Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. / 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 Bl; 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; Jakupovic, Hermina; Li, Jin; Lind, Lars; Kovacs, Peter; Hansen, Torben; Loos, Ruth JF; Kilpeläinen, Tuomas O; Leptin Exomechip Collaboration.
In: Diabetes, Vol. 69, No. 11, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
AU - Yaghootkar, Hanieh
AU - Zhang, Yiying
AU - Spracklen, Cassandra N
AU - Karaderi, Tugce
AU - Huang, Lam Opal
AU - Bradfield, Jonathan
AU - Schurmann, Claudia
AU - Fine, Rebecca S
AU - Preuss, Michael H
AU - Kutalik, Zoltan
AU - Wittemans, Laura Bl
AU - Lu, Yingchang
AU - Metz, Sophia
AU - Willems, Sara M
AU - Li-Gao, Ruifang
AU - Grarup, Niels
AU - Wang, Shuai
AU - Molnos, Sophie
AU - Sandoval-Zárate, América A
AU - Nalls, Mike A
AU - Lange, Leslie A
AU - Haesser, Jeffrey
AU - Guo, Xiuqing
AU - Lyytikäinen, Leo-Pekka
AU - Feitosa, Mary F
AU - Sitlani, Colleen M
AU - Venturini, Cristina
AU - Mahajan, Anubha
AU - Kacprowski, Tim
AU - Wang, Carol A
AU - Chasman, Daniel I
AU - Amin, Najaf
AU - Broer, Linda
AU - Robertson, Neil
AU - Young, Kristin L
AU - Allison, Matthew
AU - Auer, Paul L
AU - Blüher, Matthias
AU - Borja, Judith B
AU - Bork-Jensen, Jette
AU - Carrasquilla, Germán D
AU - Christofidou, Paraskevi
AU - Demirkan, Ayse
AU - Doege, Claudia A
AU - Jakupovic, Hermina
AU - Li, Jin
AU - Lind, Lars
AU - Kovacs, Peter
AU - Hansen, Torben
AU - Loos, Ruth JF
AU - Kilpeläinen, Tuomas O
AU - Leptin Exomechip Collaboration
PY - 2020
Y1 - 2020
N2 - 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=2x10-16, 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 leptin regulates early adiposity.
AB - 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=2x10-16, 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 leptin regulates early adiposity.
U2 - 10.2337/db20-0070
DO - 10.2337/db20-0070
M3 - Journal article
C2 - 32917775
VL - 69
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 11
ER -
ID: 248649629