Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Hanieh Yaghootkar; Yiying Zhang; Cassandra N. Spracklen; Tugce Karaderi; Lam Opal Huang; Jonathan Bradfield; Claudia Schurmann; Rebecca S. Fine; Michael H. Preuss; Zoltan Kutalik; Laura B.L. Wittemans; Yingchang Lu; Sophia Metz; Sara M. Willems; Ruifang Li-Gao; Niels Grarup; Shuai Wang; Sophie Molnos; América A. Sandoval-Zárate; Mike A. Nalls; Leslie A. Lange; Jeffrey Haesser; Xiuqing Guo; Leo Pekka Lyytikäinen; Mary F. Feitosa; Colleen M. Sitlani; Cristina Venturini; Anubha Mahajan; Tim Kacprowski; Carol A. Wang; Daniel I. Chasman; Najaf Amin; Linda Broer; Neil Robertson; Kristin L. Young; Matthew Allison; Paul L. Auer; Matthias Blüher; Judith B. Borja; Jette Bork-Jensen; Germán D. Carrasquilla; Paraskevi Christofidou; Ayse Demirkan; Claudia A. Doege; Melissa E. Garcia; Mariaelisa Graff; Kaiying Guo; Hakon Hakonarson; Jaeyoung Hong; Yii Der Ida Chen; Rebecca Jackson; Hermina Jakupovic; Pekka Jousilahti; Anne E. Justice; Mika Kähönen; Jorge R. Kizer; Jennifer Kriebel; Charles A. Leduc; Jin Li; Lars Lind; Jian’An Luan; David A. Mackey; Massimo Mangino; Satu Männistö; Jayne F.Martin Carli; Carolina Medina-Gomez; Dennis O. Mook-Kanamori; Andrew P. Morris; Renée de Mutsert; Matthias Nauck; Ivana Prokic; Craig E. Pennell; Arund D. Pradhan; Bruce M. Psaty; Olli T. Raitakari; Robert A. Scott; Tea Skaaby; Konstantin Strauch; Kent D. Taylor; Alexander Teumer; Andre G. Uitterlinden; Ying Wu; Jie Yao; Mark Walker; Kari E. North; Peter Kovacs; M. Arfan Ikram; Cornelia M. van Duijn; Paul M. Ridker; Stephen Lye; Georg Homuth; Erik Ingelsson; Tim D. Spector; Barbara McKnight; Michael A. Province; Terho Lehtimäki; Linda S. Adair; Jerome I. Rotter; Alexander P. Reiner; James G. Wilson; Tamara B. Harris; Samuli Ripatti; Harald Grallert; James B. Meigs; Veikko Salomaa; Torben Hansen; Ko Willems van Dijk; Nicholas J. Wareham; Struan F.A. Grant; Claudia Langenberg; Timothy M. Frayling; Cecilia M. Lindgren; Karen L. Mohlke; Rudolph L. Leibel; Ruth J.F. Loos; Tuomas O. Kilpeläinen

doi:10.2337/db20-0070

Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Hanieh Yaghootkar, Yiying Zhang, Cassandra N. Spracklen, Tugce Karaderi, Lam Opal Huang, Jonathan Bradfield, Claudia Schurmann, Rebecca S. Fine, Michael H. Preuss, Zoltan Kutalik, Laura B.L. Wittemans, Yingchang Lu, Sophia Metz, Sara M. Willems, Ruifang Li-Gao, Niels Grarup, Shuai Wang, Sophie Molnos, América A. Sandoval-Zárate, Mike A. NallsLeslie A. Lange, Jeffrey Haesser, Xiuqing Guo, Leo Pekka Lyytikäinen, Mary F. Feitosa, Colleen M. Sitlani, Cristina Venturini, Anubha Mahajan, Tim Kacprowski, Carol A. Wang, Daniel I. Chasman, Najaf Amin, Linda Broer, Neil Robertson, Kristin L. Young, Matthew Allison, Paul L. Auer, Matthias Blüher, Judith B. Borja, Jette Bork-Jensen, Germán D. Carrasquilla, Paraskevi Christofidou, Ayse Demirkan, Claudia A. Doege, Melissa E. Garcia, Mariaelisa Graff, Kaiying Guo, Hakon Hakonarson, Jaeyoung Hong, Yii Der Ida Chen, Rebecca Jackson, Hermina Jakupovic, Pekka Jousilahti, Anne E. Justice, Mika Kähönen, Jorge R. Kizer, Jennifer Kriebel, Charles A. Leduc, Jin Li, Lars Lind, Jian’An Luan, David A. Mackey, Massimo Mangino, Satu Männistö, Jayne F.Martin Carli, Carolina Medina-Gomez, Dennis O. Mook-Kanamori, Andrew P. Morris, Renée de Mutsert, Matthias Nauck, Ivana Prokic, Craig E. Pennell, Arund D. Pradhan, Bruce M. Psaty, Olli T. Raitakari, Robert A. Scott, Tea Skaaby, Konstantin Strauch, Kent D. Taylor, Alexander Teumer, Andre G. Uitterlinden, Ying Wu, Jie Yao, Mark Walker, Kari E. North, Peter Kovacs, M. Arfan Ikram, Cornelia M. van Duijn, Paul M. Ridker, Stephen Lye, Georg Homuth, Erik Ingelsson, Tim D. Spector, Barbara McKnight, Michael A. Province, Terho Lehtimäki, Linda S. Adair, Jerome I. Rotter, Alexander P. Reiner, James G. Wilson, Tamara B. Harris, Samuli Ripatti, Harald Grallert, James B. Meigs, Veikko Salomaa, Torben Hansen, Ko Willems van Dijk, Nicholas J. Wareham, Struan F.A. Grant, Claudia Langenberg, Timothy M. Frayling, Cecilia M. Lindgren, Karen L. Mohlke, Rudolph L. Leibel, Ruth J.F. Loos, Tuomas O. Kilpeläinen

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

7 Scopus citations

Abstract

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by admin-istering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concen-trations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10^-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

Original language	English
Pages (from-to)	2806-2818
Number of pages	13
Journal	Diabetes
Volume	69
Issue number	12
DOIs	https://doi.org/10.2337/db20-0070
State	Published - Dec 2020

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10.2337/db20-0070

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Yaghootkar, H., Zhang, Y., Spracklen, C. N., Karaderi, T., Huang, L. O., Bradfield, J., Schurmann, C., Fine, R. S., Preuss, M. H., Kutalik, Z., Wittemans, L. B. L., Lu, Y., Metz, S., Willems, S. M., Li-Gao, R., Grarup, N., Wang, S., Molnos, S., Sandoval-Zárate, A. A., ... Kilpeläinen, T. O. (2020). Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity. Diabetes, 69(12), 2806-2818. https://doi.org/10.2337/db20-0070

Yaghootkar, Hanieh ; Zhang, Yiying ; Spracklen, Cassandra N. ; Karaderi, Tugce ; Huang, Lam Opal ; Bradfield, Jonathan ; Schurmann, Claudia ; Fine, Rebecca S. ; Preuss, Michael H. ; Kutalik, Zoltan ; Wittemans, Laura B.L. ; Lu, Yingchang ; Metz, Sophia ; Willems, Sara M. ; Li-Gao, Ruifang ; Grarup, Niels ; Wang, Shuai ; Molnos, Sophie ; Sandoval-Zárate, América A. ; Nalls, Mike A. ; Lange, Leslie A. ; Haesser, Jeffrey ; Guo, Xiuqing ; Lyytikäinen, Leo Pekka ; Feitosa, Mary F. ; Sitlani, Colleen M. ; Venturini, Cristina ; Mahajan, Anubha ; Kacprowski, Tim ; Wang, Carol A. ; Chasman, Daniel I. ; Amin, Najaf ; Broer, Linda ; Robertson, Neil ; Young, Kristin L. ; Allison, Matthew ; Auer, Paul L. ; Blüher, Matthias ; Borja, Judith B. ; Bork-Jensen, Jette ; Carrasquilla, Germán D. ; Christofidou, Paraskevi ; Demirkan, Ayse ; Doege, Claudia A. ; Garcia, Melissa E. ; Graff, Mariaelisa ; Guo, Kaiying ; Hakonarson, Hakon ; Hong, Jaeyoung ; Chen, Yii Der Ida ; Jackson, Rebecca ; Jakupovic, Hermina ; Jousilahti, Pekka ; Justice, Anne E. ; Kähönen, Mika ; Kizer, Jorge R. ; Kriebel, Jennifer ; Leduc, Charles A. ; Li, Jin ; Lind, Lars ; Luan, Jian’An ; Mackey, David A. ; Mangino, Massimo ; Männistö, Satu ; Carli, Jayne F.Martin ; Medina-Gomez, Carolina ; Mook-Kanamori, Dennis O. ; Morris, Andrew P. ; de Mutsert, Renée ; Nauck, Matthias ; Prokic, Ivana ; Pennell, Craig E. ; Pradhan, Arund D. ; Psaty, Bruce M. ; Raitakari, Olli T. ; Scott, Robert A. ; Skaaby, Tea ; Strauch, Konstantin ; Taylor, Kent D. ; Teumer, Alexander ; Uitterlinden, Andre G. ; Wu, Ying ; Yao, Jie ; Walker, Mark ; North, Kari E. ; Kovacs, Peter ; Ikram, M. Arfan ; van Duijn, Cornelia M. ; Ridker, Paul M. ; Lye, Stephen ; Homuth, Georg ; Ingelsson, Erik ; Spector, Tim D. ; McKnight, Barbara ; Province, Michael A. ; Lehtimäki, Terho ; Adair, Linda S. ; Rotter, Jerome I. ; Reiner, Alexander P. ; Wilson, James G. ; Harris, Tamara B. ; Ripatti, Samuli ; Grallert, Harald ; Meigs, James B. ; Salomaa, Veikko ; Hansen, Torben ; van Dijk, Ko Willems ; Wareham, Nicholas J. ; Grant, Struan F.A. ; Langenberg, Claudia ; Frayling, Timothy M. ; Lindgren, Cecilia M. ; Mohlke, Karen L. ; Leibel, Rudolph L. ; Loos, Ruth J.F. ; Kilpeläinen, Tuomas O. / Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity. In: Diabetes. 2020 ; Vol. 69, No. 12. pp. 2806-2818.

@article{a64b2ba25265431695fc922a961df77a,

title = "Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity",

abstract = "Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by admin-istering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concen-trations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.",

author = "Hanieh Yaghootkar and Yiying Zhang and Spracklen, {Cassandra N.} and Tugce Karaderi and Huang, {Lam Opal} and Jonathan Bradfield and Claudia Schurmann and Fine, {Rebecca S.} and Preuss, {Michael H.} and Zoltan Kutalik and Wittemans, {Laura B.L.} and Yingchang Lu and Sophia Metz and Willems, {Sara M.} and Ruifang Li-Gao and Niels Grarup and Shuai Wang and Sophie Molnos and Sandoval-Z{\'a}rate, {Am{\'e}rica A.} and Nalls, {Mike A.} and Lange, {Leslie A.} and Jeffrey Haesser and Xiuqing Guo and Lyytik{\"a}inen, {Leo Pekka} and Feitosa, {Mary F.} and Sitlani, {Colleen M.} and Cristina Venturini and Anubha Mahajan and Tim Kacprowski and Wang, {Carol A.} and Chasman, {Daniel I.} and Najaf Amin and Linda Broer and Neil Robertson and Young, {Kristin L.} and Matthew Allison and Auer, {Paul L.} and Matthias Bl{\"u}her and Borja, {Judith B.} and Jette Bork-Jensen and Carrasquilla, {Germ{\'a}n D.} and Paraskevi Christofidou and Ayse Demirkan and Doege, {Claudia A.} and Garcia, {Melissa E.} and Mariaelisa Graff and Kaiying Guo and Hakon Hakonarson and Jaeyoung Hong and Chen, {Yii Der Ida} and Rebecca Jackson and Hermina Jakupovic and Pekka Jousilahti and Justice, {Anne E.} and Mika K{\"a}h{\"o}nen and Kizer, {Jorge R.} and Jennifer Kriebel and Leduc, {Charles A.} and Jin Li and Lars Lind and Jian{\textquoteright}An Luan and Mackey, {David A.} and Massimo Mangino and Satu M{\"a}nnist{\"o} and Carli, {Jayne F.Martin} and Carolina Medina-Gomez and Mook-Kanamori, {Dennis O.} and Morris, {Andrew P.} and {de Mutsert}, Ren{\'e}e and Matthias Nauck and Ivana Prokic and Pennell, {Craig E.} and Pradhan, {Arund D.} and Psaty, {Bruce M.} and Raitakari, {Olli T.} and Scott, {Robert A.} and Tea Skaaby and Konstantin Strauch and Taylor, {Kent D.} and Alexander Teumer and Uitterlinden, {Andre G.} and Ying Wu and Jie Yao and Mark Walker and North, {Kari E.} and Peter Kovacs and Ikram, {M. Arfan} and {van Duijn}, {Cornelia M.} and Ridker, {Paul M.} and Stephen Lye and Georg Homuth and Erik Ingelsson and Spector, {Tim D.} and Barbara McKnight and Province, {Michael A.} and Terho Lehtim{\"a}ki and Adair, {Linda S.} and Rotter, {Jerome I.} and Reiner, {Alexander P.} and Wilson, {James G.} and Harris, {Tamara B.} and Samuli Ripatti and Harald Grallert and Meigs, {James B.} and Veikko Salomaa and Torben Hansen and {van Dijk}, {Ko Willems} and Wareham, {Nicholas J.} and Grant, {Struan F.A.} and Claudia Langenberg and Frayling, {Timothy M.} and Lindgren, {Cecilia M.} and Mohlke, {Karen L.} and Leibel, {Rudolph L.} and Loos, {Ruth J.F.} and Kilpel{\"a}inen, {Tuomas O.}",

note = "Funding Information: The authors thank all investigators, study members, and study participants for their contributions to the participating studies. The acknowledgments for all participating studies are provided in the Supplementary Material. This research has been conducted using the UK Biobank resource and carried out under UK Biobank project 9072. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/ about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/ Summary-EGF-consultation.pdf?phpMyAdmin=trmKQlYdjjnQIgJ%2CfAzikMhEnx6. Funding and Duality of Interest. The funding information for all participating studies are provided in the Supplementary Material. 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 served on advisory boards for Novo Nordisk and Sanofi and received honoraria from these companies. V.S. also has ongoing research collaboration with Bayer Ltd. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.R.K. reports stock ownership in Bristol-Myers Squibb, Johnson & Johnson, Merck, and Pfizer. R.S.F. is currently an employee of Vertex Pharmaceut-icals Incorporated, though all work for this article was done prior to Vertex affiliation. This work was supported by NHGRI NIH F31HG009850. E.I. is now an employee of GlaxoSmithKline, but this work was done prior to joining the company. No other potential conflicts of interest relevant to this article were reported. The ongoing research by V.S. in collaboration with Bayer Ltd. is unrelated to the current study. Funding Information: Acknowledgments. The authors thank all investigators, study members, and study participants for their contributions to the participating studies. The acknowledgments for all participating studies are provided in the Supplementary Material. This research has been conducted using the UK Biobank resource and carried out under UK Biobank project 9072. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/ about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/ Summary-EGF-consultation.pdf?phpMyAdmin5trmKQlYdjjnQIgJ%2CfAzikMhEnx6. Funding and Duality of Interest. The funding information for all participating studies are provided in the Supplementary Material. 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 served on advisory boards for Novo Nordisk and Sanofi and received honoraria from these companies. V.S. also has ongoing research collaboration with Bayer Ltd. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.R.K. reports stock ownership in Bristol-Myers Squibb, Johnson & Johnson, Merck, and Pfizer. R.S.F. is currently an employee of Vertex Pharmaceuticals Incorporated, though all work for this article was done prior to Vertex affiliation. This work was supported by NHGRI NIH F31HG009850. E.I. is now an employee of GlaxoSmithKline, but this work was done prior to joining the company. No other potential conflicts of interest relevant to this article were reported. Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association.",

year = "2020",

month = dec,

doi = "10.2337/db20-0070",

language = "English",

volume = "69",

pages = "2806--2818",

journal = "Diabetes",

issn = "0012-1797",

number = "12",

}

Yaghootkar, H, Zhang, Y, Spracklen, CN, Karaderi, T, Huang, LO, Bradfield, J, Schurmann, C, Fine, RS, Preuss, MH, Kutalik, Z, Wittemans, LBL, Lu, Y, Metz, S, Willems, SM, Li-Gao, R, Grarup, N, Wang, S, Molnos, S, Sandoval-Zárate, AA, Nalls, MA, Lange, LA, Haesser, J, Guo, X, Lyytikäinen, LP, Feitosa, MF, Sitlani, CM, Venturini, C, Mahajan, A, Kacprowski, T, Wang, CA, Chasman, DI, Amin, N, Broer, L, Robertson, N, Young, KL, Allison, M, Auer, PL, Blüher, M, Borja, JB, Bork-Jensen, J, Carrasquilla, GD, Christofidou, P, Demirkan, A, Doege, CA, Garcia, ME, Graff, M, Guo, K, Hakonarson, H, Hong, J, Chen, YDI, Jackson, R, Jakupovic, H, Jousilahti, P, Justice, AE, Kähönen, M, Kizer, JR, Kriebel, J, Leduc, CA, Li, J, Lind, L, Luan, JA, Mackey, DA, Mangino, M, Männistö, S, Carli, JFM, Medina-Gomez, C, Mook-Kanamori, DO, Morris, AP, de Mutsert, R, Nauck, M, Prokic, I, Pennell, CE, Pradhan, AD, Psaty, BM, Raitakari, OT, Scott, RA, Skaaby, T, Strauch, K, Taylor, KD, Teumer, A, Uitterlinden, AG, Wu, Y, Yao, J, Walker, M, North, KE, Kovacs, P, Ikram, MA, van Duijn, CM, Ridker, PM, Lye, S, Homuth, G, Ingelsson, E, Spector, TD, McKnight, B, Province, MA, Lehtimäki, T, Adair, LS, Rotter, JI, Reiner, AP, Wilson, JG, Harris, TB, Ripatti, S, Grallert, H, Meigs, JB, Salomaa, V, Hansen, T, van Dijk, KW, Wareham, NJ, Grant, SFA, Langenberg, C, Frayling, TM, Lindgren, CM, Mohlke, KL, Leibel, RL, Loos, RJF & Kilpeläinen, TO 2020, 'Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity', Diabetes, vol. 69, no. 12, pp. 2806-2818. https://doi.org/10.2337/db20-0070

Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity. / Yaghootkar, Hanieh; Zhang, Yiying; Spracklen, Cassandra N.; Karaderi, Tugce; Huang, Lam Opal; Bradfield, Jonathan; Schurmann, Claudia; Fine, Rebecca S.; Preuss, Michael H.; Kutalik, Zoltan; Wittemans, Laura B.L.; Lu, Yingchang; Metz, Sophia; Willems, Sara M.; Li-Gao, Ruifang; Grarup, Niels; Wang, Shuai; Molnos, Sophie; Sandoval-Zárate, América A.; Nalls, Mike A.; Lange, Leslie A.; Haesser, Jeffrey; Guo, Xiuqing; Lyytikäinen, Leo Pekka; Feitosa, Mary F.; Sitlani, Colleen M.; Venturini, Cristina; Mahajan, Anubha; Kacprowski, Tim; Wang, Carol A.; Chasman, Daniel I.; Amin, Najaf; Broer, Linda; Robertson, Neil; Young, Kristin L.; Allison, Matthew; Auer, Paul L.; Blüher, Matthias; Borja, Judith B.; Bork-Jensen, Jette; Carrasquilla, Germán D.; Christofidou, Paraskevi; Demirkan, Ayse; Doege, Claudia A.; Garcia, Melissa E.; Graff, Mariaelisa; Guo, Kaiying; Hakonarson, Hakon; Hong, Jaeyoung; Chen, Yii Der Ida; Jackson, Rebecca; Jakupovic, Hermina; Jousilahti, Pekka; Justice, Anne E.; Kähönen, Mika; Kizer, Jorge R.; Kriebel, Jennifer; Leduc, Charles A.; Li, Jin; Lind, Lars; Luan, Jian’An; Mackey, David A.; Mangino, Massimo; Männistö, Satu; Carli, Jayne F.Martin; Medina-Gomez, Carolina; Mook-Kanamori, Dennis O.; Morris, Andrew P.; de Mutsert, Renée; Nauck, Matthias; Prokic, Ivana; Pennell, Craig E.; Pradhan, Arund D.; Psaty, Bruce M.; Raitakari, Olli T.; Scott, Robert A.; Skaaby, Tea; Strauch, Konstantin; Taylor, Kent D.; Teumer, Alexander; Uitterlinden, Andre G.; Wu, Ying; Yao, Jie; Walker, Mark; North, Kari E.; Kovacs, Peter; Ikram, M. Arfan; van Duijn, Cornelia M.; Ridker, Paul M.; Lye, Stephen; Homuth, Georg; Ingelsson, Erik; Spector, Tim D.; McKnight, Barbara; Province, Michael A.; Lehtimäki, Terho; Adair, Linda S.; Rotter, Jerome I.; Reiner, Alexander P.; Wilson, James G.; Harris, Tamara B.; Ripatti, Samuli; Grallert, Harald; Meigs, James B.; Salomaa, Veikko; Hansen, Torben; van Dijk, Ko Willems; Wareham, Nicholas J.; Grant, Struan F.A.; Langenberg, Claudia; Frayling, Timothy M.; Lindgren, Cecilia M.; Mohlke, Karen L.; Leibel, Rudolph L.; Loos, Ruth J.F.; Kilpeläinen, Tuomas O.

In: Diabetes, Vol. 69, No. 12, 12.2020, p. 2806-2818.

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

TY - JOUR

T1 - Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

AU - Yaghootkar, Hanieh

AU - Zhang, Yiying

AU - Spracklen, Cassandra N.

AU - Karaderi, Tugce

AU - Huang, Lam Opal

AU - Bradfield, Jonathan

AU - Schurmann, Claudia

AU - Fine, Rebecca S.

AU - Preuss, Michael H.

AU - Kutalik, Zoltan

AU - Wittemans, Laura B.L.

AU - Lu, Yingchang

AU - Metz, Sophia

AU - Willems, Sara M.

AU - Li-Gao, Ruifang

AU - Grarup, Niels

AU - Wang, Shuai

AU - Molnos, Sophie

AU - Sandoval-Zárate, América A.

AU - Nalls, Mike A.

AU - Lange, Leslie A.

AU - Haesser, Jeffrey

AU - Guo, Xiuqing

AU - Lyytikäinen, Leo Pekka

AU - Feitosa, Mary F.

AU - Sitlani, Colleen M.

AU - Venturini, Cristina

AU - Mahajan, Anubha

AU - Kacprowski, Tim

AU - Wang, Carol A.

AU - Chasman, Daniel I.

AU - Amin, Najaf

AU - Broer, Linda

AU - Robertson, Neil

AU - Young, Kristin L.

AU - Allison, Matthew

AU - Auer, Paul L.

AU - Blüher, Matthias

AU - Borja, Judith B.

AU - Bork-Jensen, Jette

AU - Carrasquilla, Germán D.

AU - Christofidou, Paraskevi

AU - Demirkan, Ayse

AU - Doege, Claudia A.

AU - Garcia, Melissa E.

AU - Graff, Mariaelisa

AU - Guo, Kaiying

AU - Hakonarson, Hakon

AU - Hong, Jaeyoung

AU - Chen, Yii Der Ida

AU - Jackson, Rebecca

AU - Jakupovic, Hermina

AU - Jousilahti, Pekka

AU - Justice, Anne E.

AU - Kähönen, Mika

AU - Kizer, Jorge R.

AU - Kriebel, Jennifer

AU - Leduc, Charles A.

AU - Li, Jin

AU - Lind, Lars

AU - Luan, Jian’An

AU - Mackey, David A.

AU - Mangino, Massimo

AU - Männistö, Satu

AU - Carli, Jayne F.Martin

AU - Medina-Gomez, Carolina

AU - Mook-Kanamori, Dennis O.

AU - Morris, Andrew P.

AU - de Mutsert, Renée

AU - Nauck, Matthias

AU - Prokic, Ivana

AU - Pennell, Craig E.

AU - Pradhan, Arund D.

AU - Psaty, Bruce M.

AU - Raitakari, Olli T.

AU - Scott, Robert A.

AU - Skaaby, Tea

AU - Strauch, Konstantin

AU - Taylor, Kent D.

AU - Teumer, Alexander

AU - Uitterlinden, Andre G.

AU - Wu, Ying

AU - Yao, Jie

AU - Walker, Mark

AU - North, Kari E.

AU - Kovacs, Peter

AU - Ikram, M. Arfan

AU - van Duijn, Cornelia M.

AU - Ridker, Paul M.

AU - Lye, Stephen

AU - Homuth, Georg

AU - Ingelsson, Erik

AU - Spector, Tim D.

AU - McKnight, Barbara

AU - Province, Michael A.

AU - Lehtimäki, Terho

AU - Adair, Linda S.

AU - Rotter, Jerome I.

AU - Reiner, Alexander P.

AU - Wilson, James G.

AU - Harris, Tamara B.

AU - Ripatti, Samuli

AU - Grallert, Harald

AU - Meigs, James B.

AU - Salomaa, Veikko

AU - Hansen, Torben

AU - van Dijk, Ko Willems

AU - Wareham, Nicholas J.

AU - Grant, Struan F.A.

AU - Langenberg, Claudia

AU - Frayling, Timothy M.

AU - Lindgren, Cecilia M.

AU - Mohlke, Karen L.

AU - Leibel, Rudolph L.

AU - Loos, Ruth J.F.

AU - Kilpeläinen, Tuomas O.

N1 - Funding Information: The authors thank all investigators, study members, and study participants for their contributions to the participating studies. The acknowledgments for all participating studies are provided in the Supplementary Material. This research has been conducted using the UK Biobank resource and carried out under UK Biobank project 9072. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/ about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/ Summary-EGF-consultation.pdf?phpMyAdmin=trmKQlYdjjnQIgJ%2CfAzikMhEnx6. Funding and Duality of Interest. The funding information for all participating studies are provided in the Supplementary Material. 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 served on advisory boards for Novo Nordisk and Sanofi and received honoraria from these companies. V.S. also has ongoing research collaboration with Bayer Ltd. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.R.K. reports stock ownership in Bristol-Myers Squibb, Johnson & Johnson, Merck, and Pfizer. R.S.F. is currently an employee of Vertex Pharmaceut-icals Incorporated, though all work for this article was done prior to Vertex affiliation. This work was supported by NHGRI NIH F31HG009850. E.I. is now an employee of GlaxoSmithKline, but this work was done prior to joining the company. No other potential conflicts of interest relevant to this article were reported. The ongoing research by V.S. in collaboration with Bayer Ltd. is unrelated to the current study. Funding Information: Acknowledgments. The authors thank all investigators, study members, and study participants for their contributions to the participating studies. The acknowledgments for all participating studies are provided in the Supplementary Material. This research has been conducted using the UK Biobank resource and carried out under UK Biobank project 9072. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/ about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/ Summary-EGF-consultation.pdf?phpMyAdmin5trmKQlYdjjnQIgJ%2CfAzikMhEnx6. Funding and Duality of Interest. The funding information for all participating studies are provided in the Supplementary Material. 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 served on advisory boards for Novo Nordisk and Sanofi and received honoraria from these companies. V.S. also has ongoing research collaboration with Bayer Ltd. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.R.K. reports stock ownership in Bristol-Myers Squibb, Johnson & Johnson, Merck, and Pfizer. R.S.F. is currently an employee of Vertex Pharmaceuticals Incorporated, though all work for this article was done prior to Vertex affiliation. This work was supported by NHGRI NIH F31HG009850. E.I. is now an employee of GlaxoSmithKline, but this work was done prior to joining the company. No other potential conflicts of interest relevant to this article were reported. Publisher Copyright: © 2020 by the American Diabetes Association.

PY - 2020/12

Y1 - 2020/12

N2 - Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by admin-istering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concen-trations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

AB - Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by admin-istering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concen-trations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

UR - http://www.scopus.com/inward/record.url?scp=85096618864&partnerID=8YFLogxK

U2 - 10.2337/db20-0070

DO - 10.2337/db20-0070

M3 - Article

C2 - 32917775

AN - SCOPUS:85096618864

VL - 69

SP - 2806

EP - 2818

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 12

ER -

Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

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