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.

Australian Phenomics Network John Curtin School of Medical Research Australian National University 131 Garran Road Canberra ACT 2601 Australia

CELPHEDIA PHENOMIN Institut Clinique de la Souris 1 Rue Laurent Fries 67404 Illkirch Graffenstaden France

Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona Bellaterra Spain

Centre National de la Recherche Scientifique UMR7104 67404 Illkirch France

Chair of Developmental Genetics Center of Life and Food Sciences Weihenstephan Technische Universität München Ingolstädter Landstrasse 1 85764 Neuherberg Germany

Chair of Experimental Genetics School of Life Science Weihenstephan Technische Universität München Alte Akademie 8 85354 Freising Germany

Chair of Molecular Nutritional Medicine Technical University of Munich TUM School of Life Sciences Weihenstephan 85354 Freising Germany

Children's Hospital Oakland Research Institute 5700 Martin Luther King Jr Way Oakland CA 94609 USA

Clinical Cooperation Group Type 2 Diabetes Helmholtz Zentrum München and Ludwig Maximilians Universität München Ingolstädter Landstr 1 85764 Neuherberg Germany

Czech Centre for Phenogenomics Institute of Molecular Genetics Prumyslova 595 252 50 Vestec Czech Republic

Department of Internal Medicine Division of Endocrinology Diabetology Vascular Medicine Nephrology and Clinical Chemistry University of Tübingen 72076 Tübingen Germany

Department of Molecular and Human Genetics Baylor College of Medicine 7702 Main St Houston Medical Center Houston TX 77030 4406 USA

Department of Ophthalmology and Vision Science School of Medicine U C Davis 77 Cadillac Drive Sacramento 95825 CA USA

Deutsches Institut für Neurodegenerative Erkrankungen Site Munich Feodor Lynen Str 17 81377 Munich Germany

Division of Metabolic Diseases Department of Medicine Technische Universität München 80333 Munich Germany

EKFZ Else Kröner Fresenius Center for Nutritional Medicine Technical University of Munich 85354 Freising Germany

European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton Cambridge CB10 1SD UK

German Center for Diabetes Research Ingolstädter Landstr 1 85764 Neuherberg Germany

German Mouse Clinic Institute of Experimental Genetics Helmholtz Zentrum München German Research Center for Environmental Health Ingolstädter Landstr 1 85764 Neuherberg Germany

IMPC San Anselmo CA 94960 USA

Institut de Génétique et de Biologie Moléculaire et Cellulaire Parc d'innovation 1 Rue Laurent Fries BP 10142 67404 Illkirch France

Institut National de la Santé et de la Recherche Médicale U964 67404 Illkirch France

Institute for Diabetes and Obesity Helmholtz Diabetes Center at Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen Otfried Müller Str 10 72076 Tübingen Germany

Institute of Bioinformatics and Systems Biology Helmholtz Zentrum München German Research Center for Environmental Health Ingolstädter Landstr 1 85764 Neuherberg Germany

Institute of Developmental Genetics Helmholtz Zentrum München German Research Center for Environmental Health GmbH Ingolstädter Landstrasse 1 85764 Neuherberg Germany

Institute of Pharmaceutical Sciences Department of Pharmacy and Biochemistry Eberhard Karls University Tübingen 72076 Tübingen Germany

Internal Medicine Nephrology and Center for Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI 48109 USA

Korea Mouse Phenotyping Consortium and BK21 Program for Veterinary Science Research Institute for Veterinary Science College of Veterinary Medicine Seoul National University 599 Gwanangno Gwanak gu Seoul 151 742 South Korea

Ludwig Maximilians Universität München Gene Center Institute of Molecular Animal Breeding and Biotechnology Feodor Lynen Strasse 25 81377 Munich Germany

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Joseph and Wolf Lebovic Health Complex 600 University Avenue Toronto ON M5G 1X5 Canada

Medical Research Council Harwell Oxfordshire OX11 0RD UK

Monterotondo Mouse Clinic Italian National Research Council Institute of Cell Biology and Neurobiology Adriano Buzzati Traverso Campus Via E Ramarini 32 Monterotondo Scalo RM 00015 Italy

Mouse Biology Program University of California One Shields Avenue Davis CA 95616 USA

Munich Cluster for Systems Neurology Adolf Butenandt Institut Ludwig Maximilians Universität München Feodor Lynen Str 17 81377 Munich Germany

National Laboratory Animal Center National Applied Research Laboratories 128 Yen Chiou Yuan Rd Sec 2 Nankang Taipei 11529 Taiwan

Research Unit of Molecular Epidemiology Institute of Epidemiology 2 Helmholtz Zentrum München Ingolstädter Landstr 1 85764 Neuherberg Germany

RIKEN BioResource Center 3 1 1 Koyadai Tsukuba Ibaraki 305 0074 Japan

SKL of Pharmaceutical Biotechnology and Model Animal Research Center Collaborative Innovation Center for Genetics and Development Nanjing Biomedical Research Institute Nanjing University Nanjing 210061 China

The Centre for Phenogenomics 25 Orde St Toronto M5T 3H7 ON Canada

The Hospital for Sick Children 600 University Avenue Toronto ON M5G 1X5 Canada

The Jackson Laboratory 600 Main Street Bar Harbor ME 04609 USA

The Wellcome Trust Sanger Institute Wellcome Genome Campus Hinxton Cambridge CB10 1SA UK

Université de Strasbourg 67404 Illkirch France

William R Pritchard Veterinary Medical Teaching Hospital School of Veterinary Medicine U C Davis One Shields Avenue Davis 95616 CA USA

ZIEL Institute for Food and Health Technical University of Munich 85354 Freising Germany

Zobrazit více v PubMed

Ahmed M. Non-alcoholic fatty liver disease in 2015. World J. Hepatol. 2015;7:1450–1459. doi: 10.4254/wjh.v7.i11.1450. PubMed DOI PMC

Boehme MW, et al. Prevalence, incidence and concomitant co-morbidities of type 2 diabetes mellitus in South Western Germany–a retrospective cohort and case control study in claims data of a large statutory health insurance. BMC Public Health. 2015;15:855. doi: 10.1186/s12889-015-2188-1. PubMed DOI PMC

Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine. 2014;42:698–702. doi: 10.1016/j.mpmed.2014.09.007. PubMed DOI PMC

Kharroubi AT, Darwish HM. Diabetes mellitus: the epidemic of the century. World J. Diabetes. 2015;6:850–867. doi: 10.4239/wjd.v6.i6.850. PubMed DOI PMC

Stevens GA, et al. National, regional, and global trends in adult overweight and obesity prevalences. Popul. Health Metr. 2012;10:22. doi: 10.1186/1478-7954-10-22. PubMed DOI PMC

Fuchsberger C, et al. The genetic architecture of type 2 diabetes. Nature. 2016;536:41–47. doi: 10.1038/nature18642. PubMed DOI PMC

Hattersley AT, Patel KA. Precision diabetes: learning from monogenic diabetes. Diabetologia. 2017;60:769–777. doi: 10.1007/s00125-017-4226-2. PubMed DOI PMC

Kraja AT, et al. Pleiotropic genes for metabolic syndrome and inflammation. Mol. Genet. Metab. 2014;112:317–338. doi: 10.1016/j.ymgme.2014.04.007. PubMed DOI PMC

Kunes J, et al. Epigenetics and a new look on metabolic syndrome. Physiol. Res. 2015;64:611–620. PubMed

Mamtani M, et al. Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families. Clin. Epigenetics. 2016;8:6. doi: 10.1186/s13148-016-0173-x. PubMed DOI PMC

Somer RA, Thummel CS. Epigenetic inheritance of metabolic state. Curr. Opin. Genet. Dev. 2014;27:43–47. doi: 10.1016/j.gde.2014.03.008. PubMed DOI PMC

Pandey AK, et al. Functionally enigmatic genes: a case study of the brain ignorome. PLoS ONE. 2014;9:e88889. doi: 10.1371/journal.pone.0088889. PubMed DOI PMC

Sahni N, et al. Widespread macromolecular interaction perturbations in human genetic disorders. Cell. 2015;161:647–660. doi: 10.1016/j.cell.2015.04.013. PubMed DOI PMC

Steckler T, et al. The preclinical data forum network: a new ECNP initiative to improve data quality and robustness for (preclinical) neuroscience. Eur. Neuropsychopharmacol. 2015;25:1803–1807. doi: 10.1016/j.euroneuro.2015.05.011. PubMed DOI

Brown SD, Moore MW. The international mouse phenotyping consortium: past and future perspectives on mouse phenotyping. Mamm. Genome. 2012;23:632–640. doi: 10.1007/s00335-012-9427-x. PubMed DOI PMC

Ring N, et al. A mouse informatics platform for phenotypic and translational discovery. Mamm. Genome. 2015;26:413–421. doi: 10.1007/s00335-015-9599-2. PubMed DOI PMC

Gailus-Durner V, et al. Introducing the German mouse clinic: open access platform for standardized phenotyping. Nat. Methods. 2005;2:403–404. doi: 10.1038/nmeth0605-403. PubMed DOI

Mallon AM, Blake A, Hancock JM. EuroPhenome and EMPReSS: online mouse phenotyping resource. Nucleic Acids Res. 2008;36:D715–D718. doi: 10.1093/nar/gkm728. PubMed DOI PMC

Meehan TF, et al. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nat. Genet. 2017;49:1231–1238. doi: 10.1038/ng.3901. PubMed DOI PMC

Bowl MR, et al. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction. Nat. Commun. 2017;8:886. doi: 10.1038/s41467-017-00595-4. PubMed DOI PMC

Hrabe de Angelis M, et al. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nat. Genet. 2015;47:969–978. doi: 10.1038/ng.3360. PubMed DOI PMC

Karp NA, et al. Applying the ARRIVE Guidelines to an in vivo database. PLoS Biol. 2015;13:e1002151. doi: 10.1371/journal.pbio.1002151. PubMed DOI PMC

Brommage R, et al. High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes. Bone Res. 2014;2:14034. doi: 10.1038/boneres.2014.34. PubMed DOI PMC

Karp NA, et al. Prevalence of sexual dimorphism in mammalian phenotypic traits. Nat. Commun. 2017;8:15475. doi: 10.1038/ncomms15475. PubMed DOI PMC

Ober C, Loisel DA, Gilad Y. Sex-specific genetic architecture of human disease. Nat. Rev. Genet. 2008;9:911–922. doi: 10.1038/nrg2415. PubMed DOI PMC

Bonnefond A, Froguel Rare and common genetic events in type 2 diabetes: what should biologists know? Cell Metab. 2015;21:357–368. doi: 10.1016/j.cmet.2014.12.020. PubMed DOI

Dauriz M, et al. Association of a 62 variants type 2 diabetes genetic risk score with markers of subclinical atherosclerosis: a transethnic, multicenter study. Circ. Cardiovasc. Genet. 2015;8:507–515. doi: 10.1161/CIRCGENETICS.114.000740. PubMed DOI PMC

Hara K, Kadowaki T, Odawara M. Genes associated with diabetes: potential for novel therapeutic targets? Expert. Opin. Ther. Targets. 2016;20:255–267. doi: 10.1517/14728222.2016.1098618. PubMed DOI

Vimaleswaran KS, et al. Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI. Hum. Mol. Genet. 2012;21:4537–4542. doi: 10.1093/hmg/dds283. PubMed DOI PMC

Arnold M, et al. SNiPA: an interactive, genetic variant-centered annotation browser. Bioinformatics. 2015;31:1334–1336. doi: 10.1093/bioinformatics/btu779. PubMed DOI PMC

Cotsapas C, et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet. 2011;7:e1002254. doi: 10.1371/journal.pgen.1002254. PubMed DOI PMC

Ehret GB, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478:103–109. doi: 10.1038/nature10405. PubMed DOI PMC

Locke AE, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206. doi: 10.1038/nature14177. PubMed DOI PMC

DIAGRAM Consortium et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat. Genet.46, 234–244 (2014). PubMed PMC

Manning AK, et al. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat. Genet. 2012;44:659–669. doi: 10.1038/ng.2274. PubMed DOI PMC

Manning AK, et al. Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP x environment regression coefficients. Genet. Epidemiol. 2011;35:11–18. doi: 10.1002/gepi.20546. PubMed DOI PMC

Scott RA, et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat. Genet. 2012;44:991–1005. doi: 10.1038/ng.2385. PubMed DOI PMC

Shungin D, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–196. doi: 10.1038/nature14132. PubMed DOI PMC

Soranzo N, et al. Common variants at 10 genomic loci influence hemoglobin A(1)(C) levels via glycemic and nonglycemic pathways. Diabetes. 2010;59:3229–3239. doi: 10.2337/db10-0502. PubMed DOI PMC

Global Lipids Genetics C, et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 2013;45:1274–1283. doi: 10.1038/ng.2797. PubMed DOI PMC

Stefan N, et al. Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia. 2005;48:2282–2291. doi: 10.1007/s00125-005-1948-3. PubMed DOI

Kanehisa M, et al. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2016;44:D457–D462. doi: 10.1093/nar/gkv1070. PubMed DOI PMC

Carroll LS, et al. Evidence that putative ADHD low risk alleles at SNAP25 may increase the risk of schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009;150B:893–899. doi: 10.1002/ajmg.b.30915. PubMed DOI

Cohen OS, et al. A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples. Mol. Psychiatry. 2016;21:975–982. doi: 10.1038/mp.2015.137. PubMed DOI

Jia JM, et al. Age-dependent regulation of synaptic connections by dopamine D2 receptors. Nat. Neurosci. 2013;16:1627–1636. doi: 10.1038/nn.3542. PubMed DOI PMC

Karp NA, et al. Prevalence of sexual dimorphism in mammalian phenotypic traits. Nat. Commun. 2017;8:15475. doi: 10.1038/ncomms15475. PubMed DOI PMC

Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am. J. Clin. Nutr. 1997;65:1220S–1228S. doi: 10.1093/ajcn/65.4.1220S. PubMed DOI

Frisch M, et al. LitInspector: literature and signal transduction pathway mining in PubMed abstracts. Nucleic Acids Res. 2009;37:W135–W140. doi: 10.1093/nar/gkp303. PubMed DOI PMC

Stelzer G, et al. The genecards suite: from gene data mining to disease genome sequence analyses. Curr. Protoc. Bioinformatics. 2016;54:1 30 1–1 30 33. doi: 10.1002/cpbi.5. PubMed DOI

Yamada T, et al. iPath2.0: interactive pathway explorer. Nucleic Acids Res. 2011;39:W412–W415. doi: 10.1093/nar/gkr313. PubMed DOI PMC

Ashburner M, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 2000;25:25–29. doi: 10.1038/75556. PubMed DOI PMC

A review of standardized high-throughput cardiovascular phenotyping with a link to metabolism in mice

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

A resource of targeted mutant mouse lines for 5,061 genes

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density