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; Tarun Veer Singh 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; Stefan Söderberg; Nicholas J Timpson; Liesbeth Vandenput; Diana van Heemst; Hae-Won Uh; Marie-Claude Vohl; Mark Walker; Heinz-Erich Wichmann; Elisabeth Widén; Andrew R Wood; Jie Yao; Tanja Zeller; Yiying Zhang; Ingrid Meulenbelt; Margreet Kloppenburg; Arne Astrup; Thorkild I A Sørensen; Mark A Sarzynski; D C Rao; Pekka Jousilahti; Erkki Vartiainen; Albert Hofman; Fernando Rivadeneira; André G Uitterlinden; Eero Kajantie; Clive Osmond; Aarno Palotie; Johan G Eriksson; Markku Heliövaara; Paul B Knekt; Seppo Koskinen; Antti Jula; Markus Perola; Risto K Huupponen; Jorma S Viikari; Mika Kähönen; Terho Lehtimäki; Olli T Raitakari; Dan Mellström; Mattias Lorentzon; Juan P Casas; Stefanie Bandinelli; Winfried März; Aaron Isaacs; Ko W van Dijk; Cornelia M van Duijn; Tamara B Harris; Claude Bouchard; Matthew A Allison; Daniel I Chasman; Claes Ohlsson; Lars Lind; Robert A Scott; Claudia Langenberg; Nicholas J Wareham; Luigi Ferrucci; Timothy M Frayling; Peter P Pramstaller; Ingrid B Borecki; Dawn M Waterworth; Sven Bergmann; Gérard Waeber; Peter Vollenweider; Henrik Vestergaard; Torben Hansen; Oluf Pedersen; Frank B Hu; P Eline Slagboom; Harald Grallert; Tim D Spector; J W Jukema; Robert J Klein; Erik E Schadt; Paul W Franks; Cecilia M Lindgren; Rudolph L Leibel; Ruth J F Loos

doi:10.1038/ncomms10494

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 ErikssonPeter 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, Tarun Veer Singh 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, Stefan Söderberg, Nicholas J Timpson, Liesbeth Vandenput, Diana van Heemst, Hae-Won Uh, Marie-Claude Vohl, Mark Walker, Heinz-Erich Wichmann, Elisabeth Widén, Andrew R Wood, Jie Yao, Tanja Zeller, Yiying Zhang, Ingrid Meulenbelt, Margreet Kloppenburg, Arne Astrup, Thorkild I A Sørensen, Mark A Sarzynski, D C Rao, Pekka Jousilahti, Erkki Vartiainen, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Eero Kajantie, Clive Osmond, Aarno Palotie, Johan G Eriksson, Markku Heliövaara, Paul B Knekt, Seppo Koskinen, Antti Jula, Markus Perola, Risto K Huupponen, Jorma S Viikari, Mika Kähönen, Terho Lehtimäki, Olli T Raitakari, Dan Mellström, Mattias Lorentzon, Juan P Casas, Stefanie Bandinelli, Winfried März, Aaron Isaacs, Ko W van Dijk, Cornelia M van Duijn, Tamara B Harris, Claude Bouchard, Matthew A Allison, Daniel I Chasman, Claes Ohlsson, Lars Lind, Robert A Scott, Claudia Langenberg, Nicholas J Wareham, Luigi Ferrucci, Timothy M Frayling, Peter P Pramstaller, Ingrid B Borecki, Dawn M Waterworth, Sven Bergmann, Gérard Waeber, Peter Vollenweider, Henrik Vestergaard, Torben Hansen, Oluf Pedersen, Frank B Hu, P Eline Slagboom, Harald Grallert, Tim D Spector, J W Jukema, Robert J Klein, Erik E Schadt, Paul W Franks, Cecilia M Lindgren, Rudolph L Leibel, Ruth J F Loos

83 Citations (Scopus)

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 × 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.

Original language	English
Article number	10494
Journal	Nature Communications
Volume	7
Number of pages	14
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms10494
Publication status	Published - 1 Feb 2016

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Kilpeläinen, T. O., Carli, J. F. M., Skowronski, A. A., Sun, Q., Kriebel, J., Feitosa, M. F., Hedman, Å. K., Drong, A. W., Hayes, J. E., Zhao, J., Pers, T. H., Schick, U., Grarup, N., Kutalik, Z., Trompet, S., Mangino, M., Kristiansson, K., Beekman, M., Lyytikäinen, L.-P., ... Loos, R. J. F. (2016). Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nature Communications, 7, Article 10494. https://doi.org/10.1038/ncomms10494

Kilpeläinen, TO, Carli, JFM, Skowronski, AA, Sun, Q, Kriebel, J, Feitosa, MF, Hedman, ÅK, Drong, AW, Hayes, JE, Zhao, J, Pers, TH, Schick, U, Grarup, N, Kutalik, Z, Trompet, S, Mangino, M, Kristiansson, K, Beekman, M, Lyytikäinen, L-P, Eriksson, J, Henneman, P, Lahti, J, Tanaka, T, Luan, J, Greco M, FD, Pasko, D, Renström, F, Willems, SM, Mahajan, A, Rose, LM, Guo, X, Liu, Y, Kleber, ME, Pérusse, L, Gaunt, T, Ahluwalia, TVS, Ju Sung, Y, Ramos, YF, Amin, N, Amuzu, A, Barroso, I, Bellis, C, Blangero, J, Buckley, BM, Böhringer, S, I Chen, Y-D, 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, J-O, Jenny, NS, Jørgensen, ME, Jørgensen, T, Karlsson, M, Koenig, W, Kraft, P, Kwekkeboom, J, Laatikainen, T, Ladwig, K-H, LeDuc, CA, Lowe, G, Lu, Y, Marques-Vidal, P, Meisinger, C, Menni, C, Morris, AP, Myers, RH, Männistö, S, Nalls, MA, Paternoster, L, Peters, A, Pradhan, AD, Rankinen, T, Rasmussen-Torvik, LJ, Rathmann, W, Rice, TK, Brent Richards, J, Ridker, PM, Sattar, N, Savage, DB, Söderberg, S, Timpson, NJ, Vandenput, L, van Heemst, D, Uh, H-W, Vohl, M-C, Walker, M, Wichmann, H-E, Widén, E, Wood, AR, Yao, J, Zeller, T, Zhang, Y, Meulenbelt, I, Kloppenburg, M, Astrup, A, Sørensen, TIA, Sarzynski, MA, Rao, DC, Jousilahti, P, Vartiainen, E, Hofman, A, Rivadeneira, F, Uitterlinden, AG, Kajantie, E, Osmond, C, Palotie, A, Eriksson, JG, Heliövaara, M, Knekt, PB, Koskinen, S, Jula, A, Perola, M, Huupponen, RK, Viikari, JS, Kähönen, M, Lehtimäki, T, Raitakari, OT, Mellström, D, Lorentzon, M, Casas, JP, Bandinelli, S, März, 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, Eline Slagboom, P, Grallert, H, Spector, TD, Jukema, JW, Klein, RJ, Schadt, EE, Franks, PW, Lindgren, CM, Leibel, RL & Loos, RJF 2016, 'Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels', Nature Communications, vol. 7, 10494. https://doi.org/10.1038/ncomms10494

@article{986f07fedc5a440ab9437bfdaee78434,

title = "Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels",

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 × 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.",

author = "Kilpel{\"a}inen, {Tuomas O} and Carli, {Jayne F Martin} and Skowronski, {Alicja A} and Qi Sun and Jennifer Kriebel and Feitosa, {Mary F} and Hedman, {{\AA}sa K} and Drong, {Alexander W} and Hayes, {James E} and Jinghua Zhao and Pers, {Tune H} and Ursula Schick and Niels Grarup and Zolt{\'a}n Kutalik and Stella Trompet and Massimo Mangino and Kati Kristiansson and Marian Beekman and Leo-Pekka Lyytik{\"a}inen and Joel Eriksson and Peter Henneman and Jari Lahti and Toshiko Tanaka and Jian'an Luan and {Greco M}, {Fabiola Del} and Dorota Pasko and Frida Renstr{\"o}m and Willems, {Sara M} and Anubha Mahajan and Rose, {Lynda M} and Xiuqing Guo and Yongmei Liu and Kleber, {Marcus E} and Louis P{\'e}russe and Tom Gaunt and Ahluwalia, {Tarun Veer Singh} and {Ju Sung}, Yun and Ramos, {Yolande F} and Najaf Amin and Antoinette Amuzu and In{\^e}s Barroso and Claire Bellis and John Blangero and Buckley, {Brendan M} and Stefan B{\"o}hringer and {I Chen}, Yii-Der and {de Craen}, {Anton J N} and Crosslin, {David R} and Dale, {Caroline E} and Zari Dastani and Day, {Felix R} and Joris Deelen and Delgado, {Graciela E} and Ayse Demirkan and Finucane, {Francis M} and Ian Ford and Garcia, {Melissa E} and Christian Gieger and Stefan Gustafsson and G{\"o}ran Hallmans and Hankinson, {Susan E} and Havulinna, {Aki S} and Christian Herder and Dena Hernandez and Hicks, {Andrew A} and Hunter, {David J} and Thomas Illig and Erik Ingelsson and Andreea Ioan-Facsinay and John-Olov Jansson and Jenny, {Nancy S} and J{\o}rgensen, {Marit E} and Torben J{\o}rgensen and Magnus Karlsson and Wolfgang Koenig and Peter Kraft and Joanneke Kwekkeboom and Tiina Laatikainen and Karl-Heinz Ladwig and LeDuc, {Charles A} and Gordon Lowe and Yingchang Lu and Pedro Marques-Vidal and Christa Meisinger and Cristina Menni and Morris, {Andrew P} and Myers, {Richard H} and Satu M{\"a}nnist{\"o} and Nalls, {Mike A} and Lavinia Paternoster and Annette Peters and Pradhan, {Aruna D} and Tuomo Rankinen and Rasmussen-Torvik, {Laura J} and Wolfgang Rathmann and Rice, {Treva K} and {Brent Richards}, J and Ridker, {Paul M} and Naveed Sattar and Savage, {David B} and Stefan S{\"o}derberg and Timpson, {Nicholas J} and Liesbeth Vandenput and {van Heemst}, Diana and Hae-Won Uh and Marie-Claude Vohl and Mark Walker and Heinz-Erich Wichmann and Elisabeth Wid{\'e}n and Wood, {Andrew R} and Jie Yao and Tanja Zeller and Yiying Zhang and Ingrid Meulenbelt and Margreet Kloppenburg and Arne Astrup and S{\o}rensen, {Thorkild I A} and Sarzynski, {Mark A} and Rao, {D C} and Pekka Jousilahti and Erkki Vartiainen and Albert Hofman and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G} and Eero Kajantie and Clive Osmond and Aarno Palotie and Eriksson, {Johan G} and Markku Heli{\"o}vaara and Knekt, {Paul B} and Seppo Koskinen and Antti Jula and Markus Perola and Huupponen, {Risto K} and Viikari, {Jorma S} and Mika K{\"a}h{\"o}nen and Terho Lehtim{\"a}ki and Raitakari, {Olli T} and Dan Mellstr{\"o}m and Mattias Lorentzon and Casas, {Juan P} and Stefanie Bandinelli and Winfried M{\"a}rz and Aaron Isaacs and {van Dijk}, {Ko W} and {van Duijn}, {Cornelia M} and Harris, {Tamara B} and Claude Bouchard and Allison, {Matthew A} and Chasman, {Daniel I} and Claes Ohlsson and Lars Lind and Scott, {Robert A} and Claudia Langenberg and Wareham, {Nicholas J} and Luigi Ferrucci and Frayling, {Timothy M} and Pramstaller, {Peter P} and Borecki, {Ingrid B} and Waterworth, {Dawn M} and Sven Bergmann and G{\'e}rard Waeber and Peter Vollenweider and Henrik Vestergaard and Torben Hansen and Oluf Pedersen and Hu, {Frank B} and {Eline Slagboom}, P and Harald Grallert and Spector, {Tim D} and Jukema, {J W} and Klein, {Robert J} and Schadt, {Erik E} and Franks, {Paul W} and Lindgren, {Cecilia M} and Leibel, {Rudolph L} and Loos, {Ruth J F}",

note = "CURIS 2016 NEXS 411",

year = "2016",

month = feb,

day = "1",

doi = "10.1038/ncomms10494",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

}

TY - JOUR

T1 - Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

AU - Kilpeläinen, Tuomas O

AU - Carli, Jayne F Martin

AU - Skowronski, Alicja A

AU - Sun, Qi

AU - Kriebel, Jennifer

AU - Feitosa, Mary F

AU - Hedman, Åsa K

AU - Drong, Alexander W

AU - Hayes, James E

AU - Zhao, Jinghua

AU - Pers, Tune H

AU - Schick, Ursula

AU - Grarup, Niels

AU - Kutalik, Zoltán

AU - Trompet, Stella

AU - Mangino, Massimo

AU - Kristiansson, Kati

AU - Beekman, Marian

AU - Lyytikäinen, Leo-Pekka

AU - Eriksson, Joel

AU - Henneman, Peter

AU - Lahti, Jari

AU - Tanaka, Toshiko

AU - Luan, Jian'an

AU - Greco M, Fabiola Del

AU - Pasko, Dorota

AU - Renström, Frida

AU - Willems, Sara M

AU - Mahajan, Anubha

AU - Rose, Lynda M

AU - Guo, Xiuqing

AU - Liu, Yongmei

AU - Kleber, Marcus E

AU - Pérusse, Louis

AU - Gaunt, Tom

AU - Ahluwalia, Tarun Veer Singh

AU - Ju Sung, Yun

AU - Ramos, Yolande F

AU - Amin, Najaf

AU - Amuzu, Antoinette

AU - Barroso, Inês

AU - Bellis, Claire

AU - Blangero, John

AU - Buckley, Brendan M

AU - Böhringer, Stefan

AU - I Chen, Yii-Der

AU - de Craen, Anton J N

AU - Crosslin, David R

AU - Dale, Caroline E

AU - Dastani, Zari

AU - Day, Felix R

AU - Deelen, Joris

AU - Delgado, Graciela E

AU - Demirkan, Ayse

AU - Finucane, Francis M

AU - Ford, Ian

AU - Garcia, Melissa E

AU - Gieger, Christian

AU - Gustafsson, Stefan

AU - Hallmans, Göran

AU - Hankinson, Susan E

AU - Havulinna, Aki S

AU - Herder, Christian

AU - Hernandez, Dena

AU - Hicks, Andrew A

AU - Hunter, David J

AU - Illig, Thomas

AU - Ingelsson, Erik

AU - Ioan-Facsinay, Andreea

AU - Jansson, John-Olov

AU - Jenny, Nancy S

AU - Jørgensen, Marit E

AU - Jørgensen, Torben

AU - Karlsson, Magnus

AU - Koenig, Wolfgang

AU - Kraft, Peter

AU - Kwekkeboom, Joanneke

AU - Laatikainen, Tiina

AU - Ladwig, Karl-Heinz

AU - LeDuc, Charles A

AU - Lowe, Gordon

AU - Lu, Yingchang

AU - Marques-Vidal, Pedro

AU - Meisinger, Christa

AU - Menni, Cristina

AU - Morris, Andrew P

AU - Myers, Richard H

AU - Männistö, Satu

AU - Nalls, Mike A

AU - Paternoster, Lavinia

AU - Peters, Annette

AU - Pradhan, Aruna D

AU - Rankinen, Tuomo

AU - Rasmussen-Torvik, Laura J

AU - Rathmann, Wolfgang

AU - Rice, Treva K

AU - Brent Richards, J

AU - Ridker, Paul M

AU - Sattar, Naveed

AU - Savage, David B

AU - Söderberg, Stefan

AU - Timpson, Nicholas J

AU - Vandenput, Liesbeth

AU - van Heemst, Diana

AU - Uh, Hae-Won

AU - Vohl, Marie-Claude

AU - Walker, Mark

AU - Wichmann, Heinz-Erich

AU - Widén, Elisabeth

AU - Wood, Andrew R

AU - Yao, Jie

AU - Zeller, Tanja

AU - Zhang, Yiying

AU - Meulenbelt, Ingrid

AU - Kloppenburg, Margreet

AU - Astrup, Arne

AU - Sørensen, Thorkild I A

AU - Sarzynski, Mark A

AU - Rao, D C

AU - Jousilahti, Pekka

AU - Vartiainen, Erkki

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G

AU - Kajantie, Eero

AU - Osmond, Clive

AU - Palotie, Aarno

AU - Eriksson, Johan G

AU - Heliövaara, Markku

AU - Knekt, Paul B

AU - Koskinen, Seppo

AU - Jula, Antti

AU - Perola, Markus

AU - Huupponen, Risto K

AU - Viikari, Jorma S

AU - Kähönen, Mika

AU - Lehtimäki, Terho

AU - Raitakari, Olli T

AU - Mellström, Dan

AU - Lorentzon, Mattias

AU - Casas, Juan P

AU - Bandinelli, Stefanie

AU - März, Winfried

AU - Isaacs, Aaron

AU - van Dijk, Ko W

AU - van Duijn, Cornelia M

AU - Harris, Tamara B

AU - Bouchard, Claude

AU - Allison, Matthew A

AU - Chasman, Daniel I

AU - Ohlsson, Claes

AU - Lind, Lars

AU - Scott, Robert A

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

AU - Ferrucci, Luigi

AU - Frayling, Timothy M

AU - Pramstaller, Peter P

AU - Borecki, Ingrid B

AU - Waterworth, Dawn M

AU - Bergmann, Sven

AU - Waeber, Gérard

AU - Vollenweider, Peter

AU - Vestergaard, Henrik

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Hu, Frank B

AU - Eline Slagboom, P

AU - Grallert, Harald

AU - Spector, Tim D

AU - Jukema, J W

AU - Klein, Robert J

AU - Schadt, Erik E

AU - Franks, Paul W

AU - Lindgren, Cecilia M

AU - Leibel, Rudolph L

AU - Loos, Ruth J F

N1 - CURIS 2016 NEXS 411

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms10494

DO - 10.1038/ncomms10494

M3 - Journal article

C2 - 26833098

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10494

ER -

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

Abstract

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