Body Mass Index Quantitative Trait Locus 14

A number sign (#) is used with this entry because of evidence that susceptibility to obesity can be influenced by variation in the FTO gene (610966) on chromosome 16q12.

For a phenotypic description and a discussion of genetic heterogeneity of body mass index (BMI), see 606641.

Mapping

Frayling et al. (2007) identified a common variant in the FTO gene (610966) on 16q12.2 as a risk factor for obesity. The authors performed a genomewide association study of type II diabetes by screening 1,924 patients and 2,938 controls from the UK for more than 490,000 autosomal SNPs. SNPs in the FTO region showed strong association (as high as p of 5 x 10(-8) for rs9939609) in this screen and in a replication study with an additional 3,757 type II diabetics and 5,346 controls (p of 9 x 10(-6) for rs9939609). The diabetes risk alleles at FTO were strongly associated with increased BMI, and further analysis showed that the association of the FTO SNPs with type II diabetes was mediated through an increased risk for BMI. Frayling et al. (2007) analyzed an additional 19,424 white European adults from 7 population-based studies and 10,172 white European children from 2 population-based studies and confirmed association of the A allele of rs9939609 with increased BMI. In all adult population-based studies, the risk for higher BMI was additive, such that those homozygous for the A allele had a higher BMI than those heterozygous for the A allele and the low-risk T allele. When all the data were combined, the p value was 3 x 10(-35), or 1.2 x 10(-29) when a Bonferroni correction was performed for the approximately 400,000 SNPs tested. The attributable risk for rs9939609 was approximately 20% for obesity (BMI more than 30 kg/m2) and approximately 13% for being overweight (BMI more than 25 kg/m2). Overall, Frayling et al. (2007) determined that about 16% of white Europeans are homozygous for the A allele of rs9939609 and are 1.67 times as likely to be obese compared with those homozygous for the T allele. Study of at-risk children showed that rs9939609 was associated with increased BMI and obesity by the age of 7 years.

Frayling et al. (2007) determined that rs9939609 occurs in intron 1 of the FTO gene and is highly correlated with 45 other SNPs within a 47-kb region encompassing the first 2 introns and exon 2. It was not clear which, if any, of these SNPs represented the functional variant, and sequence analysis of 47 patients with a BMI of more than 40 kg/m2 did not reveal any obvious functional variants in the FTO coding region, minimal splice sites, or 3-prime UTR. Frayling et al. (2007) noted that the FTO gene is closely adjacent to the KIAA1005 gene (RPGRIP1L; 610937), which is transcribed in the opposite orientation and shows a similar expression profile, suggesting that the FTO SNPs may have an effect on KIAA1005 regulation.

Dina et al. (2007) identified 2 potentially functional SNPs in intron 1 of the FTO gene that were consistently strongly associated with early-onset and severe obesity in 2,900 affected individuals and 5,100 controls (p = 1.67 x 10 (-26) for the C allele of rs1421085 and p = 1.07 x 10 (-24) for the G allele of rs17817449). The at-risk haplotype yielded a proportion of attributable risk of 22% for common obesity. Dina et al. (2007) concluded that FTO contributes to human obesity, and noted that there were at least 44 not-yet-genotyped SNPs in linkage disequilibrium with these 2 markers.

Ohashi et al. (2007) found no association between the SNPs rs9939609, rs1421085, and rs17817449 in the FTO gene and BMI in Oceanic populations (4 Melanesian, 1 Micronesian, and 1 Polynesian).

Loos et al. (2008) performed a metaanalysis of data from 4 European population-based studies and 3 disease-case series, involving a total of 16,876 individuals of European descent, and confirmed the previously reported association between the FTO gene and BMI (p = 3.6 x 10(-8) at rs1121980).

Wardle et al. (2008) genotyped the intronic FTO SNP rs9939609 in 3,337 United Kingdom children in whom measures of habitual appetitive behavior had been assessed using 2 scales (Satiety Responsiveness and Enjoyment of Food) from the Child Eating Behaviour Questionnaire, a psychometric tool that has been validated against objective measures of food intake. The A allele was associated with increased adiposity in this cohort and in an independent case-control replication study of United Kingdom children of similar age. AA homozygotes had significantly reduced Satiety Responsiveness scores (p = 0.008). Mediation analysis indicated that the association of the AA genotype with increased adiposity was explained in part through effects on Satiety Responsiveness.

Cecil et al. (2008) genotyped 2,726 Scottish children for the FTO variant rs9939609 and found that the A allele was associated with increased weight and BMI (p = 0.003 for both). In an intensively phenotyped subsample of 97 children, the A allele was also associated with increased fat mass (p = 0.01) but not with lean mass. Although total and resting energy expenditure was increased in children with the A allele (p = 0.009 and p = 0.03, respectively), it was consistent with their increased body mass. The A allele was associated with increased energy intake (p = 0.006) independently of body weight; however, the weight of the food ingested by the children who had the A allele was similar to that of children who did not. Cecil et al. (2008) concluded that the FTO variant that confers a predisposition to obesity may play a role in the control of food intake and food choice, perhaps involving a hyperphagic phenotype or a preference for energy-dense foods.

In a study of 15,931 Swedish adults without diabetes, Jonsson and Franks (2009) found that the minor A allele of rs9939609 was associated with increased BMI (p less than 0.001 for AA vs TT or TA genotypes) and, after adjustment for age, sex, and BMI, also with self-reported increased physical activity levels (p = 0.02).

Palmer et al. (2009) stated that they had confirmed the previously reported findings by Cecil et al. (2008) regarding an association between rs9939609 and measured intake and preferential selection of energy-rich foods in a questionnaire-based study of more than 6,000 children.

Meyre et al. (2009) analyzed genomewide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls and found the strongest association signal in the first intron of the FTO gene for an imputed SNP rs1421085 (p = 3 x 10(-12)). Subsequent analysis confirmed the association in an additional 14,186 European individuals (combined p = 1.2 x 10(-28)).

Renstrom et al. (2009) performed association studies between 9 SNPs from 9 target genes and adiposity and type 2 diabetes (125853) in 3,885 nondiabetic and 1,038 diabetic Swedish adults. In models with BMI, adipose mass traits, or obesity as outcomes, rs1121980 in the FTO gene was the most strongly associated SNP (p less than 0.0001, p = 0.0007, p = 0.0016, respectively) in 3,885 nondiabetic individuals.

Willer et al. (2009) performed a metaanalysis of 15 genomewide association studies for BMI comprising 32,387 participants and followed up top signals in 14 additional cohorts comprising 59,082 participants. They strongly confirmed association with FTO, represented by rs9939609, as associated with obesity with a per-allele change in BMI of 0.33 and an overall P value of 4.9 x 10(-74).

Hardy et al. (2010) genotyped variants in FTO rs9939609 and near MC4R (155541; rs17782313) in 1,240 men and 1,239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2-20 years) or adulthood (20-53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; p less than 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele), and then weakened during adulthood (-0.003 SDS/A-allele/year, P = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; P = 0.006), peaked at age 20 years (0.13 SDS/C-allele), and weakened during adulthood (-0.002 SDS/C-allele/year, P = 0.05). Hardy et al. (2010) concluded that genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age.

A risk polymorphism for obesity in the FTO gene, the A allele at rs9939609, has population frequencies of 46% in Western and Central Europeans, 51% in Yorubans, and 16% in Chinese individuals (summary by Ho et al., 2010). Interestingly, the effect of FTO on BMI may be mediated through impaired responsiveness to satiety (Wardle et al., 2008). Ho et al. (2010) generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. Ho et al. (2010) found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of approximately 8% in the frontal lobes and 12% in the occipital lobes. These regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities. Ho et al. (2010) concluded that these brain maps revealed that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Kilpelainen et al. (2011) noted that while GWAS had identified 32 loci influencing body mass index to that time, this measure does not distinguish lean from fat mass. To identify adiposity loci, Kilpelainen et al. (2011) performed a metaanalysis of associations between 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (p less than 10(-6)) independent loci in 39,576 individuals. They confirmed the established adiposity locus in FTO (rs8050136, effect allele C, combined p = 2.7 x 10(-26)) and identified 2 new loci associated with body fat percentage, one near IRS1 (147545) and one near SPRY2 (602466). Kilpelainen et al. (2011) noted that the body fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes, and coronary artery disease, and decreased adiponectin levels.

Yang et al. (2012) performed a metaanalysis of genomewide association studies of phenotypic variation using approximately 170,000 samples on height and BMI in human populations. They reported evidence that the SNP 7202116 at the FTO gene locus, which is known to be associated with obesity, as measured by mean BMI for each rs7202116 genotype, is also associated with phenotypic variability. The results were not due to scale effects or other artifacts, and the authors found no experimentwise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of approximately 0.5 kg in the standard deviation of weight. Yang et al. (2012) concluded that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The authors also concluded that their BMI results for other SNPs and their height results for all SNPs suggested that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with sample sizes greater than 100,000.

Molecular Genetics

Using a range of genomic techniques to examine the contribution of a risk haplotype for obesity involving 3 SNPs in introns 1 and 2 of the FTO gene (rs1421085, rs9930506, and rs1558902), Claussnitzer et al. (2015) elucidated a mechanistic basis of the association between the FTO region and obesity. Claussnitzer et al. (2015) obtained the highest phylogenetic module complexity analysis (PMCA) score for rs1421085, which they noted is in perfect linkage disequilibrium with the most significant reported SNP, rs1558902. The authors demonstrated that the rs1421085 T-C alteration disrupts a conserved motif for the regulator gene ARID5B (608538), causing derepression of a potent preadipocyte enhancer and doubling of IRX3 (612985) and IRX5 (606195) expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a 5-fold reduction in mitochondrial thermogenesis and an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from homozygous carriers of risk alleles at rs1421085, rs9930506, and rs1558902 restored thermogenesis, increasing it by a factor of 7, whereas overexpression of these genes had the opposite effect in adipocytes from carriers homozygous for the nonrisk variant of these 3 SNPs. Repair of the ARID5B motif in primary adipocytes from a patient with the risk alleles restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Claussnitzer et al. (2015) concluded that the FTO SNP rs1421085 (610966.0003) represents the causal variant that disrupts a pathway for adipocyte thermogenesis involving ARID5B, IRX3, and IRX5, providing a mechanistic basis for the genetic association between FTO and obesity.