Genome Wide Association (GWA) Study for Early Onset Extreme Obesity Supports the Role of Fat Mass and Obesity Associated Gene (FTO) Variants

Abstract

BackgroundObesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.Methodology/Principal Findingsa) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13×10−7, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95% confidence interval (CI) 1.22–2.27; ORTT 2.76, 95% CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.Conclusions/SignificanceOur GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.

Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans

“…[1][2][3][4] The role of FTO variants as predisposing to obesity in Caucasian populations is now established more firmly. [5][6][7][8] The association to general fatness irrespective of its distribution is confirmed throughout the range of fatness 9 and the association between FTO variants and obesity is also seen in Japanese people. 10 In search for the mechanism by which allelic variation in FTO affect adiposity, both central 11 and peripheral 12,13 mechanisms have been examined.…”

A loop matters for FTO substrate selection

“…People carrying variants in the FTO gene are more susceptible to obesity. Many other groups have subsequently confirmed such a correlation among individuals of different cohorts (Hinney et al, 2007;Ohashi et al, 2007;Scuteri et al, 2007). FTO locates on chromosome 16 in human and on chromosome 8 in mouse.…”

The genetics of childhood obesity and interaction with dietary macronutrients

“…The common FTO gene variant (rs9939609) was subsequently used in a population-based GWAS to identify this gene as the first to be associated with common childhood obesity (Frayling et al 2007). Consistent with this result, a later case-control GWAS performed with lean and extremely obese German children indicated that this particular FTO gene variant was associated with common childhood obesity (Hinney et al 2007). A number of other studies performed with both children and adults indicated that this FTO gene variant was associated with increased and preferential consumption of energy-dense macronutrients, particularly foods enriched with saturated fatty acids (Cecil et al 2008;Timpson et al 2008;Bauer et al 2009).…”

“…Five of these obesity susceptibility genes (FTO, MC4R, MAF, NPC1, and PTER) were identified in the first or second casecontrol GWAS for early-onset (less than 6 years of age) and morbid-adult obesity (BMI C 40 kg/m 2 ) (Hinney et al 2007;Meyre et al 2009). More recent meta-analysis of several case-control GWAS using *40,000 individuals has determined that three of these obesity susceptibility genes (FTO, MC4R, and NPC1) are also associated with body fat percentage which serves as an accurate measure for whole body adiposity (Kilpelainen et al 2011;den Hoed et al 2012).…”