New genetic loci link adipose and insulin biology to body fat distribution

ADIPOGen Consortium; ReproGen Consortium; The CARDIOGRAMplusC4D Consortium; CDKGen Consortium; The GEFOS Consortium; The GENIE Consortium; The GLGC; ICBP Consortium; The International Endogene Consortium; The LifeLines Cohort Study; The MAGIC Investigators; The MuTHER Consortium; The PAGE Consortium; Dmitry Shungin; Thomas W Winkler; Damien C Croteau-Chonka; Teresa Ferreira; Adam E Locke; Reedik Mägi; Rona J Strawbridge; Tune H Pers; Krista Fischer; Anne E Justice; Tsegaselassie Workalemahu; Joseph M W Wu; Martin L Buchkovich; Nancy L Heard-Costa; Tamara S Roman; Alexander W Drong; Ci Song; Stefan Gustafsson; Felix R Day; Tonu Esko; Tove Fall; Zoltán Kutalik; Jian'an Luan; Joshua C Randall; André Scherag; Sailaja Vedantam; Andrew R Wood; Jin Chen; Rudolf Fehrmann; Juha Karjalainen; Bratati Kahali; Ching-Ti Liu; Najaf Amin; Ayse Demirkan; Marjolein J Peters; Alexander Teumer; Aaron Isaacs; Floor van Oort; Niek Verweij; Jing Hua Zhao; John Rb Perry; Lisette Stolk; Albert Hofman; Yongmei Liu; Ben A Oostra; Fernando Rivadeneira; André G Uitterlinden; Cornelia M van Duijn; Jian Yang; M Carola Zillikens; Mark I. McCarthy; Elizabeth K. Speliotes; Kari E. North; Caroline S. Fox; Inês Barroso; Paul W. Franks; Erik Ingelsson; Iris M. Heid; Ruth J.F. Loos; L. Adrienne Cupples; Andrew P. Morris; Cecilia M. Lindgren; Karen L. Mohlke; Lisette Stolk; André Uitterlinden; Fernando Rivadeneira; Bert Hofman; OH (Oscar) Franco Duran; JCM Witteman; Karol Estrada Gil

doi:10.1038/nature14132

New genetic loci link adipose and insulin biology to body fat distribution

ADIPOGen Consortium, ReproGen Consortium, The CARDIOGRAMplusC4D Consortium, CDKGen Consortium, The GEFOS Consortium, The GENIE Consortium, The GLGC, ICBP Consortium, The International Endogene Consortium, The LifeLines Cohort Study, The MAGIC Investigators, The MuTHER Consortium, The PAGE Consortium, Dmitry Shungin, Thomas W Winkler, Damien C Croteau-Chonka, Teresa Ferreira, Adam E Locke, Reedik Mägi, Rona J StrawbridgeTune H Pers, Krista Fischer, Anne E Justice, Tsegaselassie Workalemahu, Joseph M W Wu, Martin L Buchkovich, Nancy L Heard-Costa, Tamara S Roman, Alexander W Drong, Ci Song, Stefan Gustafsson, Felix R Day, Tonu Esko, Tove Fall, Zoltán Kutalik, Jian'an Luan, Joshua C Randall, André Scherag, Sailaja Vedantam, Andrew R Wood, Jin Chen, Rudolf Fehrmann, Juha Karjalainen, Bratati Kahali, Ching-Ti Liu, Najaf Amin, Ayse Demirkan, Marjolein J Peters, Alexander Teumer, Aaron Isaacs, Floor van Oort, Niek Verweij, Jing Hua Zhao, John Rb Perry, Lisette Stolk, Albert Hofman, Yongmei Liu, Ben A Oostra, Fernando Rivadeneira, André G Uitterlinden, Cornelia M van Duijn, Jian Yang, M Carola Zillikens, Mark I. McCarthy, Elizabeth K. Speliotes, Kari E. North, Caroline S. Fox, Inês Barroso, Paul W. Franks, Erik Ingelsson, Iris M. Heid, Ruth J.F. Loos, L. Adrienne Cupples, Andrew P. Morris, Cecilia M. Lindgren^*, Karen L. Mohlke^*, Lisette Stolk, André Uitterlinden, Fernando Rivadeneira, Bert Hofman, OH (Oscar) Franco Duran, JCM Witteman, Karol Estrada Gil

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

1216 Citations (Scopus)

Abstract

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Original language	English
Pages (from-to)	187-196
Number of pages	10
Journal	Nature
Volume	518
Issue number	7538
DOIs	https://doi.org/10.1038/nature14132
Publication status	Published - 11 Feb 2015

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EMC COEUR-09
EMC MGC-02-96-01
EMC MM-01-39-04
EMC MM-01-39-09-A
EMC MM-01-52-07
EMC NIHES-01-64-01
EMC NIHES-04-55-01
EMC OR-01-39-08

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10.1038/nature14132

http://hdl.handle.net/1765/83752

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ADIPOGen Consortium, ReproGen Consortium, The CARDIOGRAMplusC4D Consortium, CDKGen Consortium, The GEFOS Consortium, The GENIE Consortium, The GLGC, ICBP Consortium, The International Endogene Consortium, The LifeLines Cohort Study, The MAGIC Investigators, The MuTHER Consortium, The PAGE Consortium, Shungin, D., Winkler, T. W., Croteau-Chonka, D. C., Ferreira, T., Locke, A. E., Mägi, R., ... Estrada Gil, K. (2015). New genetic loci link adipose and insulin biology to body fat distribution. Nature, 518(7538), 187-196. https://doi.org/10.1038/nature14132

@article{46b9c38a2f124d95b1b0dc60e9cc44a6,

title = "New genetic loci link adipose and insulin biology to body fat distribution",

abstract = "Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.",

author = "{ADIPOGen Consortium} and {ReproGen Consortium} and {The CARDIOGRAMplusC4D Consortium} and {CDKGen Consortium} and {The GEFOS Consortium} and {The GENIE Consortium} and {The GLGC} and {ICBP Consortium} and {The International Endogene Consortium} and {The LifeLines Cohort Study} and {The MAGIC Investigators} and {The MuTHER Consortium} and {The PAGE Consortium} and Dmitry Shungin and Winkler, {Thomas W} and Croteau-Chonka, {Damien C} and Teresa Ferreira and Locke, {Adam E} and Reedik M{\"a}gi and Strawbridge, {Rona J} and Pers, {Tune H} and Krista Fischer and Justice, {Anne E} and Tsegaselassie Workalemahu and Wu, {Joseph M W} and Buchkovich, {Martin L} and Heard-Costa, {Nancy L} and Roman, {Tamara S} and Drong, {Alexander W} and Ci Song and Stefan Gustafsson and Day, {Felix R} and Tonu Esko and Tove Fall and Zolt{\'a}n Kutalik and Jian'an Luan and Randall, {Joshua C} and Andr{\'e} Scherag and Sailaja Vedantam and Wood, {Andrew R} and Jin Chen and Rudolf Fehrmann and Juha Karjalainen and Bratati Kahali and Ching-Ti Liu and Najaf Amin and Ayse Demirkan and Peters, {Marjolein J} and Alexander Teumer and Aaron Isaacs and {van Oort}, Floor and Niek Verweij and Zhao, {Jing Hua} and Perry, {John Rb} and Lisette Stolk and Albert Hofman and Yongmei Liu and Oostra, {Ben A} and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G} and {van Duijn}, {Cornelia M} and Jian Yang and Zillikens, {M Carola} and McCarthy, {Mark I.} and Speliotes, {Elizabeth K.} and North, {Kari E.} and Fox, {Caroline S.} and In{\^e}s Barroso and Franks, {Paul W.} and Erik Ingelsson and Heid, {Iris M.} and Loos, {Ruth J.F.} and Cupples, {L. Adrienne} and Morris, {Andrew P.} and Lindgren, {Cecilia M.} and Mohlke, {Karen L.} and Lisette Stolk and Visser, {Jenny A.} and Andr{\'e} Uitterlinden and Fernando Rivadeneira and Bert Hofman and {Franco Duran}, {OH (Oscar)} and JCM Witteman and {Estrada Gil}, Karol and {Mattace Raso}, F.U.S.",

year = "2015",

month = feb,

day = "11",

doi = "10.1038/nature14132",

language = "English",

volume = "518",

pages = "187--196",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7538",

}

ADIPOGen Consortium, ReproGen Consortium, The CARDIOGRAMplusC4D Consortium, CDKGen Consortium, The GEFOS Consortium, The GENIE Consortium, The GLGC, ICBP Consortium, The International Endogene Consortium, The LifeLines Cohort Study, The MAGIC Investigators, The MuTHER Consortium, The PAGE Consortium, Shungin, D, Winkler, TW, Croteau-Chonka, DC, Ferreira, T, Locke, AE, Mägi, R, Strawbridge, RJ, Pers, TH, Fischer, K, Justice, AE, Workalemahu, T, Wu, JMW, Buchkovich, ML, Heard-Costa, NL, Roman, TS, Drong, AW, Song, C, Gustafsson, S, Day, FR, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, JC, Scherag, A, Vedantam, S, Wood, AR, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C-T, Amin, N, Demirkan, A, Peters, MJ, Teumer, A, Isaacs, A, van Oort, F, Verweij, N, Zhao, JH, Perry, JR, Stolk, L, Hofman, A, Liu, Y, Oostra, BA, Rivadeneira, F , Uitterlinden, AG, van Duijn, CM, Yang, J, Zillikens, MC, McCarthy, MI, Speliotes, EK, North, KE, Fox, CS, Barroso, I, Franks, PW, Ingelsson, E, Heid, IM, Loos, RJF, Cupples, LA, Morris, AP, Lindgren, CM, Mohlke, KL, Stolk, L, Uitterlinden, A , Rivadeneira, F , Hofman, B, Franco Duran, OH, Witteman, JCM & Estrada Gil, K 2015, 'New genetic loci link adipose and insulin biology to body fat distribution', Nature, vol. 518, no. 7538, pp. 187-196. https://doi.org/10.1038/nature14132

TY - JOUR

T1 - New genetic loci link adipose and insulin biology to body fat distribution

AU - ADIPOGen Consortium

AU - ReproGen Consortium

AU - The CARDIOGRAMplusC4D Consortium

AU - CDKGen Consortium

AU - The GEFOS Consortium

AU - The GENIE Consortium

AU - The GLGC

AU - ICBP Consortium

AU - The International Endogene Consortium

AU - The LifeLines Cohort Study

AU - The MAGIC Investigators

AU - The MuTHER Consortium

AU - The PAGE Consortium

AU - Shungin, Dmitry

AU - Winkler, Thomas W

AU - Croteau-Chonka, Damien C

AU - Ferreira, Teresa

AU - Locke, Adam E

AU - Mägi, Reedik

AU - Strawbridge, Rona J

AU - Pers, Tune H

AU - Fischer, Krista

AU - Justice, Anne E

AU - Workalemahu, Tsegaselassie

AU - Wu, Joseph M W

AU - Buchkovich, Martin L

AU - Heard-Costa, Nancy L

AU - Roman, Tamara S

AU - Drong, Alexander W

AU - Song, Ci

AU - Gustafsson, Stefan

AU - Day, Felix R

AU - Esko, Tonu

AU - Fall, Tove

AU - Kutalik, Zoltán

AU - Luan, Jian'an

AU - Randall, Joshua C

AU - Scherag, André

AU - Vedantam, Sailaja

AU - Wood, Andrew R

AU - Chen, Jin

AU - Fehrmann, Rudolf

AU - Karjalainen, Juha

AU - Kahali, Bratati

AU - Liu, Ching-Ti

AU - Amin, Najaf

AU - Demirkan, Ayse

AU - Peters, Marjolein J

AU - Teumer, Alexander

AU - Isaacs, Aaron

AU - van Oort, Floor

AU - Verweij, Niek

AU - Zhao, Jing Hua

AU - Perry, John Rb

AU - Stolk, Lisette

AU - Hofman, Albert

AU - Liu, Yongmei

AU - Oostra, Ben A

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G

AU - van Duijn, Cornelia M

AU - Yang, Jian

AU - Zillikens, M Carola

AU - McCarthy, Mark I.

AU - Speliotes, Elizabeth K.

AU - North, Kari E.

AU - Fox, Caroline S.

AU - Barroso, Inês

AU - Franks, Paul W.

AU - Ingelsson, Erik

AU - Heid, Iris M.

AU - Loos, Ruth J.F.

AU - Cupples, L. Adrienne

AU - Morris, Andrew P.

AU - Lindgren, Cecilia M.

AU - Mohlke, Karen L.

AU - Stolk, Lisette

AU - Visser, Jenny A.

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - Hofman, Bert

AU - Franco Duran, OH (Oscar)

AU - Witteman, JCM

AU - Estrada Gil, Karol

AU - Mattace Raso, F.U.S.

PY - 2015/2/11

Y1 - 2015/2/11

N2 - Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

AB - Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

U2 - 10.1038/nature14132

DO - 10.1038/nature14132

M3 - Article

C2 - 25673412

SN - 0028-0836

VL - 518

SP - 187

EP - 196

JO - Nature

JF - Nature

IS - 7538

ER -

New genetic loci link adipose and insulin biology to body fat distribution

Abstract

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