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

Nat Commun
Authors
Tuomas Kilpeläinen
Jayne Carli
Alicja Skowronski
Qi Sun
Jennifer Kriebel
Mary Feitosa
Ã…sa Hedman
Alexander Drong
James Hayes
Jinghua Zhao
Tune 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 M
Dorota Pasko
Frida Renström
Sara Willems
Anubha Mahajan
Lynda Rose
Xiuqing Guo
Yongmei Liu
Marcus Kleber
Louis Pérusse
Tom Gaunt
Tarunveer Ahluwalia
Yun Sung
Yolande Ramos
Najaf Amin
Antoinette Amuzu
Inês Barroso
Claire Bellis
John Blangero
Brendan Buckley
Stefan Böhringer
Yii-Der Chen
Anton de Craen
David Crosslin
Caroline Dale
Zari Dastani
Felix Day
Joris Deelen
Graciela Delgado
Ayse Demirkan
Francis Finucane
Ian Ford
Melissa Garcia
Christian Gieger
Stefan Gustafsson
Göran Hallmans
Susan Hankinson
Aki Havulinna
Christian Herder
Dena Hernandez
Andrew Hicks
David Hunter
Thomas Illig
Erik Ingelsson
Andreea Ioan-Facsinay
John-Olov Jansson
Nancy Jenny
Marit Jørgensen
Torben Jørgensen
Magnus Karlsson
Wolfgang Koenig
Peter Kraft
Joanneke Kwekkeboom
Tiina Laatikainen
Karl-Heinz Ladwig
Charles LeDuc
Gordon Lowe
Yingchang Lu
Pedro Marques-Vidal
Christa Meisinger
Cristina Menni
Andrew Morris
Richard Myers
Satu Männistö
Mike Nalls
Lavinia Paternoster
Annette Peters
Aruna Pradhan
Tuomo Rankinen
Laura Rasmussen-Torvik
Wolfgang Rathmann
Treva Rice
Brent Richards
Paul Ridker
Naveed Sattar
David Savage
Stefan Söderberg
Nicholas Timpson
Liesbeth Vandenput
Diana van Heemst
Hae-Won Uh
Marie-Claude Vohl
Mark Walker
Heinz-Erich Wichmann
Elisabeth Widén
Andrew Wood
Jie Yao
Tanja Zeller
Yiying Zhang
Ingrid Meulenbelt
Margreet Kloppenburg
Arne Astrup
Thorkild Sørensen
Mark Sarzynski
D Rao
Pekka Jousilahti
Erkki Vartiainen
Albert Hofman
Fernando Rivadeneira
André Uitterlinden
Eero Kajantie
Clive Osmond
Aarno Palotie
Johan Eriksson
Markku Heliövaara
Paul Knekt
Seppo Koskinen
Antti Jula
Markus Perola
Risto Huupponen
Jorma Viikari
Mika Kähönen
Terho Lehtimäki
Olli Raitakari
Dan Mellström
Mattias Lorentzon
Juan Casas
Stefanie Bandinelli
Winfried März
Aaron Isaacs
Ko van Dijk
Cornelia van Duijn
Tamara Harris
Claude Bouchard
Matthew Allison
Daniel Chasman
Claes Ohlsson
Lars Lind
Robert Scott
Claudia Langenberg
Nicholas Wareham
Luigi Ferrucci
Timothy Frayling
Peter Pramstaller
Ingrid Borecki
Dawn Waterworth
Sven Bergmann
Gérard Waeber
Peter Vollenweider
Henrik Vestergaard
Torben Hansen
Oluf Pedersen
Frank Hu
Eline Slagboom
Harald Grallert
Tim Spector
J Jukema
Robert Klein
Erik Schadt
Paul Franks
Cecilia Lindgren
Rudolph Leibel
Ruth Loos
Keywords
Animals
Male
Mice
Gene Expression Regulation
Genome-Wide Association Study
RNA, Messenger
Tissue Culture Techniques
Gene Knockdown Techniques
Adipose Tissue
Leptin
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 P10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P5 × 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.
Year of Publication
2016
Journal
Nat Commun
Volume
7
Pages
10494
Date Published
2016 Feb 01
ISSN
2041-1723
URL
DOI
10.1038/ncomms10494
PubMed ID
26833098
PubMed Central ID
PMC4740377
Links
Grant list
R01 CA050385 / CA / NCI NIH HHS / United States
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R01 DK058845 / DK / NIDDK NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
5R01DK075681 / DK / NIDDK NIH HHS / United States
PG/13/66/30442 / British Heart Foundation / United Kingdom
N01HC95160 / HL / NHLBI NIH HHS / United States
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