Common variants near MC4R are associated with fat mass, weight and risk of obesity.
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.
Loos
Ruth J F
RJ
MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Lindgren
Cecilia M
CM
Li
Shengxu
S
Wheeler
Eleanor
E
Zhao
Jing Hua
JH
Prokopenko
Inga
I
Inouye
Michael
M
Freathy
Rachel M
RM
Attwood
Antony P
AP
Beckmann
Jacques S
JS
Berndt
Sonja I
SI
Jacobs
Kevin B
KB
Chanock
Stephen J
SJ
Hayes
Richard B
RB
Bergmann
Sven
S
Bennett
Amanda J
AJ
Bingham
Sheila A
SA
Bochud
Murielle
M
Brown
Morris
M
Cauchi
Stéphane
S
Connell
John M
JM
Cooper
Cyrus
C
Smith
George Davey
GD
Day
Ian
I
Dina
Christian
C
De
Subhajyoti
S
Dermitzakis
Emmanouil T
ET
Doney
Alex S F
AS
Elliott
Katherine S
KS
Elliott
Paul
P
Evans
David M
DM
Sadaf Farooqi
I
I
Froguel
Philippe
P
Ghori
Jilur
J
Groves
Christopher J
CJ
Gwilliam
Rhian
R
Hadley
David
D
Hall
Alistair S
AS
Hattersley
Andrew T
AT
Hebebrand
Johannes
J
Heid
Iris M
IM
Lamina
Claudia
C
Gieger
Christian
C
Illig
Thomas
T
Meitinger
Thomas
T
Wichmann
H-Erich
HE
Herrera
Blanca
B
Hinney
Anke
A
Hunt
Sarah E
SE
Jarvelin
Marjo-Riitta
MR
Johnson
Toby
T
Jolley
Jennifer D M
JD
Karpe
Fredrik
F
Keniry
Andrew
A
Khaw
Kay-Tee
KT
Luben
Robert N
RN
Mangino
Massimo
M
Marchini
Jonathan
J
McArdle
Wendy L
WL
McGinnis
Ralph
R
Meyre
David
D
Munroe
Patricia B
PB
Morris
Andrew D
AD
Ness
Andrew R
AR
Neville
Matthew J
MJ
Nica
Alexandra C
AC
Ong
Ken K
KK
O'Rahilly
Stephen
S
Owen
Katharine R
KR
Palmer
Colin N A
CN
Papadakis
Konstantinos
K
Potter
Simon
S
Pouta
Anneli
A
Qi
Lu
L
Randall
Joshua C
JC
Rayner
Nigel W
NW
Ring
Susan M
SM
Sandhu
Manjinder S
MS
Scherag
André
A
Sims
Matthew A
MA
Song
Kijoung
K
Soranzo
Nicole
N
Speliotes
Elizabeth K
EK
Syddall
Holly E
HE
Teichmann
Sarah A
SA
Timpson
Nicholas J
NJ
Tobias
Jonathan H
JH
Uda
Manuela
M
Vogel
Carla I Ganz
CI
Wallace
Chris
C
Waterworth
Dawn M
DM
Weedon
Michael N
MN
Willer
Cristen J
CJ
Wraight
Yuan
Xin
X
Zeggini
Eleftheria
E
Hirschhorn
Joel N
JN
Strachan
David P
DP
Ouwehand
Willem H
WH
Caulfield
Mark J
MJ
Samani
Nilesh J
NJ
Frayling
Timothy M
TM
Vollenweider
Peter
P
Waeber
Gerard
G
Mooser
Vincent
V
Deloukas
Panos
P
McCarthy
Mark I
MI
Wareham
Nicholas J
NJ
Barroso
Inês
I
Jacobs
Kevin B
KB
Chanock
Stephen J
SJ
Hayes
Richard B
RB
Lamina
Claudia
C
Gieger
Christian
C
Illig
Thomas
T
Meitinger
Thomas
T
Wichmann
H-Erich
HE
Kraft
Peter
P
Hankinson
Susan E
SE
Hunter
David J
DJ
Hu
Frank B
FB
Lyon
Helen N
HN
Voight
Benjamin F
BF
Ridderstrale
Martin
M
Groop
Leif
L
Scheet
Paul
P
Sanna
Serena
S
Abecasis
Goncalo R
GR
Albai
Giuseppe
G
Nagaraja
Ramaiah
R
Schlessinger
David
D
Jackson
Anne U
AU
Tuomilehto
Jaakko
J
Collins
Francis S
FS
Boehnke
Michael
M
Mohlke
Karen L
KL
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*
D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human