| Literature DB >> 32917775 |
Hanieh Yaghootkar1,2,3, Yiying Zhang4, Cassandra N Spracklen5,6, Tugce Karaderi7,8,9,10, Lam Opal Huang11, Jonathan Bradfield12,13, Claudia Schurmann14, Rebecca S Fine15,16,17, Michael H Preuss14, Zoltan Kutalik18,19,20, Laura B L Wittemans7,21, Yingchang Lu14,22, Sophia Metz11, Sara M Willems21, Ruifang Li-Gao23, Niels Grarup11, Shuai Wang24, Sophie Molnos25,26, América A Sandoval-Zárate27, Mike A Nalls28,29, Leslie A Lange30, Jeffrey Haesser31, Xiuqing Guo32, Leo-Pekka Lyytikäinen33,34, Mary F Feitosa35, Colleen M Sitlani36, Cristina Venturini37, Anubha Mahajan7,38, Tim Kacprowski39,40, Carol A Wang24, Daniel I Chasman41,42, Najaf Amin43, Linda Broer44, Neil Robertson7,38, Kristin L Young45, Matthew Allison46, Paul L Auer47, Matthias Blüher48, Judith B Borja49,50, Jette Bork-Jensen11, Germán D Carrasquilla11, Paraskevi Christofidou37, Ayse Demirkan43, Claudia A Doege51, Melissa E Garcia52, Mariaelisa Graff45,53, Kaiying Guo4, Hakon Hakonarson12,54, Jaeyoung Hong24, Yii-Der Ida Chen32, Rebecca Jackson55, Hermina Jakupović11, Pekka Jousilahti56, Anne E Justice57, Mika Kähönen58,59, Jorge R Kizer60,61, Jennifer Kriebel25,26, Charles A LeDuc4, Jin Li62, Lars Lind63, Jian'an Luan21, David A Mackey64, Massimo Mangino37,65, Satu Männistö56, Jayne F Martin Carli4, Carolina Medina-Gomez43,44, Dennis O Mook-Kanamori23,66, Andrew P Morris7,67,68, Renée de Mutsert23, Matthias Nauck40,69, Ivana Prokic43, Craig E Pennell24, Arund D Pradhan41,42, Bruce M Psaty70,71, Olli T Raitakari72,73,74, Robert A Scott21, Tea Skaaby75, Konstantin Strauch76,77, Kent D Taylor32, Alexander Teumer40,78, Andre G Uitterlinden43,44, Ying Wu5, Jie Yao32, Mark Walker79, Kari E North45, Peter Kovacs48, M Arfan Ikram43,44, Cornelia M van Duijn43, Paul M Ridker41,42, Stephen Lye80, Georg Homuth39, Erik Ingelsson62,81,82,83, Tim D Spector37, Barbara McKnight84, Michael A Province35, Terho Lehtimäki33,34, Linda S Adair85, Jerome I Rotter32, Alexander P Reiner31, James G Wilson86, Tamara B Harris87, Samuli Ripatti17,27,88, Harald Grallert25,26, James B Meigs89,90,91, Veikko Salomaa56, Torben Hansen11, Ko Willems van Dijk92,93,94, Nicholas J Wareham21, Struan F A Grant12,54,95,96,97, Claudia Langenberg21, Timothy M Frayling18, Cecilia M Lindgren7,17,98, Karen L Mohlke5, Rudolph L Leibel4, Ruth J F Loos14,99, Tuomas O Kilpeläinen100,101.
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.Entities:
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Year: 2020 PMID： 32917775 PMCID： PMC7679778 DOI： 10.2337/db20-0070
Source DB: PubMed Journal: Diabetes ISSN： 0012-1797 Impact factor: 9.461