Genome Wide Association Scan shows Genetic Variants in the FTO gene are Associated with Obesity Related Traits

Abstract

The obesity epidemic is responsible for a substantial economic burden in developed countries 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 also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p ¼ 8.6 310 À7 ), hip circumference (p ¼ 3.4 3 10 À8 ), and weight (p ¼ 9.1 3 10 À7 ). In Sardinia, homozygotes for the rare ''G'' allele of this SNP (minor allele frequency ¼ 0.46) were 1.3 BMI units heavier than homozygotes for the common ''A'' allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p ¼ 4.9 3 10 À6 ). Homozygotes for the rare ''A'' allele of this SNP (minor allele frequency ¼ 0.12) were 1.8 BMI units heavier than homozygotes for the common ''G'' allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N ¼ 1,496) and in Hispanic Americans (N ¼ 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p ¼ 0.001), weight (p ¼ 0.001), and hip circumference (p ¼ 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare ''A'' allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common ''G'' allele. In summary, we have completed a whole genomeassociation scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.

Postprandial responses in hunger and satiety are associated with the rs9939609 single nucleotide polymorphism in FTO

“…30 were included. This contrasts sharply with case-control studies (6,46) and with cohort studies (5,7), in which the association between BMI and rs9939609 was evaluated. In fact, the lack of association between BMI and the rs9939609 SNP is consistent with the results from Frayling et al (5), who did not observe a significant association between BMI and rs9939609 genotype in samples of ,1000 individuals.…”

“…In this respect, the recent realization of genome-wide association studies has provided researchers with the promising opportunity to identify risk variants for obesity without the need to select candidate genes a priori. The first series of genome-wide association studies for body mass index (BMI; in kg/m 2 ) and obesity showed strong and consistent associations with variants in the fat mass and obesity-associated (FTO) gene (4)(5)(6)(7).…”

Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies

“…We genotyped rs3101336, rs10913469, rs6548238, rs7647305, rs10938397, rs925946, rs10838738, rs7498665, rs7132908, rs1121980, rs17782313, and rs368794, which represent the obesity-susceptibility loci near or in the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FAIM2, FTO, MC4R, and KCTD15 genes, respectively, which have been identified recently by using GWAS for BMI (9,10,12,14,15).…”

“…The fat mass and obesity-associated (FTO) gene was the first obesity locus identified by using this approach (9)(10)(11), followed by the identification of common variants near the melanocortin 4 receptor (MC4R) gene (12,13). The latest largescale efforts by the Genetic Investigation for Anthropometric Traits (GIANT) Consortium (14) and the deCODE (15) found 10 additional common variants for BMI (14,15).…”

“…In the current study, we examined 1) the associations of the 12 newly identified variants for BMI by GWAS (9,10,12,14,15), individually and in combination, with obesity-related traits including BMI (as a measure of overall adiposity), waist circumference (as a measure of abdominal adiposity), and weight and height (as measures of overall size) and with the risk of obesity and overweight and 2) the predictive value for obesity risk of the 12 loci combined in a large population-based cohort from the European Prospective Investigation into Cancer and Nutrition (EPIC), Norfolk, United Kingdom.…”