{"doi":"10.2337/figshare.12933737.v1","title":"Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity","abstract":"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.","journal":null,"year":2020,"id":133669,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":324189,"name":"Hanieh Yaghootkar","orcid":"0000-0001-9672-9477","position":1,"is_corresponding":false},{"id":324190,"name":"Yiying Zhang","orcid":"0000-0002-0366-0165","position":2,"is_corresponding":false},{"id":108737,"name":"Cassandra N. 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