rs10521307 (FTO): BMI and pancreatic gene expression

Key takeaways

• rs10521307 is in the FTO gene region, one of the most replicated genetic regions tied to body mass index
• In pancreatic tissue, carriers of the alt allele show reduced expression of the nearby IRX3 gene
• BMI-associated genetic variants collectively link to more than 300 distinct diagnoses, spanning cardiovascular, kidney, and respiratory conditions
• Evidence for BMI associations draws from genome-wide analyses of over 1.1 million people

What the research says A large-scale meta-analysis identified 906 genome-wide significant loci for body mass index (BMI, a measure of weight relative to height) in approximately 1.1 million European-ancestry participants and 41 loci in approximately 100,000 African-ancestry participants, including the FTO region where rs10521307 is located. Using Mendelian randomization (a method that uses genetic variants as proxies for lifetime exposure to a trait to help assess causal relationships) with a 2,446-variant BMI genetic risk score, 316 distinct diagnoses were associated with higher genetically predicted BMI in the Million Veteran Program biobank, with 96.5% showing increased risk. Tissue-level expression data from GTEx v11 shows that carriers of the alt allele have reduced expression of IRX3 and ENSG00000287885 specifically in pancreatic tissue GTEx Portal.

Reported associations

• Body mass index: rs10521307 is in the FTO gene region, a locus captured within a genome-wide scan of approximately 1.1 million European-ancestry participants that identified 906 independent BMI-associated loci
• Heart failure, ischemic heart disease, and atrial fibrillation: Mendelian randomization using BMI genetic instruments identified associations with these cardiovascular outcomes; rs10521307 is one component of the 2,446-variant BMI instrument used
• Chronic renal failure: Among the 316 diagnoses associated with genetically elevated BMI in the Million Veteran Program phenome-wide analysis
• Respiratory failure and asthma: Also represented among the 316 BMI-associated diagnoses spanning multiple organ systems
• Musculoskeletal and dermatologic conditions: Included in the interconnected disease communities identified through co-morbidity network analysis of the broader BMI genetic architecture
• Type 2 diabetes mellitus and coronary heart disease: Named explicitly as leading comorbidities tied to the BMI genetic architecture in Mendelian randomization analyses
• Pancreatic IRX3 expression: The alt allele is associated with reduced IRX3 expression in pancreatic tissue (slope -0.35, p=3.3e-6) GTEx Portal
• Pancreatic ENSG00000287885 expression: The alt allele is also associated with reduced expression of ENSG00000287885 in pancreatic tissue (slope -0.31, p=4.2e-5) GTEx Portal

Evidence quality BMI GWAS findings for the FTO region draw on a meta-analysis of approximately 1.1 million European-ancestry and approximately 100,000 African-ancestry participants, providing substantial statistical power for discovery. The available study does not report an effect size or p-value for rs10521307 in isolation; it is characterized as part of the broader genome-wide scan. The 316-diagnosis phenome-wide study used a 2,446-variant genetic risk score, so reported disease associations reflect the joint effect of many BMI variants rather than this locus alone; individual variant contributions are not disaggregated. Replication was conducted via meta-analysis incorporating the UK Biobank and other large consortia. Tissue-specific expression evidence comes from GTEx v11 eQTL data (expression quantitative trait loci, which measure how genetic variants influence nearby gene activity; 953 donors, cis-window, FDR below 0.05); these are mechanistic findings and eQTL effects on gene expression are not equivalent to clinical outcomes.

Tissue-specific expression effects

• IRX3: The alt allele is associated with reduced expression of IRX3 in pancreatic tissue GTEx Portal
• ENSG00000287885: The alt allele is also associated with reduced expression of ENSG00000287885 in pancreatic tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.