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 × 10⁻⁵, and obese with an OR of 2.62 (1.76–3.92), P = 6.4 × 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 (AUC = 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.The prevalence of obesity is increasing rapidly in all parts of the world. The primary cause of the current epidemic development is likely an unhealthy lifestyle, especially high calorie intake and insufficient physical activity. However, studies have established that the pathogenesis of obesity also includes a genetic component predisposing some individuals to gain more weight from a sedentary lifestyle (1–3). Until 2007 none of the suggested susceptibility variants for common obesity were convincingly validated. Genome-wide association studies (GWAS) have, however, with an agnostic approach changed the success of identifying common single nucleotide polymorphisms (SNPs), modifying the risk for common complex diseases including obesity. FTO was the first well-replicated obesity susceptibility locus to be identified through GWAS (4) and moreover has been identified in other independent studies (5–7).Subsequently, variants downstream of MC4R (8,9) were identified in meta-analyses of GWAS, and linkage peaks in PCSK1 were re-sequenced identifying two coding variants reaching the genome-wide significance threshold (10). A second wave of GWAS of obesity have recently identified 15 additional loci: TMEM18, SH2B1, KCTD15, NEGR1 (11,12), SEC16B, SFRS10, BDNF, FAIM2, BAT2 (11), GNPDA2, MTCH2 (12), NCP1, MAF, PTER, and PRL (13).Individually all of these common variants exert small-to-modest effect sizes, however, whether the combined effect of the 20 variants increases in an additive manner has not been elucidated. So far the combined ability of nine obesity variants to discriminate obese individuals from lean individuals has been reported (14). In the present study, we estimate the discriminative value of 20 SNPs in the 18 newly identified obesity loci in a Danish population-based cohort both separately and in combination with conventional nongenetic risk factors of obesity. We also examine whether the 20 obesity-related variants exhibit additive combined effects or whether synergistic effects caused by gene-gene interactions are present.