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

Tuomas O Kilpeläinen; Jayne F Martin Carli; Alicja A Skowronski; Qi Sun; Jennifer Kriebel; Mary F Feitosa; Åsa K Hedman; Alexander W Drong; James E Hayes; Jinghua Zhao; Tune H Pers; Ursula Schick; Niels Grarup; Zoltán Kutalik; Stella Trompet; Massimo Mangino; Kati Kristiansson; Marian Beekman; Leo-Pekka Lyytikäinen; Joel Eriksson; Peter Henneman; Jari Lahti; Toshiko Tanaka; Jian'an Luan; Fabiola Del Greco M; Dorota Pasko; Frida Renström; Sara M Willems; Anubha Mahajan; Lynda M Rose; Xiuqing Guo; Yongmei Liu; Marcus E Kleber; Louis Pérusse; Tom Gaunt; Tarunveer S Ahluwalia; Yun Ju Sung; Yolande F Ramos; Najaf Amin; Antoinette Amuzu; Inês Barroso; Claire Bellis; John Blangero; Brendan M Buckley; Stefan Böhringer; Yii-Der I Chen; Anton J N de Craen; David R Crosslin; Caroline E Dale; Zari Dastani; Felix R Day; Joris Deelen; Graciela E Delgado; Ayse Demirkan; Francis M Finucane; Ian Ford; Melissa E Garcia; Christian Gieger; Stefan Gustafsson; Göran Hallmans; Susan E Hankinson; Aki S Havulinna; Christian Herder; Dena Hernandez; Andrew A Hicks; David J Hunter; Thomas Illig; Erik Ingelsson; Andreea Ioan-Facsinay; John-Olov Jansson; Nancy S Jenny; Marit E Jørgensen; Torben Jørgensen; Magnus Karlsson; Wolfgang Koenig; Peter Kraft; Joanneke Kwekkeboom; Tiina Laatikainen; Karl-Heinz Ladwig; Charles A LeDuc; Gordon Lowe; Yingchang Lu; Pedro Marques-Vidal; Christa Meisinger; Cristina Menni; Andrew P Morris; Richard H Myers; Satu Männistö; Mike A Nalls; Lavinia Paternoster; Annette Peters; Aruna D Pradhan; Tuomo Rankinen; Laura J Rasmussen-Torvik; Wolfgang Rathmann; Treva K Rice; J Brent Richards; Paul M Ridker; Naveed Sattar; David B Savage

doi:10.1038/ncomms10494

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

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

Tuomas O Kilpeläinen, Jayne F Martin Carli, Alicja A Skowronski, Qi Sun, Jennifer Kriebel, Mary F Feitosa, Åsa K Hedman, Alexander W Drong, James E Hayes, Jinghua Zhao, …

Nature communications, Vol.7(1), pp.10494-14

01/02/2016

DOI: https://doi.org/10.1038/ncomms10494

PMID: 26833098

Abstract

Adipose Tissue - metabolism

Animals

Gene Expression Regulation - physiology

Gene Knockdown Techniques

Genome-Wide Association Study

Leptin - blood

Leptin - genetics

Leptin - metabolism

Male

Mice

RNA, Messenger - genetics

RNA, Messenger - metabolism

Tissue Culture Techniques

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 × 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.

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Title: Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
Creators: Tuomas O Kilpeläinen - University of Copenhagen
Jayne F Martin Carli - Columbia University
Alicja A Skowronski - Columbia University
Qi Sun - Harvard University
Jennifer Kriebel - Helmholtz Zentrum München
Mary F Feitosa - Washington University in St. Louis
Åsa K Hedman - Uppsala University
Alexander W Drong - Wellcome Centre for Human Genetics
James E Hayes - Cornell University
Jinghua Zhao - MRC Epidemiology Unit
Tune H Pers - University of Copenhagen
Ursula Schick - Icahn School of Medicine at Mount Sinai
Niels Grarup - Novo Nordisk Foundation
Zoltán Kutalik - Institute of Social and Preventive Medicine
Stella Trompet - Leiden University Medical Center
Massimo Mangino - King's College London
Kati Kristiansson - Finnish Institute for Health and Welfare
Marian Beekman - Leiden University Medical Center
Leo-Pekka Lyytikäinen - University of Tampere
Joel Eriksson - University of Gothenburg
Peter Henneman - Leiden University Medical Center
Jari Lahti - University of Helsinki
Toshiko Tanaka - National Institute on Aging
Jian'an Luan - University of Cambridge
Fabiola Del Greco M - Eurac Research
Dorota Pasko - University of Exeter
Frida Renström - Lund University
Sara M Willems - Erasmus University Rotterdam
Anubha Mahajan - Wellcome Centre for Human Genetics
Lynda M Rose - Brigham and Women's Hospital
Xiuqing Guo - Ronald Reagan UCLA Medical Center
Yongmei Liu - Wake Forest University
Marcus E Kleber - Heidelberg University
Louis Pérusse - Université Laval
Tom Gaunt - University of Bristol
Tarunveer S Ahluwalia - University of Copenhagen
Yun Ju Sung - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Yolande F Ramos - Leiden University Medical Center
Najaf Amin - Erasmus University Rotterdam
Antoinette Amuzu - University of London
Inês Barroso - Wellcome Sanger Institute
Claire Bellis - Genome Institute of Singapore
John Blangero - Texas Biomedical Research Institute
Brendan M Buckley - University College Cork
Stefan Böhringer - Leiden University Medical Center
Yii-Der I Chen - Harbor–UCLA Medical Center
Anton J N de Craen - Leiden University Medical Center
David R Crosslin - University of Washington Medical Center
Caroline E Dale - University of London
Zari Dastani - McGill University
Felix R Day - University of Cambridge
Joris Deelen - Leiden University Medical Center
Graciela E Delgado - Heidelberg University
Ayse Demirkan - Leiden University Medical Center
Francis M Finucane - MRC Epidemiology Unit
Ian Ford - University of Glasgow
Melissa E Garcia - National Heart Lung and Blood Institute
Christian Gieger - Helmholtz Zentrum München
Stefan Gustafsson - Uppsala University
Göran Hallmans - Umeå University
Susan E Hankinson - Harvard University
Aki S Havulinna - Finnish Institute for Health and Welfare
Christian Herder - German Center for Diabetes Research
Dena Hernandez - National Institute on Aging
Andrew A Hicks - Eurac Research
David J Hunter - Harvard University
Thomas Illig - Helmholtz Zentrum München
Erik Ingelsson - Uppsala University
Andreea Ioan-Facsinay - Leiden University Medical Center
John-Olov Jansson - University of Gothenburg
Nancy S Jenny - University of Vermont
Marit E Jørgensen - Steno Diabetes Center
Torben Jørgensen - Glostrup Hospital
Magnus Karlsson - Lund University
Wolfgang Koenig - Universität Ulm
Peter Kraft - Harvard University
Joanneke Kwekkeboom - Leiden University Medical Center
Tiina Laatikainen - Finnish Institute for Health and Welfare
Karl-Heinz Ladwig - Klinikum rechts der Isar
Charles A LeDuc - Columbia University
Gordon Lowe - University of Glasgow
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Pedro Marques-Vidal - University Hospital of Lausanne
Christa Meisinger - Heinrich Heine University Düsseldorf
Cristina Menni - King's College London
Andrew P Morris - University of Oxford
Richard H Myers - Boston University
Satu Männistö - Finnish Institute for Health and Welfare
Mike A Nalls - National Institute on Aging
Lavinia Paternoster - University of Bristol
Annette Peters - German Center for Diabetes Research
Aruna D Pradhan - Brigham and Women's Hospital
Tuomo Rankinen - Pennington Biomedical Research Center
Laura J Rasmussen-Torvik - Preventive Medicine, Northwestern Feinberg School of Medicine, Chicago, Illinois 60611, USA
Wolfgang Rathmann - Deutsches Diabetes-Zentrum e.V.
Treva K Rice - Washington University in St. Louis
J Brent Richards - McGill University
Paul M Ridker - Brigham and Women's Hospital
Naveed Sattar - British Heart Foundation
David B Savage - Wellcome/MRC Institute of Metabolic Science
Publication Details: Nature communications, Vol.7(1), pp.10494-14
Date published: 01/02/2016
Grant note: R01 HL087700 / NHLBI NIH HHS R01 HL045670 / NHLBI NIH HHS N01HC95169 / NHLBI NIH HHS R01-HL-071259 / NHLBI NIH HHS G0701863 / Medical Research Council MR/J012165/1 / Medical Research Council U01-HG007033 / NHGRI NIH HHS 090532 / Wellcome Trust R01 HL071251 / NHLBI NIH HHS Intramural NIH HHS
Identifiers: 99929061402346
Academic Unit: Institute for Sustainability; Surrey Institute for People-Centred AI; School of Biosciences
Language: English
Resource Type: Journal article

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

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