Nat Genet. 2008 Jun;40(6):768-75. doi: 10.1038/ng.140. Epub 2008 May 4.
Common variants near MC4R are associated with fat mass, weight and risk of obesity.
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.
Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Burton PR, Davison D, Donnelly P, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Cardon LR, Clayton DG, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Todd JA, Ouwehand WH, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Craddock N, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop DT, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Burton PR, Dixon RJ, Mangino M, Stevens S, Tobin MD, Thompson JR, Samani NJ, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Mathew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Clayton DG, Lathrop GM, Connell J, Dominiczak A, Samani NJ, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hider SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Clayton DG, Dunger DB, Nutland S, Stevens HE, Walker NM, Widmer B, Todd JA, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, McCarthy MI, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Newport M, Sirugo G, Rockett KA, Kwiatkowski DP, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Deloukas P, Leung HT, Nutland S, Stevens HE, Walker NM, Todd JA, Easton D, Clayton DG, Burton PR, Tobin MD, Barrett JC, Evans DM, Morris AP, Cardon LR, Cardin NJ, Davison D, Ferreira T, Pereira-Gale J, Hallgrimsdóttir IB, Howie BN, Marchini JL, Spencer CC, Su Z, Teo YY, Vukcevic D, Donnelly P, Bentley D, Brown MA, Cardon LR, Caulfield M, Clayton DG, Compston A, Craddock N, Deloukas P, Donnelly P, Farrall M, Gough SC, Hall AS, Hattersley AT, Hill AV, Kwiatkowski DP, Mathew CG, McCarthy MI, Ouwehand WH, Parkes M, Pembrey M, Rahman N, Samani NJ, Stratton MR, Todd JA, Worthington J.
Source
MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
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.
- PMID:
- 18454148
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC2669167
Free PMC ArticleFigure 1
Regional plot of chromosome 18q21 (55,700–56,400 kb), showing the association signals for obesity for the meta-analysis of all 16,876 samples with genome-wide association scans. On the x axis is chromosomal position in kilobases (as NCBI build 35 coordinates), and on the y axis is the P value for association (expressed as −log10 P value). The imputed data signals are shown in gray diamonds and the directly genotyped signals in white. Estimated recombination rates (taken from HapMap) are plotted (light blue) to reflect the local LD structure around the associated SNP. Gene annotations were taken from the University of California Santa Cruz genome browser. The yellow diamond corresponds to the directly genotyped SNP in this region, which shows the strongest association with obesity (rs17782313, P = 2.9 × 10−6), the lower blue diamond represents the result from rs17700633 (P = 4.8 × 10−5, directly genotyped), and the green diamond represents the result from rs2229616 (or V103I, P = 0.056, imputed). LD structure across the interval, as calculated by D′, and r2 measures are shown in Supplementary Figure 5a.
Nat Genet. 2008 June;40(6):768-775.
Figure 2
Meta-analysis plot showing the rs17782313[C] per-allele effect size on BMI in 77,228 adults, expressed in log10BMI sex-specific Z-score units.
Nat Genet. 2008 June;40(6):768-775.
Figure 3
Effects of rs17782313 on regulation of weight in early life. (a) Longitudinal data for BMI at age 7–11 for children in the ALSPAC study by rs17782313 genotypes. Mean values represented as geometric means and back-transformed 95% confidence intervals. P values represent significance of the additive model (per-allele effect) of log10-transformed data, adjusted for sex. (b) Association between rs17782313 and body fat percentage in 9-year-old children from the ALSPAC study. Mean values represented as geometric means and back-transformed 95% confidence intervals. P values represent significance of the additive model (per-allele effect) of log10-transformed data, adjusted for sex. (c) Meta-analysis plot showing the rs17782313[C] per-allele effect size on risk of severe obesity in childhood and adolescence in 10,583 children from three studies.
Nat Genet. 2008 June;40(6):768-775.
Figure 4
Association between the combined rs17782313 and FTO genotypes and BMI in adults (EPIC-Norfolk, n = 15,622) and children (ALSPAC age 7 years, n = 5,779). BMI is expressed in log10BMI Z-score units adjusted for age (in adults) and sex. Both SNPs have a significant additive effect on BMI in adults (rs17782313, P = 4.0 × 10−4; rs1121980, P = 2.0 × 10−14) and in children (rs17782313, P = 8.0 × 10−6; rs9939609, P = 7.6 × 10−5).
Nat Genet. 2008 June;40(6):768-775.
Publication Types
MeSH Terms
Substances
Grant Support
Full Text Sources
Other Literature Sources
Medical