FTO

HIGH

Fat mass and obesity-associated protein

Chromosome: 16q12.2

Gene Overview

FTO encodes fat mass and obesity-associated protein, an alpha-ketoglutarate-dependent dioxygenase that demethylates nucleic acids. The FTO locus harbors the strongest common genetic association with obesity (e.g., rs9939609); risk alleles confer ~3 kg higher body weight per copy. FTO influences energy balance through effects on appetite, food preference, and possibly energy expenditure. Risk variants regulate expression of neighboring genes (RPGRIP1L, IRX3) rather than FTO itself, via long-range regulatory elements. FTO is widely expressed, with high levels in brain (hypothalamus), adipose tissue, and muscle. The gene links genetic susceptibility to obesogenic environmental exposures.

Molecular Function

  • RNA demethylation
  • nucleotide modification
  • epigenetic regulation

Protein class: alpha-ketoglutarate dioxygenase

Regulatory Annotation

Promoter activity: Obesity-associated variants lie in intron 1; act as distal enhancers for IRX3.

Enhancer associations: Risk locus forms chromatin loops to IRX3 and RPGRIP1L promoters; allele-specific enhancer activity.

Methylation sensitivity: FTO regulates m6A levels; locus methylation correlates with BMI.

eQTL tissues: brain, adipose tissue

Tissue Expression Context

brainTPM range: 8-30GTEx vv8
adipose tissueTPM range: 12-40GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

FTO risk variants enhance IRX3 expression in hypothalamic neurons, altering energy balance and food intake; obesogenic diet amplifies genetic predisposition.

Claussnitzer et al. showed allele-specific enhancer driving IRX3; FTO genotype-diet interaction in weight gain.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Claussnitzer M, et al. (2015). FTO obesity variant circuitry and adipocyte browning in humans. New England Journal of Medicine. doi:10.1056/NEJMoa1502214
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.Frayling TM, et al. (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. doi:10.1126/science.1141634