title: Common variants near MC4R are associated with fat mass, weight and risk of obesity.
abstract: To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
authors.affiliation: MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Shengxu
authors.initials: S
authors.lastname: Li
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.forename: Jing Hua
authors.initials: JH
authors.lastname: Zhao
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Michael
authors.initials: M
authors.lastname: Inouye
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.forename: Antony P
authors.initials: AP
authors.lastname: Attwood
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jacobs
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bennett
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Bingham
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.forename: Morris
authors.initials: M
authors.lastname: Brown
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cauchi
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Ian
authors.initials: I
authors.lastname: Day
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Subhajyoti
authors.initials: S
authors.lastname: De
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Alex S F
authors.initials: AS
authors.lastname: Doney
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Elliott
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: I
authors.initials: I
authors.lastname: Sadaf Farooqi
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Jilur
authors.initials: J
authors.lastname: Ghori
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Groves
authors.forename: Rhian
authors.initials: R
authors.lastname: Gwilliam
authors.forename: David
authors.initials: D
authors.lastname: Hadley
authors.forename: Alistair S
authors.initials: AS
authors.lastname: Hall
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Iris M
authors.initials: IM
authors.lastname: Heid
authors.forename: Claudia
authors.initials: C
authors.lastname: Lamina
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Blanca
authors.initials: B
authors.lastname: Herrera
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hunt
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.forename: Jennifer D M
authors.initials: JD
authors.lastname: Jolley
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: Andrew
authors.initials: A
authors.lastname: Keniry
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Robert N
authors.initials: RN
authors.lastname: Luben
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Jonathan
authors.initials: J
authors.lastname: Marchini
authors.forename: Wendy L
authors.initials: WL
authors.lastname: McArdle
authors.forename: Ralph
authors.initials: R
authors.lastname: McGinnis
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Ness
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Neville
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Nica
authors.forename: Ken K
authors.initials: KK
authors.lastname: Ong
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Papadakis
authors.forename: Simon
authors.initials: S
authors.lastname: Potter
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Randall
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Rayner
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Manjinder S
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authors.lastname: Sandhu
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sims
authors.forename: Kijoung
authors.initials: K
authors.lastname: Song
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Speliotes
authors.forename: Holly E
authors.initials: HE
authors.lastname: Syddall
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Tobias
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Carla I Ganz
authors.initials: CI
authors.lastname: Vogel
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Waterworth
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
authors.lastname: Wraight
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Nilesh J
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authors.lastname: Samani
authors.forename: Timothy M
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authors.lastname: Frayling
authors.forename: Peter
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authors.lastname: Vollenweider
authors.forename: Gerard
authors.initials: G
authors.lastname: Waeber
authors.forename: Vincent
authors.initials: V
authors.lastname: Mooser
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jacobs
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Claudia
authors.initials: C
authors.lastname: Lamina
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Susan E
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authors.lastname: Hankinson
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.forename: Helen N
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authors.lastname: Lyon
authors.forename: Benjamin F
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authors.lastname: Voight
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authors.lastname: Sanna
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authors.forename: Anne U
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authors.lastname: Collins
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011506:Proteins; D040641:Quantitative Trait Loci; D016032:Randomized Controlled Trials as Topic; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*
chemical_list: D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human