Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Cassandra N. Spracklen; Tugce Karaderi; Hanieh Yaghootkar; Claudia Schurmann; Rebecca S. Fine; Zoltan Kutalik; Michael H. Preuss; Yingchang Lu; Laura B.L. Wittemans; Linda S. Adair; Matthew Allison; Najaf Amin; Paul L. Auer; Traci M. Bartz; Matthias Blüher; Michael Boehnke; Judith B. Borja; Jette Bork-Jensen; Linda Broer; Daniel I. Chasman; Yii Der Ida Chen; Paraskevi Chirstofidou; Ayse Demirkan; Cornelia M. van Duijn; Mary F. Feitosa; Melissa E. Garcia; Mariaelisa Graff; Harald Grallert; Niels Grarup; Xiuqing Guo; Jeffrey Haesser; Torben Hansen; Tamara B. Harris; Heather M. Highland; Jaeyoung Hong; M. Arfan Ikram; Erik Ingelsson; Rebecca Jackson; Pekka Jousilahti; Mika Kähönen; Jorge R. Kizer; Peter Kovacs; Jennifer Kriebel; Markku Laakso; Leslie A. Lange; Terho Lehtimäki; Jin Li; Ruifang Li-Gao; Lars Lind; Jian'an Luan; Leo Pekka Lyytikäinen; Stuart MacGregor; David A. Mackey; Anubha Mahajan; Massimo Mangino; Satu Männistö; Mark I. McCarthy; Barbara McKnight; Carolina Medina-Gomez; James B. Meigs; Sophie Molnos; Dennis Mook-Kanamori; Andrew P. Morris; Renee de Mutsert; Mike A. Nalls; Ivana Nedeljkovic; Kari E. North; Craig E. Pennell; Aruna D. Pradhan; Michael A. Province; Olli T. Raitakari; Chelsea K. Raulerson; Alex P. Reiner; Paul M. Ridker; Samuli Ripatti; Neil Roberston; Jerome I. Rotter; Veikko Salomaa; America A. Sandoval-Zárate; Colleen M. Sitlani; Tim D. Spector; Konstantin Strauch; Michael Stumvoll; Kent D. Taylor; Betina Thuesen; Anke Tönjes; Andre G. Uitterlinden; Cristina Venturini; Mark Walker; Carol A. Wang; Shuai Wang; Nicholas J. Wareham; Sara M. Willems; Ko Willems van Dijk; James G. Wilson; Ying Wu; Jie Yao; Kristin L. Young; Claudia Langenberg; Timothy M. Frayling; Tuomas O. Kilpeläinen; Cecilia M. Lindgren; Ruth J.F. Loos; Karen L. Mohlke

doi:10.1016/j.ajhg.2019.05.002

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Cassandra N. Spracklen, Tugce Karaderi, Hanieh Yaghootkar, Claudia Schurmann, Rebecca S. Fine, Zoltan Kutalik, Michael H. Preuss, Yingchang Lu, Laura B.L. Wittemans, Linda S. Adair, Matthew Allison, Najaf Amin, Paul L. Auer, Traci M. Bartz, Matthias Blüher, Michael Boehnke, Judith B. Borja, Jette Bork-Jensen, Linda Broer, Daniel I. ChasmanYii Der Ida Chen, Paraskevi Chirstofidou, Ayse Demirkan, Cornelia M. van Duijn, Mary F. Feitosa, Melissa E. Garcia, Mariaelisa Graff, Harald Grallert, Niels Grarup, Xiuqing Guo, Jeffrey Haesser, Torben Hansen, Tamara B. Harris, Heather M. Highland, Jaeyoung Hong, M. Arfan Ikram, Erik Ingelsson, Rebecca Jackson, Pekka Jousilahti, Mika Kähönen, Jorge R. Kizer, Peter Kovacs, Jennifer Kriebel, Markku Laakso, Leslie A. Lange, Terho Lehtimäki, Jin Li, Ruifang Li-Gao, Lars Lind, Jian'an Luan, Leo Pekka Lyytikäinen, Stuart MacGregor, David A. Mackey, Anubha Mahajan, Massimo Mangino, Satu Männistö, Mark I. McCarthy, Barbara McKnight, Carolina Medina-Gomez, James B. Meigs, Sophie Molnos, Dennis Mook-Kanamori, Andrew P. Morris, Renee de Mutsert, Mike A. Nalls, Ivana Nedeljkovic, Kari E. North, Craig E. Pennell, Aruna D. Pradhan, Michael A. Province, Olli T. Raitakari, Chelsea K. Raulerson, Alex P. Reiner, Paul M. Ridker, Samuli Ripatti, Neil Roberston, Jerome I. Rotter, Veikko Salomaa, America A. Sandoval-Zárate, Colleen M. Sitlani, Tim D. Spector, Konstantin Strauch, Michael Stumvoll, Kent D. Taylor, Betina Thuesen, Anke Tönjes, Andre G. Uitterlinden, Cristina Venturini, Mark Walker, Carol A. Wang, Shuai Wang, Nicholas J. Wareham, Sara M. Willems, Ko Willems van Dijk, James G. Wilson, Ying Wu, Jie Yao, Kristin L. Young, Claudia Langenberg, Timothy M. Frayling, Tuomas O. Kilpeläinen, Cecilia M. Lindgren, Ruth J.F. Loos, Karen L. Mohlke

Medicine

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

15 Scopus citations

Abstract

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10⁻⁷). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r² > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10⁻⁴) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Original language	English (US)
Pages (from-to)	15-28
Number of pages	14
Journal	American Journal of Human Genetics
Volume	105
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2019.05.002
State	Published - Jul 3 2019

Keywords

adiponectin
cardio metabolic traits
exome
genetics
genome-wide association study
lipids
obesity

ASJC Scopus subject areas

Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2019.05.002

Cite this

Spracklen, C. N., Karaderi, T., Yaghootkar, H., Schurmann, C., Fine, R. S., Kutalik, Z., Preuss, M. H., Lu, Y., Wittemans, L. B. L., Adair, L. S., Allison, M., Amin, N., Auer, P. L., Bartz, T. M., Blüher, M., Boehnke, M., Borja, J. B., Bork-Jensen, J., Broer, L., ... Mohlke, K. L. (2019). Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology. American Journal of Human Genetics, 105(1), 15-28. https://doi.org/10.1016/j.ajhg.2019.05.002

Spracklen, CN, Karaderi, T, Yaghootkar, H, Schurmann, C, Fine, RS, Kutalik, Z, Preuss, MH, Lu, Y, Wittemans, LBL, Adair, LS, Allison, M, Amin, N, Auer, PL, Bartz, TM, Blüher, M, Boehnke, M, Borja, JB, Bork-Jensen, J, Broer, L, Chasman, DI, Chen, YDI, Chirstofidou, P, Demirkan, A, van Duijn, CM, Feitosa, MF, Garcia, ME, Graff, M, Grallert, H, Grarup, N, Guo, X, Haesser, J, Hansen, T, Harris, TB, Highland, HM, Hong, J, Ikram, MA, Ingelsson, E, Jackson, R, Jousilahti, P, Kähönen, M, Kizer, JR, Kovacs, P, Kriebel, J, Laakso, M, Lange, LA, Lehtimäki, T, Li, J, Li-Gao, R, Lind, L, Luan, J, Lyytikäinen, LP, MacGregor, S, Mackey, DA, Mahajan, A, Mangino, M, Männistö, S, McCarthy, MI, McKnight, B, Medina-Gomez, C, Meigs, JB, Molnos, S, Mook-Kanamori, D, Morris, AP, de Mutsert, R, Nalls, MA, Nedeljkovic, I, North, KE, Pennell, CE, Pradhan, AD, Province, MA, Raitakari, OT, Raulerson, CK, Reiner, AP, Ridker, PM, Ripatti, S, Roberston, N, Rotter, JI, Salomaa, V, Sandoval-Zárate, AA, Sitlani, CM, Spector, TD, Strauch, K, Stumvoll, M, Taylor, KD, Thuesen, B, Tönjes, A, Uitterlinden, AG, Venturini, C, Walker, M, Wang, CA, Wang, S, Wareham, NJ, Willems, SM, Willems van Dijk, K, Wilson, JG, Wu, Y, Yao, J, Young, KL, Langenberg, C, Frayling, TM, Kilpeläinen, TO, Lindgren, CM, Loos, RJF & Mohlke, KL 2019, 'Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology', American Journal of Human Genetics, vol. 105, no. 1, pp. 15-28. https://doi.org/10.1016/j.ajhg.2019.05.002

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title = "Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology",

abstract = "Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10−7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10−4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.",

keywords = "adiponectin, cardio metabolic traits, exome, genetics, genome-wide association study, lipids, obesity",

author = "Spracklen, {Cassandra N.} and Tugce Karaderi and Hanieh Yaghootkar and Claudia Schurmann and Fine, {Rebecca S.} and Zoltan Kutalik and Preuss, {Michael H.} and Yingchang Lu and Wittemans, {Laura B.L.} and Adair, {Linda S.} and Matthew Allison and Najaf Amin and Auer, {Paul L.} and Bartz, {Traci M.} and Matthias Bl{\"u}her and Michael Boehnke and Borja, {Judith B.} and Jette Bork-Jensen and Linda Broer and Chasman, {Daniel I.} and Chen, {Yii Der Ida} and Paraskevi Chirstofidou and Ayse Demirkan and {van Duijn}, {Cornelia M.} and Feitosa, {Mary F.} and Garcia, {Melissa E.} and Mariaelisa Graff and Harald Grallert and Niels Grarup and Xiuqing Guo and Jeffrey Haesser and Torben Hansen and Harris, {Tamara B.} and Highland, {Heather M.} and Jaeyoung Hong and Ikram, {M. Arfan} and Erik Ingelsson and Rebecca Jackson and Pekka Jousilahti and Mika K{\"a}h{\"o}nen and Kizer, {Jorge R.} and Peter Kovacs and Jennifer Kriebel and Markku Laakso and Lange, {Leslie A.} and Terho Lehtim{\"a}ki and Jin Li and Ruifang Li-Gao and Lars Lind and Jian'an Luan and Lyytik{\"a}inen, {Leo Pekka} and Stuart MacGregor and Mackey, {David A.} and Anubha Mahajan and Massimo Mangino and Satu M{\"a}nnist{\"o} and McCarthy, {Mark I.} and Barbara McKnight and Carolina Medina-Gomez and Meigs, {James B.} and Sophie Molnos and Dennis Mook-Kanamori and Morris, {Andrew P.} and {de Mutsert}, Renee and Nalls, {Mike A.} and Ivana Nedeljkovic and North, {Kari E.} and Pennell, {Craig E.} and Pradhan, {Aruna D.} and Province, {Michael A.} and Raitakari, {Olli T.} and Raulerson, {Chelsea K.} and Reiner, {Alex P.} and Ridker, {Paul M.} and Samuli Ripatti and Neil Roberston and Rotter, {Jerome I.} and Veikko Salomaa and Sandoval-Z{\'a}rate, {America A.} and Sitlani, {Colleen M.} and Spector, {Tim D.} and Konstantin Strauch and Michael Stumvoll and Taylor, {Kent D.} and Betina Thuesen and Anke T{\"o}njes and Uitterlinden, {Andre G.} and Cristina Venturini and Mark Walker and Wang, {Carol A.} and Shuai Wang and Wareham, {Nicholas J.} and Willems, {Sara M.} and {Willems van Dijk}, Ko and Wilson, {James G.} and Ying Wu and Jie Yao and Young, {Kristin L.} and Claudia Langenberg and Frayling, {Timothy M.} and Kilpel{\"a}inen, {Tuomas O.} and Lindgren, {Cecilia M.} and Loos, {Ruth J.F.} and Mohlke, {Karen L.}",

note = "Funding Information: This work was conducted prior to M.E.G.{\textquoteright}s current affiliation with the National Heart, Lung, and Blood Institute, and, as such, the views expressed in this article do not represent the views of the NHLBI, NIH, or other government entity. D.M.-K. is a part-time clinical research consultant for Metabolon, Inc. M.A.N.{\textquoteright}s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health. V.S. has participated in a conference trip and received an honorarium sponsored by Novo Nordisk. Funding Information: The authors thank all investigators, staff members, and study participants for their contributions to all the participating studies. Funding information for all participating cohorts are provided in the Supplemental Data. J.B.-J. and T.H. were partially funded by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent Research Center at the University of Copenhagen. R.S.F. was supported by NHGRI F31 HG009850. T.M.F. was supported by the European Research Council (grant 323195:GLUCOSEGENES-FP7-IDEAS-ERC). H.M.H. was supported by NHLBI T32 HL007055 and T32 HL129982. T.K. was supported by the Novo Nordisk Foundation Center for Protein Research (grants NNF17OC0027594 and NNF14CC0001). T.O.K. was supported by the Danish Council for Independent Research (grant DFF – 6110-00183) and the Novo Nordisk Foundation (grant NNF17OC0026848). C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds, the NIHR Biomedical Research Centre, Oxford, Widenlife, and NIH (grant 5P50HD028138-27). M.I. McCarthy is a Wellcome Trust Senior Investigator (grant WT098381) and a National Institute of Health Research Senior Investigator, and the views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. J.B. Meigs is supported by NIH K24 DK080140. K.L.M. was supported by NIH R01DK072193 and R01DK093757. D.M.-K. is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). K.E.N. was supported by NIH R01DK089256, R01HD057194, U01HG007416, and R01DK101855 and AHA 13GRNT16490017. C.K.R. was supported by National Institutes of Health (grant 5T32GM67553). S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grant 312062) and the Academy of Finland (grant 285380). V.S. was supported by the Finnish Foundation for Cardiovascular Research. C.N.S. was supported by the American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. J.G.W. is supported by U54GM115428 from the National Institute of General Medical Sciences. L.B.L.W. was supported by Wellcome Trust (WT083442AIA). H.Y. was funded by Diabetes UK RD Lawrence fellowship (grant 17/ 0005594). K.L.Y. was supported by KL2TR001109. Funding Information: J.B.-J. and T.H. were partially funded by the Novo Nordisk Foundation Center for Basic Metabolic Research , an independent Research Center at the University of Copenhagen. R.S.F. was supported by NHGRI F31 HG009850 . T.M.F. was supported by the European Research Council (grant 323195:GLUCOSEGENES-FP7-IDEAS-ERC ). H.M.H. was supported by NHLBI T32 HL007055 and T32 HL129982 . T.K. was supported by the Novo Nordisk Foundation Center for Protein Research (grants NNF17OC0027594 and NNF14CC0001 ). T.O.K. was supported by the Danish Council for Independent Research (grant DFF – 6110-00183 ) and the Novo Nordisk Foundation (grant NNF17OC0026848 ). C.M.L. is supported by the Li Ka Shing Foundation , WT-SSI/John Fell funds , the NIHR Biomedical Research Centre, Oxford , Widenlife , and NIH (grant 5P50HD028138-27 ). M.I. McCarthy is a Wellcome Trust Senior Investigator (grant WT098381 ) and a National Institute of Health Research Senior Investigator, and the views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. J.B. Meigs is supported by NIH K24 DK080140 . K.L.M. was supported by NIH R01DK072193 and R01DK093757 . D.M.-K. is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023 ). K.E.N. was supported by NIH R01DK089256 , R01HD057194 , U01HG007416 , and R01DK101855 and AHA 13GRNT16490017 . C.K.R. was supported by National Institutes of Health (grant 5T32GM67553 ). S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grant 312062 ) and the Academy of Finland (grant 285380 ). V.S. was supported by the Finnish Foundation for Cardiovascular Research . C.N.S. was supported by the American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016 . J.G.W. is supported by U54GM115428 from the National Institute of General Medical Sciences . L.B.L.W. was supported by Wellcome Trust ( WT083442AIA ). H.Y. was funded by Diabetes UK RD Lawrence fellowship (grant 17/ 0005594 ). K.L.Y. was supported by KL2TR001109 . Publisher Copyright: {\textcopyright} 2019 American Society of Human Genetics",

year = "2019",

month = jul,

day = "3",

doi = "10.1016/j.ajhg.2019.05.002",

language = "English (US)",

volume = "105",

pages = "15--28",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

AU - Spracklen, Cassandra N.

AU - Karaderi, Tugce

AU - Yaghootkar, Hanieh

AU - Schurmann, Claudia

AU - Fine, Rebecca S.

AU - Kutalik, Zoltan

AU - Preuss, Michael H.

AU - Lu, Yingchang

AU - Wittemans, Laura B.L.

AU - Adair, Linda S.

AU - Allison, Matthew

AU - Amin, Najaf

AU - Auer, Paul L.

AU - Bartz, Traci M.

AU - Blüher, Matthias

AU - Boehnke, Michael

AU - Borja, Judith B.

AU - Bork-Jensen, Jette

AU - Broer, Linda

AU - Chasman, Daniel I.

AU - Chen, Yii Der Ida

AU - Chirstofidou, Paraskevi

AU - Demirkan, Ayse

AU - van Duijn, Cornelia M.

AU - Feitosa, Mary F.

AU - Garcia, Melissa E.

AU - Graff, Mariaelisa

AU - Grallert, Harald

AU - Grarup, Niels

AU - Guo, Xiuqing

AU - Haesser, Jeffrey

AU - Hansen, Torben

AU - Harris, Tamara B.

AU - Highland, Heather M.

AU - Hong, Jaeyoung

AU - Ikram, M. Arfan

AU - Ingelsson, Erik

AU - Jackson, Rebecca

AU - Jousilahti, Pekka

AU - Kähönen, Mika

AU - Kizer, Jorge R.

AU - Kovacs, Peter

AU - Kriebel, Jennifer

AU - Laakso, Markku

AU - Lange, Leslie A.

AU - Lehtimäki, Terho

AU - Li, Jin

AU - Li-Gao, Ruifang

AU - Lind, Lars

AU - Luan, Jian'an

AU - Lyytikäinen, Leo Pekka

AU - MacGregor, Stuart

AU - Mackey, David A.

AU - Mahajan, Anubha

AU - Mangino, Massimo

AU - Männistö, Satu

AU - McCarthy, Mark I.

AU - McKnight, Barbara

AU - Medina-Gomez, Carolina

AU - Meigs, James B.

AU - Molnos, Sophie

AU - Mook-Kanamori, Dennis

AU - Morris, Andrew P.

AU - de Mutsert, Renee

AU - Nalls, Mike A.

AU - Nedeljkovic, Ivana

AU - North, Kari E.

AU - Pennell, Craig E.

AU - Pradhan, Aruna D.

AU - Province, Michael A.

AU - Raitakari, Olli T.

AU - Raulerson, Chelsea K.

AU - Reiner, Alex P.

AU - Ridker, Paul M.

AU - Ripatti, Samuli

AU - Roberston, Neil

AU - Rotter, Jerome I.

AU - Salomaa, Veikko

AU - Sandoval-Zárate, America A.

AU - Sitlani, Colleen M.

AU - Spector, Tim D.

AU - Strauch, Konstantin

AU - Stumvoll, Michael

AU - Taylor, Kent D.

AU - Thuesen, Betina

AU - Tönjes, Anke

AU - Uitterlinden, Andre G.

AU - Venturini, Cristina

AU - Walker, Mark

AU - Wang, Carol A.

AU - Wang, Shuai

AU - Wareham, Nicholas J.

AU - Willems, Sara M.

AU - Willems van Dijk, Ko

AU - Wilson, James G.

AU - Wu, Ying

AU - Yao, Jie

AU - Young, Kristin L.

AU - Langenberg, Claudia

AU - Frayling, Timothy M.

AU - Kilpeläinen, Tuomas O.

AU - Lindgren, Cecilia M.

AU - Loos, Ruth J.F.

AU - Mohlke, Karen L.

N1 - Funding Information: This work was conducted prior to M.E.G.’s current affiliation with the National Heart, Lung, and Blood Institute, and, as such, the views expressed in this article do not represent the views of the NHLBI, NIH, or other government entity. D.M.-K. is a part-time clinical research consultant for Metabolon, Inc. M.A.N.’s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health. V.S. has participated in a conference trip and received an honorarium sponsored by Novo Nordisk. Funding Information: The authors thank all investigators, staff members, and study participants for their contributions to all the participating studies. Funding information for all participating cohorts are provided in the Supplemental Data. J.B.-J. and T.H. were partially funded by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent Research Center at the University of Copenhagen. R.S.F. was supported by NHGRI F31 HG009850. T.M.F. was supported by the European Research Council (grant 323195:GLUCOSEGENES-FP7-IDEAS-ERC). H.M.H. was supported by NHLBI T32 HL007055 and T32 HL129982. T.K. was supported by the Novo Nordisk Foundation Center for Protein Research (grants NNF17OC0027594 and NNF14CC0001). T.O.K. was supported by the Danish Council for Independent Research (grant DFF – 6110-00183) and the Novo Nordisk Foundation (grant NNF17OC0026848). C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds, the NIHR Biomedical Research Centre, Oxford, Widenlife, and NIH (grant 5P50HD028138-27). M.I. McCarthy is a Wellcome Trust Senior Investigator (grant WT098381) and a National Institute of Health Research Senior Investigator, and the views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. J.B. Meigs is supported by NIH K24 DK080140. K.L.M. was supported by NIH R01DK072193 and R01DK093757. D.M.-K. is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). K.E.N. was supported by NIH R01DK089256, R01HD057194, U01HG007416, and R01DK101855 and AHA 13GRNT16490017. C.K.R. was supported by National Institutes of Health (grant 5T32GM67553). S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grant 312062) and the Academy of Finland (grant 285380). V.S. was supported by the Finnish Foundation for Cardiovascular Research. C.N.S. was supported by the American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. J.G.W. is supported by U54GM115428 from the National Institute of General Medical Sciences. L.B.L.W. was supported by Wellcome Trust (WT083442AIA). H.Y. was funded by Diabetes UK RD Lawrence fellowship (grant 17/ 0005594). K.L.Y. was supported by KL2TR001109. Funding Information: J.B.-J. and T.H. were partially funded by the Novo Nordisk Foundation Center for Basic Metabolic Research , an independent Research Center at the University of Copenhagen. R.S.F. was supported by NHGRI F31 HG009850 . T.M.F. was supported by the European Research Council (grant 323195:GLUCOSEGENES-FP7-IDEAS-ERC ). H.M.H. was supported by NHLBI T32 HL007055 and T32 HL129982 . T.K. was supported by the Novo Nordisk Foundation Center for Protein Research (grants NNF17OC0027594 and NNF14CC0001 ). T.O.K. was supported by the Danish Council for Independent Research (grant DFF – 6110-00183 ) and the Novo Nordisk Foundation (grant NNF17OC0026848 ). C.M.L. is supported by the Li Ka Shing Foundation , WT-SSI/John Fell funds , the NIHR Biomedical Research Centre, Oxford , Widenlife , and NIH (grant 5P50HD028138-27 ). M.I. McCarthy is a Wellcome Trust Senior Investigator (grant WT098381 ) and a National Institute of Health Research Senior Investigator, and the views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. J.B. Meigs is supported by NIH K24 DK080140 . K.L.M. was supported by NIH R01DK072193 and R01DK093757 . D.M.-K. is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023 ). K.E.N. was supported by NIH R01DK089256 , R01HD057194 , U01HG007416 , and R01DK101855 and AHA 13GRNT16490017 . C.K.R. was supported by National Institutes of Health (grant 5T32GM67553 ). S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grant 312062 ) and the Academy of Finland (grant 285380 ). V.S. was supported by the Finnish Foundation for Cardiovascular Research . C.N.S. was supported by the American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016 . J.G.W. is supported by U54GM115428 from the National Institute of General Medical Sciences . L.B.L.W. was supported by Wellcome Trust ( WT083442AIA ). H.Y. was funded by Diabetes UK RD Lawrence fellowship (grant 17/ 0005594 ). K.L.Y. was supported by KL2TR001109 . Publisher Copyright: © 2019 American Society of Human Genetics

PY - 2019/7/3

Y1 - 2019/7/3

N2 - Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10−7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10−4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

AB - Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10−7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10−4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

KW - adiponectin

KW - cardio metabolic traits

KW - exome

KW - genetics

KW - genome-wide association study

KW - lipids

KW - obesity

UR - http://www.scopus.com/inward/record.url?scp=85068057969&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068057969&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2019.05.002

DO - 10.1016/j.ajhg.2019.05.002

M3 - Article

C2 - 31178129

AN - SCOPUS:85068057969

SN - 0002-9297

VL - 105

SP - 15

EP - 28

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

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