ArticleNature2014
Obesity-associated variants within FTO form long-range functional connections with IRX3.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03766191 (The Relation of Genetic Factors, Food Cues, and Self-Regulation With Excess Consumption and Adiposity in Children), which is not on this map. Cited by 747 papers, 5 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Relation of Genetic Factors, Food Cues, and Self-Regulation With Excess Consumption and Adiposity in Children
Who cites it
747 citing papers in PubMed, 5 syntheses or guidelines pooled it, 1,274 citations in OpenAlex.
- Impact of fat mass and obesity-associated (FTO) gene variants on adult obesity and overweight: a comprehensive meta-analysis.BMC endocrine disorders · 2026Pooled it
- The Genetic Associations Between Kidney Stones, Obesity, Type 2 Diabetes, and Hypertension.Mayo Clinic proceedings · 2025Pooled it
- Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus.Nature communications · 2025Pooled it
- Genetic Variants in the Fat Mass and Obesity-Associated Gene and Risk of Obesity/Overweight in Children and Adolescents: A Systematic Review and Meta-Analysis.Endocrinology, diabetes & metabolism · 2024Pooled it
- Establishing gene regulatory networks from Parkinson's disease risk loci.Brain : a journal of neurology · 2022Pooled it
- Association between FTO rs9939609 genotype and breast cancer risk after bariatric surgery in the Swedish Obese Subjects study.Scientific reports · 2026Trial
- Shared and distinct genetic architectures of eating disorders and obesity: From monogenic causes to polygenic risk.Reviews in endocrine & metabolic disorders · 2026Review
- Functional Annotation of Alzheimer's Disease-Associated SNPs Based on Three-Dimensional Chromatin Structure.International journal of molecular sciences · 2026Article
- Post-genome-wide association study variant-to-function challenges in asthma research.The Journal of allergy and clinical immunology · 2026Review
- Synthetic Regulatory Genomics.Annual review of genomics and human genetics · 2026Review
- Article
- Massively parallel characterization and predictive modelling of neuronal regulatory variation.bioRxiv : the preprint server for biology · 2026Article
- CCR2-dependent monocytes gut-homing contributes to enteric neuroplastic changes in a mouse model of diet-induced obesity.Molecular medicine (Cambridge, Mass.) · 2026Article
- Hi-C informed kernel association test for integrating 3D genome structure into variant-set analysis.Briefings in bioinformatics · 2026Article
- Functionally informed annotation influences pathway-specific polygenic risk and disease inference in Alzheimer's disease.medRxiv : the preprint server for health sciences · 2026Article
- A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes for Glomerular Diseases.Biomedicines · 2026Article
- Optimizing phenotype scale improves genetic analyses in large-scale biobanks.bioRxiv : the preprint server for biology · 2026Article
- Regulatory risk loci link disrupted androgen response to the pathophysiology of polycystic ovary syndrome.Journal of the Endocrine Society · 2026Article
- N6-methyladenosine (m6A) methylation in adipose tissue: role, regulation, and therapeutic potential.Cellular and molecular life sciences : CMLS · 2026Review
- Role ofInternational journal of molecular sciences · 2026Article
687 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 10 institutions in 3 countries.
Funding
Abstract
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.