Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

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Citation

Yaghootkar, Hanieh; Zhang, Yiying; Spracklen, Cassandra N.; Karaderi, Tugce; Huang, Lam Opal; Bradfield, Jonathan P.; Schurmann, Claudia; Fine, Rebecca S.; Preuss, Michael H.; & Kutalik, Zoltan, et al. (2020). Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. Diabetes, 69(12), 2806-2818. PMCID: PMC7679778

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 administering 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 concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF (14) 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=2x10(-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 leptin regulates early adiposity.

URL

http://dx.doi.org/10.2337/db20-0070

Reference Type

Journal Article

Year Published

2020

Journal Title

Diabetes

Author(s)

Yaghootkar, Hanieh
Zhang, Yiying
Spracklen, Cassandra N.
Karaderi, Tugce
Huang, Lam Opal
Bradfield, Jonathan P.
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.
Haessler, 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 R.
Young, Kristin L.
Allison, Matthew A.
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
Ida Chen, Yii-Der
Jackson, Rebecca D.
Jakupović, 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
Martin Carli, Jayne F.
Medina-Gomez, Carolina
Mook-Kanamori, Dennis O.
Morris, Andrew P.
de Mutsert, Renée
Nauck, Matthias
Nedeljkovic, 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 J.
Homuth, Georg
Ingelsson, Erik
Spector, Timothy 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
Willems van Dijk, Ko
Wareham, Nicholas J.
Grant, Struan Fa
Langenberg, Claudia
Frayling, Timothy M.
Lindgren, Cecilia M.
Mohlke, Karen L.
Leibel, Rudolph L.
Loos, Ruth J. F.
Kilpeläinen, Tuomas O.

Article Type

Regular

PMCID

PMC7679778

Continent/Country

Nonspecific

Race/Ethnicity

African Ancestry
European Ancestry
East Asian Ancestry
Hispanic Ancestry

ORCiD

Adair - 0000-0002-3670-8073
Graff - 0000-0001-6380-1735