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 & 84 others 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*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .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 x 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 languageEnglish
Pages (from-to)15-28
JournalAmerican Journal of Human Genetics
Volume105
Issue number1
DOIs
Publication statusPublished - 2019

Fingerprint

Exome
Adiponectin
Lipids
Adipocytes
Adipose Tissue

Keywords

  • ADIPOSE-TISSUE
  • CANDIDATE GENES
  • CIRCULATING ADIPONECTIN
  • DISEASE
  • EXPRESSION
  • GENOME-WIDE ASSOCIATION
  • GLYCEMIC TRAITS
  • METAANALYSIS
  • PLASMA ADIPONECTIN
  • RARE

Cite this

Spracklen, C. N., Karaderi, T., Yaghootkar, H., Schurmann, C., Fine, R. S., Kutalik, Z., ... 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, Cassandra N. ; Karaderi, Tugce ; Yaghootkar, Hanieh ; Schurmann, Claudia ; Fine, Rebecca S. ; Kutalik, Zoltan ; Preuss, Michael H. ; Lu, Yingchang ; Wittemans, Laura B.l. ; Adair, Linda S. ; Allison, Matthew ; Amin, Najaf ; Auer, Paul L. ; Bartz, Traci M. ; Blüher, Matthias ; Boehnke, Michael ; Borja, Judith B. ; Bork-jensen, Jette ; Broer, Linda ; Chasman, Daniel I. ; Chen, Yii-der Ida ; Chirstofidou, Paraskevi ; Demirkan, Ayse ; Van Duijn, Cornelia M. ; Feitosa, Mary F. ; Garcia, Melissa E. ; Graff, Mariaelisa ; Grallert, Harald ; Grarup, Niels ; Guo, Xiuqing ; Haesser, Jeffrey ; Hansen, Torben ; Harris, Tamara B. ; Highland, Heather M. ; Hong, Jaeyoung ; Ikram, M. Arfan ; Ingelsson, Erik ; Jackson, Rebecca ; Jousilahti, Pekka ; Kähönen, Mika ; Kizer, Jorge R. ; Kovacs, Peter ; Kriebel, Jennifer ; Laakso, Markku ; Lange, Leslie A. ; Lehtimäki, Terho ; Li, Jin ; Li-gao, Ruifang ; Lind, Lars ; Luan, Jian’an ; Lyytikäinen, Leo-pekka ; Macgregor, Stuart ; Mackey, David A. ; Mahajan, Anubha ; Mangino, Massimo ; Männistö, Satu ; Mccarthy, Mark I. ; Mcknight, Barbara ; Medina-gomez, Carolina ; Meigs, James B. ; Molnos, Sophie ; Mook-kanamori, Dennis ; Morris, Andrew P. ; De Mutsert, Renee ; Nalls, Mike A. ; Nedeljkovic, Ivana ; North, Kari E. ; Pennell, Craig E. ; Pradhan, Aruna D. ; Province, Michael A. ; Raitakari, Olli T. ; Raulerson, Chelsea K. ; Reiner, Alex P. ; Ridker, Paul M. ; Ripatti, Samuli ; Roberston, Neil ; Rotter, Jerome I. ; Salomaa, Veikko ; Sandoval-zárate, America A. ; Sitlani, Colleen M. ; Spector, Tim D. ; Strauch, Konstantin ; Stumvoll, Michael ; Taylor, Kent D. ; Thuesen, Betina ; Tönjes, Anke ; Uitterlinden, Andre G. ; Venturini, Cristina ; Walker, Mark ; Wang, Carol A. ; Wang, Shuai ; Wareham, Nicholas J. ; Willems, Sara M. ; Willems Van Dijk, Ko ; Wilson, James G. ; Wu, Ying ; Yao, Jie ; Young, Kristin L. ; Langenberg, Claudia ; Frayling, Timothy M. ; Kilpeläinen, Tuomas O. ; Lindgren, Cecilia M. ; Loos, Ruth J.f. ; Mohlke, Karen L. / Exome-derived adiponectin-associated variants implicate obesity and lipid biology. In: American Journal of Human Genetics. 2019 ; Vol. 105, No. 1. pp. 15-28.
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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 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .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 x 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.",
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language = "English",
volume = "105",
pages = "15--28",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
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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, YI, 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, L, 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

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

In: American Journal of Human Genetics, Vol. 105, No. 1, 2019, p. 15-28.

Research output: Contribution to journalArticleScientificpeer-review

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.

PY - 2019

Y1 - 2019

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 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .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 x 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 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .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 x 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 - ADIPOSE-TISSUE

KW - CANDIDATE GENES

KW - CIRCULATING ADIPONECTIN

KW - DISEASE

KW - EXPRESSION

KW - GENOME-WIDE ASSOCIATION

KW - GLYCEMIC TRAITS

KW - METAANALYSIS

KW - PLASMA ADIPONECTIN

KW - RARE

U2 - 10.1016/j.ajhg.2019.05.002

DO - 10.1016/j.ajhg.2019.05.002

M3 - Article

VL - 105

SP - 15

EP - 28

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -