, Terrence F.
AU - Mason, Jeremy
AU - Haselimashhadi, Hamed
AU - Aguilar-Pimentel, Antonio
AU - Becker, Lore
AU - Treise, Irina
AU - Moreth, Kristin
AU - Garrett, Lillian
AU - Hölter, Sabine M.
AU - Zimprich, Annemarie
AU - Marschall, Susan
AU - Amarie, Oana V.
AU - Calzada-Wack, Julia
AU - Neff, Frauke
AU - Brachthäuser, Laura
AU - Lengger, Christoph
AU - Stoeger, Claudia
AU - Zapf, Lilly
AU - Cho, Yi Li
AU - Da Silva-Buttkus, Patricia
AU - Kraiger, Markus J.
AU - Mayer-Kuckuk, Philipp
AU - Gampe, Karen Kristine
AU - Wu, Moya
AU - Conte, Nathalie
AU - Warren, Jonathan
AU - Chen, Chao Kung
AU - Tudose, Ilinca
AU - Relac, Mike
AU - Matthews, Peter
AU - Cater, Heather L.
AU - Natukunda, Helen P.
AU - Cleak, James
AU - Teboul, Lydia M.
AU - Clementson-Mobbs, Sharon
AU - Szoke-Kovacs, Zsombor
AU - Walling, Alison P.
AU - Johnson, Sara J.
AU - Codner, Gemma F.
AU - Fiegel, Tanja
AU - Ring, Natalie
AU - Westerberg, Henrik
AU - Greenaway, Simon
AU - Sneddon, Duncan
AU - Morgan, Hugh
AU - Loeffler, Jorik
AU - Stewart, Michelle E.
AU - Ramirez-Solis, Ramiro
AU - Bradley, Allan
AU - Skarnes, William C.
AU - Steel, Karen P.
AU - Maguire, Simon A.
AU - Dench, Joshua
AU - Lafont, David
AU - Vancollie, Valerie E.
AU - Pearson, Selina A.
AU - Gates, Amy S.
AU - Sanderson, Mark
AU - Shannon, Carl
AU - Anthony, Lauren F.E.
AU - Sumowski, Maksymilian T.
AU - McLaren, Robbie S.B.
AU - Doe, Brendan
AU - Wardle-Jones, Hannah
AU - Griffiths, Mark N.D.
AU - Galli, Antonella
AU - Swiatkowska, Agnieszka
AU - Isherwood, Christopher M.
AU - Speak, Anneliese O.
AU - Cambridge, Emma L.
AU - Wilson, Heather M.
AU - Caetano, Susana S.
AU - Maguire, Anna Karin B.
AU - Adams, David J.
AU - Bottomley, Joanna
AU - Ryder, Ed
AU - Gleeson, Diane
AU - Pouilly, Laurent
AU - Rousseau, Stephane
AU - Auburtin, Aurélie
AU - Reilly, Patrick
AU - Ayadi, Abdel
AU - Selloum, Mohammed
AU - Wood, Joshua A.
AU - Clary, Dave
AU - Havel, Peter
AU - Tolentino, Todd
AU - Tolentino, Heather
AU - Schuchbauer, Mike
AU - Pedroia, Sheryl
AU - Trainor, Amanda
AU - Djan, Esi
AU - Pham, Milton
AU - Huynh, Alison
AU - De Vera, Vincent
AU - Seavitt, John
AU - Gallegos, Juan
AU - Garza, Arturo
AU - Mangin, Elise
AU - Senderstrom, Joel
AU - Lazo, Iride
AU - Mowrey, Kate
AU - Bohat, Ritu
AU - Samaco, Rodney
AU - Veeraragavan, Surabi
AU - Beeton, Christine
AU - Kalaga, Sowmya
AU - Kelsey, Lois
AU - Vukobradovic, Igor
AU - Berberovic, Zorana
AU - Owen, Celeste
AU - Qu, Dawei
AU - Guo, Ruolin
AU - Newbigging, Susan
AU - Morikawa, Lily
AU - Law, Napoleon
AU - Shang, Xueyuan
AU - Feugas, Patricia
AU - Wang, Yanchun
AU - Eskandarian, Mohammad
AU - Zhu, Yingchun
AU - Penton, Patricia
AU - Laurin, Valerie
AU - Clarke, Shannon
AU - Lan, Qing
AU - Sleep, Gillian
AU - Creighton, Amie
AU - Jacob, Elsa
AU - Danisment, Ozge
AU - Gertsenstein, Marina
AU - Pereira, Monica
AU - MacMaster, Suzanne
AU - Tondat, Sandra
AU - Carroll, Tracy
AU - Cabezas, Jorge
AU - Hunter, Jane
AU - Clark, Greg
AU - Bubshait, Mohammed
AU - Miller, David
AU - Sohel, Khondoker
AU - Adissu, Hibret
AU - Ganguly, Milan
AU - Bezginov, Alexandr
AU - Chiani, Francesco
AU - Di Pietro, Chiara
AU - Di Segni, Gianfranco
AU - Ermakova, Olga
AU - Ferrara, Filomena
AU - Fruscoloni, Paolo
AU - Gambadoro, Aalessia
AU - Gastaldi, Serena
AU - Golini, Elisabetta
AU - La Sala, Gina
AU - Mandillo, Silvia
AU - Marazziti, Daniela
AU - Massimi, Marzia
AU - Matteoni, Rafaele
AU - Orsini, Tiziana
AU - Pasquini, Miriam
AU - Raspa, Marcello
AU - Rauch, Aline
AU - Rossi, Gianfranco
AU - Rossi, Nicoletta
AU - Putti, Sabrina
AU - Scavizzi, Ferdinando
AU - Tocchini-Valentini, Giuseppe D.
AU - Wakana, Shigeharu
AU - Suzuki, Tomohiro
AU - Tamura, Masaru
AU - Kaneda, Hideki
AU - Furuse, Tamio
AU - Kobayashi, Kimio
AU - Miura, Ikuo
AU - Yamada, Ikuko
AU - Obata, Yuichi
AU - Yoshiki, Atsushi
AU - Ayabe, Shinya
AU - Chambers, J. Nicole
AU - Chalupsky, Karel
AU - Seisenberger, Claudia
AU - Bürger, Antje
AU - Beig, Joachim
AU - Kühn, Ralf
AU - Hörlein, Andreas
AU - Schick, Joel
AU - Oritz, Oskar
AU - Giesert, Florian
AU - Graw, Jochen
AU - Ollert, Markus
AU - Schmidt-Weber, Carsten
AU - Stoeger, Tobias
AU - Önder Yildirim, Ali
AU - Eickelberg, Oliver
AU - Klopstock, Thomas
AU - Busch, Dirk H.
AU - Bekeredjian, Raffi
AU - Zimmer, Andreas
AU - Jacobsen, Jules O.
AU - Smedley, Damian
AU - Dickinson, Mary E.
AU - Benso, Frank
AU - Morse, Iva
AU - Kim, Hyoung Chin
AU - Lee, Ho
AU - Cho, Soo Young
AU - Hough, Tertius
AU - Mallon, Ann Marie
AU - Wells, Sara
AU - Santos, Luis
AU - Lelliott, Christopher J.
AU - White, Jacqueline K.
AU - Sorg, Tania
AU - Champy, Marie France
AU - Bower, Lynette R.
AU - Reynolds, Corey L.
AU - Flenniken, Ann M.
AU - Murray, Stephen A.
AU - Nutter, Lauryl M.J.
AU - Svenson, Karen L.
AU - West, David
AU - Tocchini-Valentini, Glauco P.
AU - Beaudet, Arthur L.
AU - Bosch, Fatima
AU - Braun, Robert B.
AU - Dobbie, Michael S.
AU - Gao, Xiang
AU - Herault, Yann
AU - Moshiri, Ala
AU - Moore, Bret A.
AU - Kent Lloyd, K. C.
AU - McKerlie, Colin
AU - Masuya, Hiroshi
AU - Tanaka, Nobuhiko
AU - Flicek, Paul
AU - Parkinson, Helen E.
AU - Sedlacek, Radislav
AU - Seong, Je Kyung
AU - Wang, Chi Kuang Leo
AU - Moore, Mark
AU - Brown, Steve D.
AU - Tschöp, Matthias H.
AU - Wurst, Wolfgang
AU - Klingenspor, Martin
AU - Wolf, Eckhard
AU - Beckers, Johannes
AU - MacHicao, Fausto
AU - Peter, Andreas
AU - Staiger, Harald
AU - Häring, Hans Ulrich
AU - Grallert, Harald
AU - Campillos, Monica
AU - Maier, Holger
AU - Fuchs, Helmut
AU - Gailus-Durner, Valerie
AU - Werner, Thomas
AU - De Angelis, Martin Hrabe
N1 - Funding Information: This work was supported by the German Federal Ministry of Education and Research: Infrafrontier [no. 01KX1012] (M.HdA.), the German Center for Diabetes Research (DZD), EU Horizon2020: IPAD-MD [no 653961] (M.HdA.), by NIH grants U54 HG006370 (T.F.M., P.F., A.-M.M., H.E.P. D.S., and S.D.M.B), U42 OD011185 (S.A.M.), UM1 OD023222 (S.A.M., K.L.S., and R.E.B.), U54 HG006332 (R.E.B. and K.S.), U54 HG006348-S1 and OD011174 (A.L.B.), 1R24OD011883 (C.J.M.), U54 HG006364, and U42 OD011175, and UM1 OD023221 (K.C.K.L.), and additional support provided by the The Wellcome Trust, Medical Research Council Strategic Award 53658 (S.W. and S.D.M. B.), Government of Canada through Genome Canada and Ontario Genomics (OGI-051) (C.M. and S.D.M.B.), Wellcome Trust Strategic Award, National Centre for Scientific Research (CNRS), the French National Institute of Health and Medical Research (INSERM), the University of Strasbourg (UDS), the “Centre Européen de Recherche en Biologie et en Médecine,” the “Agence Nationale de la Recherche” under the frame program “Investissements d’Avenir” labeled ANR-10-IDEX-0002-02, ANR-10-INBS-07 PHENOMIN to (Y.H.), “EUCOMM: Tools for Functional Annotation of the Mouse Genome” (EUCOMMTOOLS) project—grant agreement no. [FP7-HEALTH-F4-2010-261492] (W.G.W.), the Government of Australia through the National Collaborative Research Infrastructure Strategy to the Australian Phenomics Network Project (M.S.D.) and by the Grants for Korea Mouse Phenotype Consortium (2013M3A9D5072550) funded by National Research Foundation, Korean Government (J.K.S.). Regarding the NIH grants listed: “The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Publisher Copyright: © 2017 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040788526&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/29348434
U2 - 10.1038/s41467-017-01995-2
DO - 10.1038/s41467-017-01995-2
M3 - Article
C2 - 29348434
AN - SCOPUS:85040788526
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 288
ER -