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

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 & 43 others 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, Ellen M. Schmidt, Devin Absher, Najaf Amin, Denise Anderson, Marian Beekman, Jennifer L. Bragg-Gresham, Steven Buyske, Ayse Demirkan, Georg B. Ehret, Mary F. Feitosa, Anuj Goel, Anne U. Jackson, Toby Johnson, Marcus E. Kleber, Kati Kristiansson, Massimo Mangino, Irene Mateo Leach, Elina Hyppönen, The LifeLines Cohort Study, The ADIPOGen Consortium, The CARDIOGRAMplusC4D Consortium, The CKDGen Consortium, The GEFOS Consortium, The GENIE Consortium, The GLGC, The ICBP, The International Endogene Consortium, The MAGIC Investigators, The MuTHER Consortium, The PAGE Consortium, The ReproGen Consortium

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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, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10-8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed 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.

LanguageEnglish
Pages187-196
Number of pages10
JournalNature
Volume518
Issue number7538
DOIs
Publication statusPublished - 12 Feb 2015

ASJC Scopus subject areas

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Cite this

Shungin, D., Winkler, T. W., Croteau-Chonka, D. C., Ferreira, T., Locke, A. E., Mägi, R., ... The ReproGen Consortium (2015). New genetic loci link adipose and insulin biology to body fat distribution. Nature, 518(7538), 187-196. https://doi.org/10.1038/nature14132
Shungin, Dmitry ; Winkler, Thomas W. ; Croteau-Chonka, Damien C. ; Ferreira, Teresa ; Locke, Adam E. ; Mägi, Reedik ; Strawbridge, Rona J. ; Pers, Tune H. ; Fischer, Krista ; Justice, Anne E. ; Workalemahu, Tsegaselassie ; Wu, Joseph M.W. ; Buchkovich, Martin L. ; Heard-Costa, Nancy L. ; Roman, Tamara S. ; Drong, Alexander W. ; Song, Ci ; Gustafsson, Stefan ; Day, Felix R. ; Esko, Tonu ; Fall, Tove ; Kutalik, Zoltán ; Luan, Jian’an ; Randall, Joshua C. ; Scherag, André ; Vedantam, Sailaja ; Wood, Andrew R. ; Chen, Jin ; Fehrmann, Rudolf ; Karjalainen, Juha ; Kahali, Bratati ; Liu, Ching Ti ; Schmidt, Ellen M. ; Absher, Devin ; Amin, Najaf ; Anderson, Denise ; Beekman, Marian ; Bragg-Gresham, Jennifer L. ; Buyske, Steven ; Demirkan, Ayse ; Ehret, Georg B. ; Feitosa, Mary F. ; Goel, Anuj ; Jackson, Anne U. ; Johnson, Toby ; Kleber, Marcus E. ; Kristiansson, Kati ; Mangino, Massimo ; Leach, Irene Mateo ; Hyppönen, Elina ; The LifeLines Cohort Study ; The ADIPOGen Consortium ; The CARDIOGRAMplusC4D Consortium ; The CKDGen Consortium ; The GEFOS Consortium ; The GENIE Consortium ; The GLGC ; The ICBP ; The International Endogene Consortium ; The MAGIC Investigators ; The MuTHER Consortium ; The PAGE Consortium ; The ReproGen Consortium. / New genetic loci link adipose and insulin biology to body fat distribution. In: Nature. 2015 ; Vol. 518, No. 7538. pp. 187-196.
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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, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10-8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed 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 = "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 Liu, {Ching Ti} and Schmidt, {Ellen M.} and Devin Absher and Najaf Amin and Denise Anderson and Marian Beekman and Bragg-Gresham, {Jennifer L.} and Steven Buyske and Ayse Demirkan and Ehret, {Georg B.} and Feitosa, {Mary F.} and Anuj Goel and Jackson, {Anne U.} and Toby Johnson and Kleber, {Marcus E.} and Kati Kristiansson and Massimo Mangino and Leach, {Irene Mateo} and Elina Hypp{\"o}nen and {The LifeLines Cohort Study} and {The ADIPOGen Consortium} and {The CARDIOGRAMplusC4D Consortium} and {The CKDGen Consortium} and {The GEFOS Consortium} and {The GENIE Consortium} and {The GLGC} and {The ICBP} and {The International Endogene Consortium} and {The MAGIC Investigators} and {The MuTHER Consortium} and {The PAGE Consortium} and {The ReproGen Consortium}",
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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, CT, Schmidt, EM, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg-Gresham, JL, Buyske, S, Demirkan, A, Ehret, GB, Feitosa, MF, Goel, A, Jackson, AU, Johnson, T, Kleber, ME, Kristiansson, K, Mangino, M, Leach, IM, Hyppönen, E, The LifeLines Cohort Study, The ADIPOGen Consortium, The CARDIOGRAMplusC4D Consortium, The CKDGen Consortium, The GEFOS Consortium, The GENIE Consortium, The GLGC, The ICBP, The International Endogene Consortium, The MAGIC Investigators, The MuTHER Consortium, The PAGE Consortium & The ReproGen Consortium 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

New genetic loci link adipose and insulin biology to body fat distribution. / Shungin, Dmitry; Winkler, Thomas W.; Croteau-Chonka, Damien C.; Ferreira, Teresa; Locke, Adam E.; Mägi, Reedik; Strawbridge, Rona J.; Pers, Tune H.; Fischer, Krista; Justice, Anne E.; Workalemahu, Tsegaselassie; Wu, Joseph M.W.; Buchkovich, Martin L.; Heard-Costa, Nancy L.; Roman, Tamara S.; Drong, Alexander W.; Song, Ci; Gustafsson, Stefan; Day, Felix R.; Esko, Tonu; Fall, Tove; Kutalik, Zoltán; Luan, Jian’an; Randall, Joshua C.; Scherag, André; Vedantam, Sailaja; Wood, Andrew R.; Chen, Jin; Fehrmann, Rudolf; Karjalainen, Juha; Kahali, Bratati; Liu, Ching Ti; Schmidt, Ellen M.; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bragg-Gresham, Jennifer L.; Buyske, Steven; Demirkan, Ayse; Ehret, Georg B.; Feitosa, Mary F.; Goel, Anuj; Jackson, Anne U.; Johnson, Toby; Kleber, Marcus E.; Kristiansson, Kati; Mangino, Massimo; Leach, Irene Mateo; Hyppönen, Elina; The LifeLines Cohort Study; The ADIPOGen Consortium; The CARDIOGRAMplusC4D Consortium; The CKDGen Consortium; The GEFOS Consortium; The GENIE Consortium; The GLGC; The ICBP; The International Endogene Consortium; The MAGIC Investigators; The MuTHER Consortium; The PAGE Consortium; The ReproGen Consortium.

In: Nature, Vol. 518, No. 7538, 12.02.2015, p. 187-196.

Research output: Contribution to journalArticle

TY - JOUR

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

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 - Schmidt, Ellen M.

AU - Absher, Devin

AU - Amin, Najaf

AU - Anderson, Denise

AU - Beekman, Marian

AU - Bragg-Gresham, Jennifer L.

AU - Buyske, Steven

AU - Demirkan, Ayse

AU - Ehret, Georg B.

AU - Feitosa, Mary F.

AU - Goel, Anuj

AU - Jackson, Anne U.

AU - Johnson, Toby

AU - Kleber, Marcus E.

AU - Kristiansson, Kati

AU - Mangino, Massimo

AU - Leach, Irene Mateo

AU - Hyppönen, Elina

AU - The LifeLines Cohort Study

AU - The ADIPOGen Consortium

AU - The CARDIOGRAMplusC4D Consortium

AU - The CKDGen Consortium

AU - The GEFOS Consortium

AU - The GENIE Consortium

AU - The GLGC

AU - The ICBP

AU - The International Endogene Consortium

AU - The MAGIC Investigators

AU - The MuTHER Consortium

AU - The PAGE Consortium

AU - The ReproGen Consortium

PY - 2015/2/12

Y1 - 2015/2/12

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, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10-8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed 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, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10-8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed 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.

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Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015 Feb 12;518(7538):187-196. https://doi.org/10.1038/nature14132