Identification of genetic elements in metabolism by high-throughput mouse phenotyping.
Jan RozmanBirgit RathkolbManuela A OestereicherChristine SchüttAakash Chavan RavindranathStefanie LeuchtenbergerSapna SharmaMartin KistlerMonja WillershäuserRobert BrommageTerrence F MeehanJeremy C MasonHamed Haselimashhadinull nullTertius HoughAnn-Marie MallonSara WellsLuis SantosChristopher J LelliottJacqueline K WhiteTania SorgMarie-France ChampyLynette R BowerCorey L ReynoldsAnn M FlennikenStephen A MurrayLauryl M J NutterKaren L SvensonDavid WestGlauco P Tocchini-ValentiniArthur L BeaudetFatima BoschRobert B BraunMichael S DobbieXiang GaoYann HéraultAla MoshiriBret A MooreKevin C Kent LloydColin McKerlieHiroshi MasuyaNobuhiko TanakaPaul FlicekHelen E ParkinsonRadislav SedlacekJe Kyung SeongChi-Kuang Leo WangMark MooreSteve D BrownMatthias H TschöpWolfgang WurstMartin KlingensporEckhard WolfJohannes BeckersFausto MachicaoAndreas PeterHarald StaigerHans-Ulrich HäringHarald GrallertMonica CampillosHolger MaierHelmut FuchsValerie Gailus-DurnerThomas WernerMartin Hrabě de AngelisPublished in: Nature communications (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.