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dc.contributor.authorKilpeläinen, Tuomas Oen
dc.contributor.authorCarli, Jayne F Martinen
dc.contributor.authorSkowronski, Alicja Aen
dc.contributor.authorSun, Qien
dc.contributor.authorKriebel, Jenniferen
dc.contributor.authorFeitosa, Mary Fen
dc.contributor.authorHedman, Åsa Ken
dc.contributor.authorDrong, Alexander Wen
dc.contributor.authorHayes, James Een
dc.contributor.authorZhao, Jing Huaen
dc.contributor.authorPers, Tune Hen
dc.contributor.authorSchick, Ursulaen
dc.contributor.authorGrarup, Nielsen
dc.contributor.authorKutalik, Zoltánen
dc.contributor.authorTrompet, Stellaen
dc.contributor.authorMangino, Massimoen
dc.contributor.authorKristiansson, Katien
dc.contributor.authorBeekman, Marianen
dc.contributor.authorLyytikäinen, Leo-Pekkaen
dc.contributor.authorEriksson, Joelen
dc.contributor.authorHenneman, Peteren
dc.contributor.authorLahti, Jarien
dc.contributor.authorTanaka, Toshikoen
dc.contributor.authorLuan, Jian'anen
dc.contributor.authorDel, Greco M Fabiolaen
dc.contributor.authorPasko, Dorotaen
dc.contributor.authorFrida, Renströmen
dc.contributor.authorWillems, Saraen
dc.contributor.authorMahajan, Anubhaen
dc.contributor.authorRose, Lynda Men
dc.contributor.authorGuo, Xiuqingen
dc.contributor.authorLiu, Yongmeien
dc.contributor.authorKleber, Marcus Een
dc.contributor.authorPérusse, Louisen
dc.contributor.authorGaunt, Tomen
dc.contributor.authorAhluwalia, Tarunveer Sen
dc.contributor.authorSung, Yun Juen
dc.contributor.authorRamos, Yolande Fen
dc.contributor.authorAmin, Najafen
dc.contributor.authorAmuzu, Antoinetteen
dc.contributor.authorBarroso, Inesen
dc.contributor.authorBellis, Claireen
dc.contributor.authorBlangero, Johnen
dc.contributor.authorBuckley, Brendan Men
dc.contributor.authorBöhringer, Stefanen
dc.contributor.authorChen, Yii-Der Ien
dc.contributor.authorde, Craen Anton JNen
dc.contributor.authorCrosslin, David Ren
dc.contributor.authorDale, Caroline Een
dc.contributor.authorDastani, Zarien
dc.contributor.authorDay, Felixen
dc.contributor.authorDeelen, Jorisen
dc.contributor.authorDelgado, Graciela Een
dc.contributor.authorDemirkan, Ayseen
dc.contributor.authorFinucane, Francis Men
dc.contributor.authorFord, Ianen
dc.contributor.authorGarcia, Melissa Een
dc.contributor.authorGieger, Christianen
dc.contributor.authorGustafsson, Stefanen
dc.contributor.authorHallmans, Göranen
dc.contributor.authorHankinson, Susan Een
dc.contributor.authorHavulinna, Aki Sen
dc.contributor.authorHerder, Christianen
dc.contributor.authorHernandez, Denaen
dc.contributor.authorHicks, Andrew Aen
dc.contributor.authorHunter, David Jen
dc.contributor.authorIllig, Thomasen
dc.contributor.authorIngelsson, Eriken
dc.contributor.authorIoan-Facsinay, Andreeaen
dc.contributor.authorJansson, John-Oloven
dc.contributor.authorJenny, Nancy Sen
dc.contributor.authorJørgensen, Marit Een
dc.contributor.authorJørgensen, Torbenen
dc.contributor.authorKarlsson, Magnusen
dc.contributor.authorKoenig, Wolfgangen
dc.contributor.authorKraft, Peteren
dc.contributor.authorKwekkeboom, Joannekeen
dc.contributor.authorLaatikainen, Tiinaen
dc.contributor.authorLadwig, Karl-Heinzen
dc.contributor.authorLeDuc, Charles Aen
dc.contributor.authorLowe, Gordonen
dc.contributor.authorLu, Yingchangen
dc.contributor.authorMarques-Vidal, Pedroen
dc.contributor.authorMeisinger, Christaen
dc.contributor.authorMenni, Cristinaen
dc.contributor.authorMorris, Andrew Pen
dc.contributor.authorMyers, Richard Hen
dc.contributor.authorMännistö, Satuen
dc.contributor.authorNalls, Mike Aen
dc.contributor.authorPaternoster, Laviniaen
dc.contributor.authorPeters, Annetteen
dc.contributor.authorPradhan, Aruna Den
dc.contributor.authorRankinen, Tuomoen
dc.contributor.authorRasmussen-Torvik, Laura Jen
dc.contributor.authorRathmann, Wolfgangen
dc.contributor.authorRice, Treva Ken
dc.contributor.authorRichards, J Brenten
dc.contributor.authorRidker, Paul Men
dc.contributor.authorSattar, Naveeden
dc.contributor.authorSavage, Daviden
dc.contributor.authorSöderberg, Stefanen
dc.contributor.authorTimpson, Nicholas Jen
dc.contributor.authorVandenput, Liesbethen
dc.contributor.authorvan, Heemst Dianaen
dc.contributor.authorUh, Hae-Wonen
dc.contributor.authorVohl, Marie-Claudeen
dc.contributor.authorWalker, Marken
dc.contributor.authorWichmann, Heinz-Erichen
dc.contributor.authorWidén, Elisabethen
dc.contributor.authorWood, Andrew Ren
dc.contributor.authorYao, Jieen
dc.contributor.authorZeller, Tanjaen
dc.contributor.authorZhang, Yiyingen
dc.contributor.authorMeulenbelt, Ingriden
dc.contributor.authorKloppenburg, Margreeten
dc.contributor.authorAstrup, Arneen
dc.contributor.authorSørensen, Thorkild IAen
dc.contributor.authorSarzynski, Mark Aen
dc.contributor.authorRao, DCen
dc.contributor.authorJousilahti, Pekkaen
dc.contributor.authorVartiainen, Erkkien
dc.contributor.authorHofman, Alberten
dc.contributor.authorRivadeneira, Fernandoen
dc.contributor.authorUitterlinden, André Gen
dc.contributor.authorKajantie, Eeroen
dc.contributor.authorOsmond, Cliveen
dc.contributor.authorPalotie, Aarnoen
dc.contributor.authorEriksson, Johan Gen
dc.contributor.authorHeliövaara, Markkuen
dc.contributor.authorKnekt, Paul Ben
dc.contributor.authorKoskinen, Seppoen
dc.contributor.authorJula, Anttien
dc.contributor.authorPerola, Markusen
dc.contributor.authorHuupponen, Risto Ken
dc.contributor.authorViikari, Jorma Sen
dc.contributor.authorKähönen, Mikaen
dc.contributor.authorLehtimäki, Terhoen
dc.contributor.authorRaitakari, Olli Ten
dc.contributor.authorMellström, Danen
dc.contributor.authorLorentzon, Mattiasen
dc.contributor.authorCasas, Juan Pen
dc.contributor.authorBandinelli, Stefanieen
dc.contributor.authorMärz, Winfrieden
dc.contributor.authorIsaacs, Aaronen
dc.contributor.authorvan, Dijk Ko Wen
dc.contributor.authorvan, Duijn Cornelia Men
dc.contributor.authorHarris, Tamara Ben
dc.contributor.authorBouchard, Claudeen
dc.contributor.authorAllison, Matthew Aen
dc.contributor.authorChasman, Daniel Ien
dc.contributor.authorOhlsson, Claesen
dc.contributor.authorLind, Larsen
dc.contributor.authorScott, Roberten
dc.contributor.authorLangenberg, Claudiaen
dc.contributor.authorWareham, Nicholasen
dc.contributor.authorFerrucci, Luigien
dc.contributor.authorFrayling, Timothy Men
dc.contributor.authorPramstaller, Peter Pen
dc.contributor.authorBorecki, Ingrid Ben
dc.contributor.authorWaterworth, Dawn Men
dc.contributor.authorBergmann, Svenen
dc.contributor.authorWaeber, Gérarden
dc.contributor.authorVollenweider, Peteren
dc.contributor.authorVestergaard, Henriken
dc.contributor.authorHansen, Torbenen
dc.contributor.authorPedersen, Olufen
dc.contributor.authorHu, Frank Ben
dc.contributor.authorSlagboom, P Elineen
dc.contributor.authorGrallert, Haralden
dc.contributor.authorSpector, Tim Den
dc.contributor.authorJukema, JWen
dc.contributor.authorKlein, Robert Jen
dc.contributor.authorSchadt, Erik Een
dc.contributor.authorFranks, Paul Wen
dc.contributor.authorLindgren, Cecilia Men
dc.contributor.authorLeibel, Rudolph Len
dc.contributor.authorLoos, Ruthen
dc.date.accessioned2016-04-05T13:06:41Z
dc.date.available2016-04-05T13:06:41Z
dc.date.issued2016-02-01en
dc.identifier.citationT. O. Kilpeläinen et al. Nature Communications (2016). volume 7, article 10494. DOI:10.1038/ncomms10494en
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/254803
dc.description.abstractLeptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching Po10 6 in 19,979 additional individuals. We identify five loci robustly associated (Po5 10 8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
dc.description.sponsorshipFunding for this study was provided by the Academy of Finland (41071, 117787, 118065, 121584, 124282, 126925, 129494, 129322, 129378, 130326, 134309, 134791, 136895, 139635, 250207, 263836, 286284 and 263924); Ahokas Foundation; ALF/LUA research grant in Gothenburg; Amgen; Augustinus Foundation; Becket Foundation; Bristol-Myers Squibb; British Heart Foundation programme (PG/13/66/30442 and PG/07/131/24254); Canadian Institutes of Health Research (FRCN-CCT-83028); Centre for Medical Systems Biology; Danish Centre for Health Technology Assessment; Danish Council for Independent Research (DFF-1333-00124 and DFF-1331-00730B); Danish Diabetes Association; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; Department of Health Policy Research Programme (0090049); Diabetes UK; Donald W. Reynolds Foundation; Dutch Arthritis Association (DAA 2010_017); Dutch government (NWO 184.021.007); Emil Aaltonen Foundation; Erasmus MC; Erasmus University; European Commission (FP6-LSHG-CT-2006-018947, FP6-LSHG-CT-2006-01947, HEALTH-F2-2008-201865-GEFOS, FP7-201668, FP7-223004, FP7-259679, FP7-305739 and FP7-IDEAS-ERC-323195); European Regional Development Fund; EUROSPAN; Faculty of Biology and Medicine of Lausanne; Finnish Centre for Pensions; Finnish Cultural Foundation; Finnish Diabetes Research Society; Finnish Foundation of Cardiovascular Research; Finnish Foundation for Pediatric Research; Finnish National Institute for Health and Welfare; Finnish Special Governmental Subsidy for Health Sciences; Finska Läkaresällskapet; Folkhälsan Research Foundation; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; German Center for Diabetes Research (DZD); German Federal Ministry of Education and Research; GlaxoSmithKline; Göran Gustafsson Foundation; Heart Foundation of Northern Sweden; Helmholtz Zentrum München; Ib Henriksen Foundation; Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007); Italian Ministry of Health (ICS110.1/RF97.71); John W. Barton Sr. Chair in Genetics and Nutrition; Juho Vainio Foundation; King’s College London; Knut and Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001, 9M048, 9N035); Leiden University Medical Centre; Li Ka Shing Foundation; Liv och Hälsa; Local Government Pensions Institution; Ludwig-Maximilians-Universität; Lundbeck Foundation; Lundberg Foundation; Medical Research Council (MC_U106179471, MC_UU_12013/3, and MC_UU_12013/8); Medical Research Council-GlaxoSmithKline pilot programme grant (G0701863); Ministry of Education, Culture and Science of the Netherlands; Ministry of health, Welfare and Sports of the Netherlands; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; Danish Ministry of Internal Affairs and Health; Munich Center of Health Sciences; Municipality of Rotterdam; National Cancer Institute (CA047988); National Eye Institute; National Institute on Aging (Intramural research programme, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, 263MD9164 and 263 MD 821336); National Institute for Health Research; National Institutes of Health (DK52431, HG004399, HG004446, CA087969, CA055075, DK058845, CA65725, CA49449, CA67262, CA50385 and UO1CA098233); Netherlands Brain Foundation (HersenStichting Nederland); Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Genomics Initiative; Netherlands Heart Foundation (2001 D 032); Netherlands Organization for Scientific Research (175-010-2005-011, 904-61-095, 911-03-012, 911-03-016, 917-66-344 and 911-03-012); Netherlands Organization for the Health Research and Development; National Heart, Lung, and Blood Institute (5R01HL068891, 5R01HL087700, R01HL117078, HHSN26800625226C, HHSN268200782096C, HL-043851, HL-045670, HL080467, N01-HC95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N02-HL-64278, N01-HC-65226, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, R01-HL-088451, R00-HL-098459, U01-HG007033, UL1-RR-24156, UL1-RR-25005, UL1-TR-000040 and UL1-TR-001079); National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases (1R01DK080015, R01DK089256, 5R01DK068336, 5R01DK075681 and 5R01DK07568102); Novo Nordisk; Novo Nordisk Foundation; New York Obesity Nutrition Research Center Pilot and Feasilibity Grant (DK-26687); Orion-Farmos Research Foundation; Pfizer Inc.; Paavo Nurmi Foundation; Påhlssons Foundation; Research Foundation of Copenhagen County; Roche Pharmaceuticals; Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Samfundet Folkhälsan; Signe and Ane Gyllenberg Foundation; Sigrid Jusélius Foundation; Social Insurance Institution of Finland; South Tyrolean Sparkasse Foundation; Swedish Diabetes Association; Swedish Diabetes Foundation; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20140422); Swedish Research Council (2012-1397); Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 33CSCO-122661, 33CS30-139468 and 33CS30-148401); Tampere Tuberculosis Foundation; Torsten and Ragnar Söderberg’s Foundation; Umeå University Career Development Award; Unilever Colworth; Wellcome Trust (WT064890, WT089062, WT090532, WT098017, WT098051, WT091551, 081917/Z/07/Z and 086596/Z/08/Z); Wellcome Trust Centre for Human Genetics core funding (090532); Wissenschaftsoffensive TMO; Yrjö Jahnsson Foundation.
dc.languageEnglishen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.titleGenome-wide meta-analysis uncovers novel loci influencing circulating leptin levelsen
dc.typeArticle
dc.provenanceOA-8042
dc.description.versionThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms10494en
prism.publicationDate2016en
prism.publicationNameNature Communicationsen
prism.volume7en
dc.rioxxterms.funderSee article and supplementary acknowledgments note for a full list of funders.
dcterms.dateAccepted2015-12-16en
rioxxterms.versionofrecord10.1038/ncomms10494en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-02-01en
dc.contributor.orcidZhao, Jing Hua [0000-0003-4930-3582]
dc.contributor.orcidLuan, Jian'an [0000-0003-3137-6337]
dc.contributor.orcidBarroso, Ines [0000-0001-5800-4520]
dc.contributor.orcidDay, Felix [0000-0003-3789-7651]
dc.contributor.orcidSavage, David [0000-0002-7857-7032]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12015/2)
pubs.funder-project-idMRC (MC_UU_12015/1)
pubs.funder-project-idMedical Research Council (G0701863)
pubs.funder-project-idMedical Research Council (MC_U106179471)
pubs.funder-project-idWellcome Trust (091551/Z/10/A)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales