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Yaghootkar, H.* ; Zhang, Y.* ; Spracklen, C.N.* ; Karaderi, T.* ; Huang, L.O.* ; Bradfield, J.P.* ; Schurmann, C.* ; Fine, R.S.* ; Preuss, M.H.* ; Kutalik, Z.* ; Wittemans, L.B.L.* ; Lu, Y.* ; Metz, S.* ; Willems, S.M.* ; Li-Gao, R.* ; Grarup, N.* ; Wang, S.* ; Molnos, S. ; Sandoval-Zárate, A.A.* ; Nalls, M.A.* ; Lange, L.A.* ; Haesser, J.* ; Guo, X.* ; Lyytikäinen, L.P.* ; Feitosa, M.F.* ; Sitlani, C.M.* ; Venturini, C.* ; Mahajan, A.* ; Kacprowski, T.* ; Wang, C.A.* ; Chasman, D.I.* ; Amin, N.* ; Broer, L.* ; Robertson, N.* ; Young, K.L.* ; Allison, M.* ; Auer, P.L.* ; Blüher, M.* ; Borja, J.B.* ; Bork-Jensen, J.* ; Carrasquilla, G.D.* ; Christofidou, P.* ; Demirkan, A.* ; Doege, C.A.* ; Garcia, M.E.* ; Graff, M.* ; Guo, K.* ; Hakonarson, H.* ; Hong, J.* ; Chen, Y.D.I.* ; Jackson, R.* ; Jakupović, H.* ; Jousilahti, P.* ; Justice, A.E.* ; Kähönen, M.* ; Kizer, J.R.* ; Kriebel, J. ; LeDuc, C.A.* ; Li, J.* ; Lind, L.* ; Luan, J.* ; Mackey, D.A.* ; Mangino, M.* ; Männistö, S.* ; Carli, J.F.M.* ; Medina-Gomez, C.* ; Mook-Kanamori, D.O.* ; Morris, A.P.* ; de Mutsert, R.* ; Nauck, M.* ; Prokic, I.* ; Pennell, C.E.* ; Pradhan, A.D.* ; Psaty, B.M.* ; Raitakari, O.T.* ; Scott, R.A.* ; Skaaby, T.* ; Strauch, K. ; Taylor, K.D.* ; Teumer, A.* ; Uitterlinden, A.G.* ; Wu, Y.* ; Yao, J.* ; Walker, M.* ; North, K.E.* ; Kovacs, P.* ; Ikram, M.A.* ; van Duijn, C.M.* ; Ridker, P.M.* ; Lye, S.J.* ; Homuth, G.* ; Ingelsson, E.* ; Spector, T.D.* ; McKnight, B.* ; Province, M.A.* ; Lehtimäki, T.* ; Adair, L.S.* ; Rotter, J.I.* ; Reiner, A.P.* ; Wilson, J.G.* ; Harris, T.B.* ; Ripatti, S* ; Grallert, H. ; Meigs, J.B* ; Salomaa, V.* ; Hansen, T.* ; van Dijk, K.W.* ; Wareham, N.J.* ; Grant, S.F.A.* ; Langenberg, C.* ; Frayling, T.M.* ; Lindgren, C.M.* ; Mohlke, K.L.* ; Leibel, R.L.* ; Loos, R.J.F.* ; Kilpeläinen, T.O.*

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

Diabetes 69, 2806-2818 (2020)
Verlagsversion Postprint DOI PMC
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Genome-wide Association; Plasma Leptin; Obesity; Loci; Rare; Variants; Metaanalysis; Expenditure; Homeostasis; Deficiency
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Zeitschrift Diabetes
Quellenangaben Band: 69, Heft: 12, Seiten: 2806-2818 Artikelnummer: , Supplement: ,
Verlag American Diabetes Association
Verlagsort Alexandria, VA.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Förderungen NHGRI NIH
Johnson Johnson
National Institute on Aging, National Institutes of Health
Data Tecnica International