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 concentrations 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 confirmed five previously established and identified five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The novel missense Val94Met (rs17151919) variant in LEP was common in individuals with African ancestry ( minor allele frequency ( MAF) AFR=8%; MAFEUR=0.02%) and was associated with 0.34 standard deviations lower leptin concentrations per Met94 allele in adults (P=2x10-16, n=3,901). Using in vitro analyses, we showed that the Met94 allele decreases leptin secretion (P=0.025). The Met94 allele was associated with higher BMI in young African-ancestry children (P=0.002, n=2,030) but not in adults, suggesting leptin regulates early adiposity.
Yaghootkar, Hanieh and Zhang, Yiying and Spracklen, Cassandra N. and Karaderi, Tugce and Huang, Lam Opal and Bradfield, Jonathan and Schurmann, Claudia and Fine, Rebecca S. and Preuss, Michael H. and Kutalik, Zoltan and Wittemans, Laura BL and Lu, Yingchang and Metz, Sophia and Willems, Sara M. and Li-Gao, Ruifang and Grarup, Niels and Wang, Shuai and Molnos, Sophie and Sandoval-Zárate, América A. and Nalls, Mike A. and Lange, Leslie A. and Haesser, Jeffrey and Guo, Xiuqing and Lyytikäinen, Leo-Pekka and Feitosa, Mary F. and Sitlani, Colleen M. and Venturini, Cristina and Mahajan, Anubha and Kacprowski, Tim and Wang, Carol A. and Chasman, Daniel I. and Amin, Najaf and Broer, Linda and Robertson, Neil and Young, Kristin L. and Allison, Matthew and Auer, Paul L. and Blüher, Matthias and Borja, Judith B. and Bork-Jensen, Jette and Carrasquilla, Germán D. and Christofidou, Paraskevi and Demirkan, Ayse and Doege, Claudia A. and Garcia, Melissa E. and Graff, Mariaelisa and Guo, Kaiying and Hakonarson, Hakon and Hong, Jaeyoung and Chen, Yii-Der Ida and Jackson, Rebecca and Jakupović, Hermina and Jousilahti, Pekka and Justice, Anne E. and Kähönen, Mika and Kizer, Jorge R. and Kriebel, Jennifer and LeDuc, Charles A. and Li, Jin and Lind, Lars and Luan, Jian’an and Mackey, David and Mangino, Massimo and Männistö, Satu and Martin Carli, Jayne F. and Medina-Gomez, Carolina and Mook-Kanamori, Dennis O. and Morris, Andrew P. and de Mutsert, Renée and Nauck, Matthias and Nedeljkovic, Ivana and Pennell, Craig E. and Pradhan, Arund D. and Psaty, Bruce M. and Raitakari, Olli T. and Scott, Robert A. and Skaaby, Tea and Strauch, Konstantin and Taylor, Kent D. and Teumer, Alexander and Uitterlinden, Andre G. and Wu, Ying and Yao, Jie and Walker, Mark and North, Kari E. and Kovacs, Peter and Ikram, M. Arfan and van Duijn, Cornelia M. and Ridker, Paul M. and Lye, Stephen and Homuth, Georg and Ingelsson, Erik and Spector, Timothy D. and McKnight, Barbara and Province, Michael A. and Lehtimäki, Terho and Adair, Linda and Rotter, Jerome I. and Reiner, Alexander P. and Wilson, James G. and Harris, Tamara and Ripatti, Samuli and Grallert, Harald and Meigs, James B. and Salomaa, Veikko and Hansen, Torben and van Dijk, Ko Willems and Wareham, Nicholas J. and Grant, Struan FA and Langenberg, Claudia and Frayling, Timothy M. and Lindgren, Cecilia M. and Mohlke, Karen L. and Leibel, Rudolph L. and Loos, Ruth JF and Kilpeläinen, Tuomas O., Coding Variant In
Associated with Lower Leptin Concentrations Implicates Leptin in the Regulation of Early Adiposity (October 8, 2019). Available at SSRN: https://ssrn.com/abstract=3466334