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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
Luleå University of Technology, Department of Health Sciences, Medical Science. Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, U.K.; Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K..ORCID iD: 0000-0001-9672-9477
Division of Molecular Genetics, Department of PediatriQuantinuum Research LLC, San Diego, CAcs, Columbia University, New York, NY, U.S..
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, U.S.; Department of Biostatistics and Epidemiology, University of Massachusetts-Amherst, Amherst, MA, U.S..
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.; Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; DTU Health Technology, Technical University of Denmark, Lyngby, Denmark.
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2020 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 69, no 12, p. 2806-2818Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Diabetes Association , 2020. Vol. 69, no 12, p. 2806-2818
National Category
Medical Genetics and Genomics
Research subject
Medical Engineering
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URN: urn:nbn:se:ltu:diva-82754DOI: 10.2337/db20-0070ISI: 000594819600025PubMedID: 32917775Scopus ID: 2-s2.0-85096618864OAI: oai:DiVA.org:ltu-82754DiVA, id: diva2:1524933
Note

Godkänd;2021;Nivå 0;2021-02-02 (alebob);

Finansiär: Data Tecnica International, United States Department of Health & Human Services (F31HG009850), National Institutes of Health, National Institute on Aging, Johnson & Johnson USA, National Human Genome Research Institute 

Available from: 2021-02-02 Created: 2021-02-02 Last updated: 2025-03-31Bibliographically approved

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Yaghootkar, Hanieh

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