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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Lookup NU author(s): Professor Mark Walker

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Abstract

Leptin 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 P < 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P < 5 x 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.


Publication metadata

Author(s): Kilpelainen TO, Carli JFM, Skowronski AA, Sun Q, Kriebel J, Feitosa MF, Hedman AK, Drong AW, Hayes JE, Zhao JH, Pers TH, Schick U, Grarup N, Kutalik Z, Trompet S, Mangino M, Kristiansson K, Beekman M, Lyytikainen LP, Eriksson J, Henneman P, Lahti J, Tanaka T, Luan JA, Del Greco F, Pasko D, Renstrom F, Willems SM, Mahajan A, Rose LM, Guo XQ, Liu YM, Kleber ME, Perusse L, Gaunt T, Ahluwalia TS, Sung YJ, Ramos YF, Amin N, Amuzu A, Barroso I, Bellis C, Blangero J, Buckley BM, Bohringer S, Chen YDI, de Craen AJN, Crosslin DR, Dale CE, Dastani Z, Day FR, Deelen J, Delgado GE, Demirkan A, Finucane FM, Ford I, Garcia ME, Gieger C, Gustafsson S, Hallmans G, Hankinson SE, Havulinna AS, Herder C, Hernandez D, Hicks AA, Hunter DJ, Illig T, Ingelsson E, Ioan-Facsinay A, Jansson JO, Jenny NS, Jorgensen ME, Jorgensen T, Karlsson M, Koenig W, Kraft P, Kwekkeboom J, Laatikainen T, Ladwig KH, LeDuc CA, Lowe G, Lu YC, Marques-Vidal P, Meisinger C, Menni C, Morris AP, Myers RH, Mannisto S, Nalls MA, Paternoster L, Peters A, Pradhan AD, Rankinen T, Rasmussen-Torvik LJ, Rathmann W, Rice TK, Richards JB, Ridker PM, Sattar N, Savage DB, Soderberg S, Timpson NJ, Vandenput L, van Heemst D, Uh HW, Vohl MC, Walker M, Wichmann HE, Widen E, Wood AR, Yao J, Zeller T, Zhang YY, Meulenbelt I, Kloppenburg M, Astrup A, Sorensen TIA, Sarzynski MA, Rao DC, Jousilahti P, Vartiainen E, Hofman A, Rivadeneira F, Uitterlinden AG, Kajantie E, Osmond C, Palotie A, Eriksson JG, Heliovaara M, Knekt PB, Koskinen S, Jula A, Perola M, Huupponen RK, Viikari JS, Kahonen M, Lehtimaki T, Raitakari OT, Mellstrom D, Lorentzon M, Casas JP, Bandinelli S, Marz W, Isaacs A, van Dijk KW, van Duijn CM, Harris TB, Bouchard C, Allison MA, Chasman DI, Ohlsson C, Lind L, Scott RA, Langenberg C, Wareham NJ, Ferrucci L, Frayling TM, Pramstaller PP, Borecki IB, Waterworth DM, Bergmann S, Waeber G, Vollenweider P, Vestergaard H, Hansen T, Pedersen O, Hu FB, Slagboom PE, Grallert H, Spector TD, Jukema JW, Klein RJ, Schadt EE, Franks PW, Lindgren CM, Leibel RL, Loos RJF

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2016

Volume: 7

Print publication date: 01/02/2016

Online publication date: 01/02/2016

Acceptance date: 16/12/2015

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ncomms10494

DOI: 10.1038/ncomms10494


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Funding

Funder referenceFunder name
Amgen
Bristol-Myers Squibb
Danish Diabetes Association
Danish Heart Foundation
Danish Pharmaceutical Association
Danish Research Council
Erasmus MC
EUROSPAN
Finnish Centre for Pensions
Finnish Diabetes Research Society
Finnish Foundation for Pediatric Research
Finnish National Institute for Health and Welfare
Finnish Special Governmental Subsidy for Health Sciences
Finska Lakaresallskapet
Heart Foundation of Northern Sweden
Ib Henriksen Foundation
Juho Vainio Foundation
King's College London
Kuopio University Hospital Medical Fund
Leiden University Medical Centre
Local Government Pensions Institution
Ludwig-Maximilians-Universitat
Lundbeck Foundation
Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano
National Institute for Health Research
Novo Nordisk Foundation
Orion-Farmos Research Foundation
Pahlssons Foundation
Pfizer Inc.
Research Foundation of Copenhagen County
Roche Pharmaceuticals
Samfundet Folkhalsan
Signe and Ane Gyllenberg Foundation
Sigrid Juselius Foundation
Social Insurance Institution of Finland
Swedish Diabetes Association
Yrjo Jahnsson Foundation
Ahokas Foundation
ALF/LUA research grant in Gothenburg
Augustinus Foundation
Becket Foundation
Centre for Medical Systems Biology
Danish Centre for Health Technology Assessment
Danish Ministry of Internal Affairs and Health
Diabetes UK
Donald W. Reynolds Foundation
Emil Aaltonen Foundation
Erasmus University
European Regional Development Fund
Faculty of Biology and Medicine of Lausanne
Finnish Cultural Foundation
Finnish Foundation of Cardiovascular Research
Folkhalsan 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
Goran Gustafsson Foundation
Helmholtz Zentrum Munchen
John W. Barton Sr. Chair in Genetics and Nutrition
Knut and Alice Wallenberg Foundation
Li Ka Shing Foundation
Liv och Halsa
Lundberg Foundation
Ministry of Education, Culture and Science of the Netherlands
Ministry of health, Welfare and Sports of the Netherlands
Munich Center of Health Sciences
Municipality of Rotterdam
National Eye Institute
Netherlands Brain Foundation (HersenStichting Nederland)
Netherlands Genomics Initiative
Netherlands Organization for the Health Research and Development
Novo Nordisk
Paavo Nurmi Foundation
South Tyrolean Sparkasse Foundation
Swedish Diabetes Foundation
Swedish Foundation for Strategic Research
Swiss Institute of Bioinformatics
Tampere Tuberculosis Foundation
Tampere University Hospital Medical Fund
Torsten and Ragnar Soderberg's Foundation
Umea University Career Development Award
Unilever Colworth
Wissenschaftsoffensive TMO
050-060-810Netherlands Consortium for Healthy Aging
0090049Department of Health Policy Research Programme
014-93-015Research Institute for Diseases in the Elderly (RIDE2)
086596/Z/08/ZWellcome Trust
118065Academy of Finland
121584Academy of Finland
130326Academy of Finland
136895Academy of Finland
139635Academy of Finland
1R01DK080015National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases
2001 D 032Netherlands Heart Foundation
081917/Z/07/ZWellcome Trust
090532Wellcome Trust Centre for Human Genetics core funding
20140422Swedish Heart-Lung Foundation
263836Academy of Finland
263MD9164National Institute on Aging (Intramural research programme)
286284Academy of Finland
117787Academy of Finland
3100AO-116323/1Swiss National Science Foundation
124282Academy of Finland
126925Academy of Finland
129322Academy of Finland
129378Academy of Finland
129494Academy of Finland
134309Academy of Finland
134791Academy of Finland
33CSCO-122661Swiss National Science Foundation
41071Academy of Finland
175-010-2005-011Netherlands Organization for Scientific Research
1R01AG032098-01A1National Institute on Aging (Intramural research programme)
5R01DK068336National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases
5R01HL068891National Heart, Lung, and Blood Institute
2012-1397Swedish Research Council
911-03-012Netherlands Organization for Scientific Research
911-03-016Netherlands Organization for Scientific Research
250207Academy of Finland
263 MD 821336National Institute on Aging (Intramural research programme)
263924Academy of Finland
917-66-344Netherlands Organization for Scientific Research
9N035Turku University Hospital Medical Fund
33CS30-139468Swiss National Science Foundation
33CS30-148401Swiss National Science Foundation
5R01DK075681National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases
5R01DK07568102National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases
5R01HL087700National Heart, Lung, and Blood Institute
904-61-095Netherlands Organization for Scientific Research
9M048Turku University Hospital Medical Fund
CA055075National Institutes of Health
CA087969National Institutes of Health
CA49449National Institutes of Health
CA50385National Institutes of Health
DAA 2010_017Dutch Arthritis Association
DFF-1331-00730BDanish Council for Independent Research
DFF-1333-00124Danish Council for Independent Research
DK058845National Institutes of Health
DK-26687New York Obesity Nutrition Research Center Pilot and Feasilibity Grant
CA047988National Cancer Institute
CA65725National Institutes of Health
CA67262National Institutes of Health
DK52431National Institutes of Health
FP6-LSHG-CT-2006-018947European Commission
FP7-201668European Commission
FP7-223004European Commission
FP7-259679European Commission
FP7-IDEAS-ERC-323195European Commission
FRCN-CCT-83028Canadian Institutes of Health Research
FP6-LSHG-CT-2006-01947European Commission
FP7-305739European Commission
G0701863Medical Research Council-GlaxoSmithKline pilot programme grant
HG004446National Institutes of Health
HHSN26800625226CNational Heart, Lung, and Blood Institute
HHSN268200782096CNational Heart, Lung, and Blood Institute
HL-045670National Heart, Lung, and Blood Institute
HL080467National Heart, Lung, and Blood Institute
HEALTH-F2-2008-201865-GEFOSEuropean Commission
HG004399National Institutes of Health
HL-043851National Heart, Lung, and Blood Institute
ICS110.1/RF97.71Italian Ministry of Health
IGE05007Innovation-Oriented Research Program on Genomics (SenterNovem)
MC_U106179471Medical Research Council
MC_UU_12013/3Medical Research Council
MC_UU_12013/8Medical Research Council
N01AG62106National Institute on Aging (Intramural research programme)
N01-HC-95161National Heart, Lung, and Blood Institute
N01-HC-95165National Heart, Lung, and Blood Institute
N01-HC-95168National Heart, Lung, and Blood Institute
N01-HC-95169National Heart, Lung, and Blood Institute
N02-HL-64278National Heart, Lung, and Blood Institute
PG/07/131/24254British Heart Foundation programme
PG/13/66/30442British Heart Foundation programme
N01AG62101National Institute on Aging (Intramural research programme)
N01AG62103National Institute on Aging (Intramural research programme)
N01-HC-65226National Heart, Lung, and Blood Institute
N01-HC95159National Heart, Lung, and Blood Institute
N01-HC-95160National Heart, Lung, and Blood Institute
N01-HC-95162National Heart, Lung, and Blood Institute
N01-HC-95163National Heart, Lung, and Blood Institute
N01-HC-95164National Heart, Lung, and Blood Institute
N01-HC-95166National Heart, Lung, and Blood Institute
N01-HC-95167National Heart, Lung, and Blood Institute
R01-HL-071051National Heart, Lung, and Blood Institute
R01-HL-071250National Heart, Lung, and Blood Institute
R01-HL-071251National Heart, Lung, and Blood Institute
R01-HL-071252National Heart, Lung, and Blood Institute
R01-HL-088451National Heart, Lung, and Blood Institute
NWO 184.021.007Dutch government
R00-HL-098459National Heart, Lung, and Blood Institute
UL1-RR-24156National Heart, Lung, and Blood Institute
UO1CA098233National Institutes of Health
R01DK089256National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases
R01-HL-071205National Heart, Lung, and Blood Institute
R01-HL-071258National Heart, Lung, and Blood Institute
R01-HL-071259National Heart, Lung, and Blood Institute
R01HL117078National Heart, Lung, and Blood Institute
WT090532Wellcome Trust
WT098017Wellcome Trust
WT098051Wellcome Trust
U01-HG007033National Heart, Lung, and Blood Institute
UL1-RR-25005National Heart, Lung, and Blood Institute
UL1-TR-000040National Heart, Lung, and Blood Institute
UL1-TR-001079National Heart, Lung, and Blood Institute
WT064890Wellcome Trust
WT089062Wellcome Trust
WT091551Wellcome Trust
X51001Turku University Hospital Medical Fund

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