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 P. Bradfield, Claudia Schurmann, Rebecca S. Fine, Michael Preuß, Zoltán 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, Ayşe Demirkan, Claudia A. Doege, Melissa E. Garcia, Mariaelisa Graff, Kaiying Guo, Håkon Håkonarson, Jaeyoung Hong, Yii-Der Ida Chen, Rebecca D. Jackson, Hermina Jakupović, 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‐Gómez, Dennis O. Mook‐Kanamori, Andrew P. Morris, Renée de Mutsert, Matthias Nauck, Ivana Nedeljković, Craig E. Pennell, Arund D. Pradhan, Bruce M. Psaty, Olli T. Raitakari, Robert A. Scott, Tea Skaaby, Konstantin Strauch, Kent D. Taylor, Alexander Teumer, André G. Uitterlinden, Ying Wu, Jie Yao, Mark Walker, Kari E. North, Péter Kovács, M. Arfan Ikram, Cornelia M. van Duijn, Paul M. Ridker, Stephen J. Lye, Georg Homuth, Erik Ingelsson, Tim D. Spector, Barbara McKnight, Michael A. Province, Terho Lehtimäki, Linda S. Adair, Jerome I. Rotter, Alex P. Reiner, James G. Wilson
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 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.