Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.
Hanieh YaghootkarYiying ZhangCassandra N SpracklenTugce KaraderiLam Opal HuangJonathan BradfieldClaudia SchurmannRebecca S FineMichael H PreussZoltan KutalikLaura B L WittemansYingchang LuSophia MetzSara M WillemsRuifang Li-GaoNiels GrarupShuai WangSophie MolnosAmérica A Sandoval-ZárateMike A NallsLeslie A LangeJeffrey HaesserXiuqing GuoLeo-Pekka LyytikäinenMary F FeitosaColleen M SitlaniCristina VenturiniAnubha MahajanTim KacprowskiCarol A WangDaniel I ChasmanNajaf AminLinda BroerNeil RobertsonKristin L YoungMatthew AllisonPaul L AuerMatthias BlüherJudith B BorjaJette Bork-JensenGermán D CarrasquillaParaskevi ChristofidouAyse DemirkanClaudia A DoegeMelissa E GarciaMariaelisa GraffKaiying GuoHakon HakonarsonJaeyoung HongYii-Der Ida ChenRebecca JacksonHermina JakupovićPekka JousilahtiAnne E JusticeMika KähönenJorge R KizerJennifer KriebelCharles A LeDucJin LiLars LindJian'an LuanDavid A MackeyMassimo ManginoSatu MännistöJayne F Martin CarliCarolina Medina-GomezDennis O Mook-KanamoriAndrew P MorrisRenée de MutsertMatthias NauckIvana ProkicCraig E PennellArund D PradhanBruce M PsatyOlli T RaitakariRobert A ScottTea SkaabyKonstantin StrauchKent D TaylorAlexander TeumerAndre G UitterlindenYing WuJie YaoMark WalkerKari E NorthPeter KovacsM Arfan IkramCornelia M van DuijnPaul M RidkerStephen LyeGeorg HomuthErik IngelssonTim D SpectorBarbara McKnightMichael A ProvinceTerho LehtimäkiLinda S AdairJerome I RotterAlexander P ReinerJames G WilsonTamara B HarrisSamuli RipattiHarald GrallertJames B MeigsVeikko SalomaaTorben HansenKo Willems van DijkNicholas J WarehamStruan F A GrantClaudia LangenbergTimothy M FraylingCecilia M LindgrenKaren L MohlkeRudolph L LeibelRuth J F LoosTuomas O KilpeläinenPublished in: Diabetes (2020)
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.