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Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies^1,2,3

¹ From the MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, United Kingdom (SL, JHZ, JL, KKO, NJW, and RJFL); the Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom (RNL and K-TK); and the MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (SAR).

² The European Prospective Investigation into Cancer and Nutrition (EPIC)–Norfolk Study is supported by Cancer Research UK, the Medical Research Council, the British Heart Foundation, the Food Standards Agency, the Department of Health, and the Academy of Medical Sciences. SL is supported by a grant from Unilever Corporate Research, United Kingdom.

³ Address correspondence to RJF Loos, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Box 285, Hills Road, Cambridge, CB2 0QQ, United Kingdom. E-mail: ruth.loos{at}mrc-epid.cam.ac.uk.

ABSTRACT

Background: Large-scale genome-wide association studies have identified 12 genetic loci that are robustly associated with body mass index (BMI).

Objectives: We examined associations and compared effect sizes of these newly identified obesity susceptibility loci with various anthropometric traits and assessed their cumulative effects and predictive value for obesity risk.

Design: We genotyped 12 single nucleotide polymorphisms (SNPs) from each locus in 20,431 individuals (age: 39–79 y) from the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)–Norfolk cohort. General linear model and logistic regression were used to examine associations, and the area under the receiver operating characteristic curve (AUC) was used to assess the predictive value of these variants for obesity risk.

Results: Effect sizes of the risk alleles ranged between 0.058 and 0.329 for BMI (in kg/m²), between 0.094 and 0.866 kg for weight, and between 0.085 and 0.819 cm for waist circumference, with rs1121980 (FTO locus) showing the largest effect. Risk alleles of rs7132908 (FAIM2 locus) and rs17782313 (MC4R locus) were also associated with taller height. On average, each additional risk allele was associated with increases of 0.149 in BMI (P = 1.54E-22), 0.444 kg in body weight (P = 9.88E-22), and 0.357 cm in waist circumference (P = 1.10E-18) and 10.8% (P = 9.83E-16) and 5.5% (P = 3.38E-10) increased risks of obesity and overweight, respectively. All SNPs combined explained 0.9% of BMI variation, with an AUC of 0.574 (95% CI: 0.559, 0.590) for prediction of obesity.

Conclusions: Common variants for BMI have small effects on obesity measures and show different association patterns with anthropometric traits, with the largest effect shown for the FTO locus. These variants have cumulative effects, yet their predictive value for obesity risk is limited.

Received for publication July 17, 2009. Accepted for publication September 8, 2009.