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Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Lookup NU author(s): Professor Mark Walker, Dr Georg Homuth

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Abstract

© 2020 by the American Diabetes Association.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.

Publication metadata

Author(s): Yaghootkar H, Zhang Y, Spracklen CN, Karaderi T, Huang LO, Bradfield J, Schurmann C, Fine RS, Preuss MH, Kutalik Z, Wittemans LBL, Lu Y, Metz S, Willems SM, Li-Gao R, Grarup N, Wang S, Molnos S, Sandoval-Zarate AA, Nalls MA, Lange LA, Haesser J, Guo X, Lyytikainen L-P, Feitosa MF, Sitlani CM, Venturini C, Mahajan A, Kacprowski T, Wang CA, Chasman DI, Amin N, Broer L, Robertson N, Young KL, Allison M, Auer PL, Bluher M, Borja JB, Bork-Jensen J, Carrasquilla GD, Christofidou P, Demirkan A, Doege CA, Garcia ME, Graff M, Guo K, Hakonarson H, Hong J, Chen Y-DI, Jackson R, Jakupovic H, Jousilahti P, Justice AE, Kahonen M, Kizer JR, Kriebel J, Leduc CA, Li J, Lind L, Luan J, Mackey DA, Mangino M, Mannisto S, Carli JFM, Medina-Gomez C, Mook-Kanamori DO, Morris AP, de Mutsert R, Nauck M, Prokic I, Pennell CE, Pradhan AD, Psaty BM, Raitakari OT, Scott RA, Skaaby T, Strauch K, Taylor KD, Teumer A, Uitterlinden AG, Wu Y, Yao J, Walker M, North KE, Kovacs P, Ikram MA, van Duijn CM, Ridker PM, Lye S, Homuth G, Ingelsson E, Spector TD, McKnight B, Province MA, Lehtimaki T, Adair LS, Rotter JI, Reiner AP, Wilson JG, Harris TB, Ripatti S, Grallert H, Meigs JB, Salomaa V, Hansen T, van Dijk KW, Wareham NJ, Grant SFA, Langenberg C, Frayling TM, Lindgren CM, Mohlke KL, Leibel RL, Loos RJF, Kilpelainen TO

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2020

Volume: 69

Issue: 12

Pages: 2806-2818

Print publication date: 01/12/2020

Online publication date: 11/09/2020

Acceptance date: 09/09/2020

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association Inc.

URL: https://doi.org/10.2337/db20-0070

DOI: 10.2337/db20-0070

PubMed id: 32917775

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