Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
Authors: 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 , Ida Chen Yii-Der , Jackson Rebecca , 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 , 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 , Willems van Dijk Ko , 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. 
Published: September 2020

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 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.