Combined Analyses of 20 Common Obesity Susceptibility Variants

OBJECTIVE-Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes. RESEARCH DESIGN AND METHODS-In this study we investigate the combined effect of these variants and their ability to discriminate between normal weight and overweight/obese individuals. We applied receiver operating characteristics (ROC) curves, and estimated the area under the ROC curve (AUC) as a measure of the discriminatory ability. The analyses were performed cross-sectionally in the population-based Inter99 cohort: where 1,725 normal weight, 1,519 overweight, and 681 obese individuals were successfully genotyped for all 20 variants. RESULTS-When combining all variants, the 10% of the study participants who carried more than 22 risk-alleles showed a significant increase in probability of being both overweight with an odds ratio of 2.00 (1.47-2.72), P = 4.0 x 10(-5), and obese with an OR of 2.62 (1.76-3.92), P = 6.4 x 10(-7), compared with the 10% of the study participants who carried less than 14 risk-alleles. Discrimination ability for overweight and obesity, using the 20 single nucleotide polymorphisms (SNPs), was determined to AUCs of 0.53 and 0.58, respectively. When combining SNP data with conventional nongenetic risk factors of obesity, the discrimination ability increased to 0.64 for overweight and 0.69 for obesity. The latter is significantly higher (P < 0.001) than for the nongenetic factors alone (AUG = 0.67). CONCLUSIONS-The discriminative value of the 20 validated common obesity variants is at present time sparse and too weak for clinical utility, however, they add to increase the discrimination ability of conventional nongenetic risk factors. Diabetes 59:1667-1673, 2010