Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity
Authors: Admin Ada , 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 , Blüher Matthias , Borja Judith B , Bork-Jensen Jette , Carrasquilla Germán D , Christofidou Paraskevi , Demirkan Ayse , Doege Claudia A , Garcia Melissa E , Graff Mariaelisa , Guo Kaiying , Hakonarson Hakon , Hong Jaeyoung , Chen Yii-Der Ida , Jackson Rebecca , Jakupović Hermina , Jousilahti Pekka , Justice Anne E , Kähönen Mika , Kizer Jorge R , Kriebe Jennifer , LeDuc Charles A , Li Jin , Lind Lars , Luan Jian’an , Mackey David , Mangino Massimo , Männistö Satu , Carli Jayne F Martin , Medina-Gomez Carolina , Mook-Kanamori Dennis O , Morris Andrew P , Mutsert Renée de , Nauck Matthias , Nedeljkovic Ivana , Pennell Craig E , Pradhan Arund D , Psaty Bruce M , Raitakari Olli T , Scott Robert A , Skaaby Tea , Strauch Konstantin , Taylor Kent D , Teumer Alexander , Uitterlinden Andre G , Wu Ying , Yao Jie , Walker Mark , North Kari E , Kovacs Peter , Ikram M. Arfan , Duijn Cornelia M van , Ridker Paul M , Lye Stephen , Homuth Georg , Ingelsson Erik , Spector Tim D , McKnight Barbara , Province Michael A , Lehtimäki Terho , Adair Linda S , Rotter Jerome I , Reiner Alexander P , Wilson James G , Harris Tamara B , Ripatti Samuli , Grallert Harald , Meigs James B , Salomaa Veikko , Hansen Torben , Dijk Ko Willems van , Wareham Nicholas J , Grant Struan FA , Langenberg Claudia , Frayling Timothy M , Lindgren Cecilia M , Mohlke Karen L , Leibel Rudolph L , Loos Ruth JF , Kilpeläinen Tuomas O 
Published: September 2020

Leptin influences food intake by
informing the brain about the status of body fat stores. Rare <i>LEP</i> 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 <i>LEP, ZNF800, KLHL31</i>, and <i>ACTL9</i>, and one intergenic
variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African
ancestry only and its association with lower leptin concentrations was specific
to this ancestry (P=2x10<sup>-16</sup>, n=3,901). Using <i>in vitro</i> 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.