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PMID: 18454148 Published · ppublish English Journal Article Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

Nature genetics ·Vol. 40 ·No. 6 ·2008-06-00 ·Pages 768-75

Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, Prostate, Lung, Colorectal, and Ovarian PLCO Cancer Screening Trial, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM, KORA, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O'Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L, Nurses' Health Study, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK, Diabetes Genetics Initiative, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M, SardiNIA Study, Vogel CI, Wallace C, Waterworth DM, Weedon MN, Wellcome Trust Case Control Consortium, Willer CJ, FUSION, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, Mohlke KL

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.

MeSH Terms

Adiposity/genetics Adolescent Adult Aged Alleles Alpha-Ketoglutarate-Dependent Dioxygenase FTO Body Mass Index Body Weight/genetics Case-Control Studies Child Chromosomes, Human, Pair 18/genetics Cohort Studies Cross-Sectional Studies Female Genetic Predisposition to Disease Genetic Variation Genome, Human Humans Linkage Disequilibrium Male Meta-Analysis as Topic Middle Aged Obesity/epidemiology,genetics,pathology Polymorphism, Single Nucleotide Proteins Quantitative Trait Loci Randomized Controlled Trials as Topic Receptor, Melanocortin, Type 4/genetics

Chemicals

Proteins Receptor, Melanocortin, Type 4 Alpha-Ketoglutarate-Dependent Dioxygenase FTO FTO protein, human

Authors & Affiliations

143 authors, click to expand affiliations / ORCID

Loos Ruth J F

MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

Lindgren Cecilia M

Li Shengxu

Wheeler Eleanor

Zhao Jing Hua

Prokopenko Inga

Inouye Michael

Freathy Rachel M

Attwood Antony P

Beckmann Jacques S

Berndt Sonja I

Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

Jacobs Kevin B

Chanock Stephen J

Hayes Richard B

Bergmann Sven

Bennett Amanda J

Bingham Sheila A

Bochud Murielle

Brown Morris

Cauchi Stéphane

Connell John M

Cooper Cyrus

Smith George Davey

Day Ian

Dina Christian

De Subhajyoti

Dermitzakis Emmanouil T

Doney Alex S F

Elliott Katherine S

Elliott Paul

Evans David M

Sadaf Farooqi I

Froguel Philippe

Ghori Jilur

Groves Christopher J

Gwilliam Rhian

Hadley David

Hall Alistair S

Hattersley Andrew T

Hebebrand Johannes

Heid Iris M

KORA

Lamina Claudia

Gieger Christian

Illig Thomas

Meitinger Thomas

Wichmann H-Erich

Herrera Blanca

Hinney Anke

Hunt Sarah E

Jarvelin Marjo-Riitta

Johnson Toby

Jolley Jennifer D M

Karpe Fredrik

Keniry Andrew

Khaw Kay-Tee

Luben Robert N

Mangino Massimo

Marchini Jonathan

McArdle Wendy L

McGinnis Ralph

Meyre David

Munroe Patricia B

Morris Andrew D

Ness Andrew R

Neville Matthew J

Nica Alexandra C

Ong Ken K

O'Rahilly Stephen

Owen Katharine R

Palmer Colin N A

Papadakis Konstantinos

Potter Simon

Pouta Anneli

Qi Lu

Nurses' Health Study

Randall Joshua C

Rayner Nigel W

Ring Susan M

Sandhu Manjinder S

Scherag André

Sims Matthew A

Song Kijoung

Soranzo Nicole

Speliotes Elizabeth K

Diabetes Genetics Initiative

Syddall Holly E

Teichmann Sarah A

Timpson Nicholas J

Tobias Jonathan H

Uda Manuela

SardiNIA Study

Vogel Carla I Ganz

Wallace Chris

Waterworth Dawn M

Weedon Michael N

Wellcome Trust Case Control Consortium

Willer Cristen J

FUSION

Wraight

Yuan Xin

Zeggini Eleftheria

Hirschhorn Joel N

Strachan David P

Ouwehand Willem H

Caulfield Mark J

Samani Nilesh J

Frayling Timothy M

Vollenweider Peter

Waeber Gerard

Mooser Vincent

Deloukas Panos

McCarthy Mark I

Wareham Nicholas J

Barroso Inês

Jacobs Kevin B

Chanock Stephen J

Hayes Richard B

Lamina Claudia

Gieger Christian

Illig Thomas

Meitinger Thomas

Wichmann H-Erich

Kraft Peter

Hankinson Susan E

Hunter David J

Hu Frank B

Lyon Helen N

Voight Benjamin F

Ridderstrale Martin

Groop Leif

Scheet Paul

Sanna Serena

Abecasis Goncalo R

Albai Giuseppe

Nagaraja Ramaiah

Schlessinger David

Jackson Anne U

Tuomilehto Jaakko

Collins Francis S

Boehnke Michael

Mohlke Karen L

Investigators

258 investigators, click to expand

Burton Paul R

Clayton David G

Cardon Lon R

Craddock Nick

Deloukas Panos

Duncanson Audrey

Kwiatkowski Dominic P

McCarthy Mark I

Ouwehand Willem H

Samani Nilesh J

Todd John A

Donnelly Peter

Barrett Jeffrey C

Burton Paul R

Davison Dan

Donnelly Peter

Easton Doug

Evans David M

Leung Hin-Tak

Marchini Jonathan L

Morris Andrew P

Spencer Chris C A

Tobin Martin D

Cardon Lon R

Clayton David G

Attwood Antony P

Boorman James P

Cant Barbara

Everson Ursula

Hussey Judith M

Jolley Jennifer D

Knight Alexandra S

Koch Kerstin

Meech Elizabeth

Nutland Sarah

Prowse Christopher V

Stevens Helen E

Taylor Niall C

Walters Graham R

Walker Neil M

Watkins Nicholas A

Winzer Thilo

Todd John A

Ouwehand Willem H

Jones Richard W

McArdle Wendy L

Ring Susan M

Strachan David P

Pembrey Marcus

Breen Gerome

St Clair David

Caesar Sian

Gordon-Smith Katherine

Jones Lisa

Fraser Christine

Green Elaine K

Grozeva Detelina

Hamshere Marian L

Holmans Peter A

Jones Ian R

Kirov George

Moskvina Valentina

Nikolov Ivan

O'Donovan Michael C

Owen Michael J

Craddock Nick

Collier David A

Elkin Amanda

Farmer Anne

Williamson Richard

McGuffin Peter

Young Allan H

Ferrier I Nicol

Ball Stephen G

Balmforth Anthony J

Barrett Jennifer H

Bishop D Timothy

Iles Mark M

Maqbool Azhar

Yuldasheva Nadira

Hall Alistair S

Braund Peter S

Burton Paul R

Dixon Richard J

Mangino Massimo

Stevens Suzanne

Tobin Martin D

Thompson John R

Samani Nilesh J

Bredin Francesca

Tremelling Mark

Parkes Miles

Drummond Hazel

Lees Charles W

Nimmo Elaine R

Satsangi Jack

Fisher Sheila A

Forbes Alastair

Lewis Cathryn M

Onnie Clive M

Prescott Natalie J

Sanderson Jeremy

Mathew Christopher G

Barbour Jamie

Mohiuddin M Khalid

Todhunter Catherine E

Mansfield John C

Ahmad Tariq

Cummings Fraser R

Jewell Derek P

Webster John

Brown Morris J

Clayton David G

Lathrop G Mark

Connell John

Dominiczak Anna

Samani Nilesh J

Marcano Carolina A Braga

Burke Beverley

Dobson Richard

Gungadoo Johannie

Lee Kate L

Munroe Patricia B

Newhouse Stephen J

Onipinla Abiodun

Wallace Chris

Xue Mingzhan

Caulfield Mark

Farrall Martin

Barton Anne

Bruce Ian N

Donovan Hannah

Eyre Steve

Gilbert Paul D

Hider Samantha L

Hinks Anne M

John Sally L

Potter Catherine

Silman Alan J

Symmons Deborah P M

Thomson Wendy

Worthington Jane

Clayton David G

Dunger David B

Nutland Sarah

Stevens Helen E

Walker Neil M

Widmer Barry

Todd John A

Frayling Timothy M

Freathy Rachel M

Lango Hana

Perry John R B

Shields Beverley M

Weedon Michael N

Hattersley Andrew T

Hitman Graham A

Walker Mark

Elliott Kate S

Groves Christopher J

Lindgren Cecilia M

Rayner Nigel W

Timpson Nicholas J

Zeggini Eleftheria

McCarthy Mark I

Newport Melanie

Sirugo Giorgio

Lyons Emily

Vannberg Fredrik

Hill Adrian V S

Bradbury Linda A

Farrar Claire

Pointon Jennifer J

Wordsworth Paul

Brown Matthew A

Franklyn Jayne A

Heward Joanne M

Simmonds Matthew J

Gough Stephen C L

Seal Sheila

Stratton Michael R

Rahman Nazneen

Ban Maria

Goris An

Sawcer Stephen J

Compston Alastair

Conway David

Jallow Muminatou

Newport Melanie

Sirugo Giorgio

Rockett Kirk A

Kwiatkowski Dominic P

Bumpstead Suzannah J

Chaney Amy

Downes Kate

Ghori Mohammed J R

Gwilliam Rhian

Hunt Sarah E

Inouye Michael

Keniry Andrew

King Emma

McGinnis Ralph

Potter Simon

Ravindrarajah Rathi

Whittaker Pamela

Widden Claire

Withers David

Deloukas Panos

Leung Hin-Tak

Nutland Sarah

Stevens Helen E

Walker Neil M

Todd John A

Easton Doug

Clayton David G

Burton Paul R

Tobin Martin D

Barrett Jeffrey C

Evans David M

Morris Andrew P

Cardon Lon R

Cardin Niall J

Davison Dan

Ferreira Teresa

Pereira-Gale Joanne

Hallgrimsdóttir Ingeleif B

Howie Bryan N

Marchini Jonathan L

Spencer Chris C A

Su Zhan

Teo Yik Ying

Vukcevic Damjan

Donnelly Peter

Bentley David

Brown Matthew A

Cardon Lon R

Caulfield Mark

Clayton David G

Compston Alistair

Craddock Nick

Deloukas Panos

Donnelly Peter

Farrall Martin

Gough Stephen C L

Hall Alistair S

Hattersley Andrew T

Hill Adrian V S

Kwiatkowski Dominic P

Mathew Christopher G

McCarthy Mark I

Ouwehand Willem H

Parkes Miles

Pembrey Marcus

Rahman Nazneen

Samani Nilesh J

Stratton Michael R

Todd John A

Worthington Jane

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Article Info

Journal

Nature genetics

Abbr.

Nat Genet

ISSN

1546-1718

DOI

10.1038/ng.140

Published

2008-06-00

Epub

2008-00-04

Pages

768-75

Language

English

Region

United States

NLM ID

9216904

PMCID

PMC2669167

Subset

Grants

Medical Research Council · G9521010 · United Kingdom

NIDDK NIH HHS · K23 DK080145 · United States

Medical Research Council · G0600331 · United Kingdom

Medical Research Council · G0000934 · United Kingdom

British Heart Foundation · United Kingdom

NIDDK NIH HHS · K23 DK080145-01 · United States

NIDDK NIH HHS · R01 DK072193 · United States

Medical Research Council · MC_U105161047 · United Kingdom

Medical Research Council · MC_U105630924 · United Kingdom

NIDDK NIH HHS · F32 DK079466 · United States

Medical Research Council · MC_UP_A620_1014 · United Kingdom

Medical Research Council · MC_U106179472 · United Kingdom

Medical Research Council · G0401527 · United Kingdom

Wellcome Trust · 090532 · United Kingdom

Medical Research Council · G0000934(68341) · United Kingdom

Medical Research Council · G9824984 · United Kingdom

Medical Research Council · G9828345 · United Kingdom

Medical Research Council · MC_U147585824 · United Kingdom

Cancer Research UK · United Kingdom

NIDDK NIH HHS · P30 DK040561-13 · United States

Medical Research Council · G9521010(63660) · United Kingdom

NIDDK NIH HHS · P30 DK040561 · United States

Medical Research Council · G0400874 · United Kingdom

Wellcome Trust · 079557 · United Kingdom

Medical Research Council · G0600705 · United Kingdom

Wellcome Trust · 084713 · United Kingdom

Department of Health · DHCS/07/07/008 · United Kingdom

Wellcome Trust · 077016 · United Kingdom

NIDDK NIH HHS · F32 DK079466-01 · United States

Wellcome Trust · 076113 · United Kingdom

Medical Research Council · G0701863 · United Kingdom

Wellcome Trust · 068545 · United Kingdom

Medical Research Council · MC_QA137934 · United Kingdom

Medical Research Council · U.1475.00.002.00001.01 (85824) · United Kingdom

Medical Research Council · MC_U106188470 · United Kingdom

Medical Research Council · G0601261 · United Kingdom

External Links

PubMed source DOI: 10.1038/ng.140 PMC Full Text View journal details

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Common variants near MC4R are associated with fat mass, weight and risk of obesity.

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