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 | |
State | Published - Dec 2020 |
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Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity. / Yaghootkar, Hanieh; Zhang, Yiying; Spracklen, Cassandra N. et al.
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 -