Published on July 1, 2007 in PLoS Genet volume 3(7).

PubMed ID: 17658951

DOI: 07-PLGE-RA-0253

Abstract:

The obesity epidemic is responsible for a substantial economic burden in developedcountries and is a major risk factor for type 2 diabetes and cardiovascular disease.The disease is the result not only of several environmental risk factors, but alsoof genetic predisposition. To take advantage of recent advances in gene-mappingtechnology, we executed a genome-wide association scan to identify genetic variantsassociated with obesity-related quantitative traits in the genetically isolatedpopulation of Sardinia. Initial analysis suggested that several SNPs in the FTO andPFKP genes were associated with increased BMI, hip circumference, and weight. Withinthe FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7)),hip circumference (p = 3.4 x 10(-8)), and weight (p = 9.1 x 10(-7)). In Sardinia,homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46) were1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKPgene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6)).Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12) were1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate ourfindings, we genotyped these two SNPs in the GenNet study. In European Americans (N= 1,496) and in Hispanic Americans (N = 839), we replicated significant associationbetween rs9930506 in the FTO gene and BMI (p-value for meta-analysis of EuropeanAmerican and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001),and hip circumference (p = 0.0005). We did not replicate association betweenrs6602024 and obesity-related traits in the GenNet sample, although we found that inEuropean Americans, Hispanic Americans, and African Americans, homozygotes for therare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for themore common "G" allele. In summary, we have completed a whole genome-associationscan for three obesity-related quantitative traits and report that common geneticvariants in the FTO gene are associated with substantial changes in BMI, hipcircumference, and body weight. These changes could have a significant impact on therisk of obesity-related morbidity in the general population.