rs111357538 (FTO): BMI and Obesity-Related Variant

Key takeaways

• rs111357538 falls within the FTO (fat mass and obesity associated) gene, one of the most studied genetic loci for body mass index.
• A large multi-ancestry genome-wide study identified 906 significant BMI loci in European ancestry populations (N approximately 1.1 million) and 41 in African ancestry populations (N approximately 100,000).
• A BMI genetic risk score built from 2,446 variants was associated with 316 distinct clinical diagnoses, with 96.5% showing increased risk alongside higher BMI.
• Genetically elevated BMI has been causally linked to heart failure, ischemic heart disease, atrial fibrillation, chronic kidney failure, respiratory failure, and asthma.
• Risk spans multiple interconnected organ systems, including circulatory, genitourinary, respiratory, musculoskeletal, and dermatologic systems.

What the research says A genome-wide association study of BMI in approximately 1.1 million European ancestry and 100,000 African ancestry participants identified 906 (364 novel) and 41 (6 novel) genome-wide significant loci, respectively. A genetic risk score derived from 2,446 BMI-associated variants was tested against 316 clinical diagnoses in the Million Veteran Program, with 96.5% showing increased risk alongside higher BMI. Mendelian randomization analysis, a method that uses inherited genetic variants as natural experiments to estimate causal effects, confirmed associations between elevated BMI and conditions including heart failure, ischemic heart disease, atrial fibrillation, chronic renal failure, respiratory failure, and asthma.

Reported associations

• Body mass index: The locus containing rs111357538 is identified as a genome-wide significant region for BMI in this large multi-ancestry study.
• Heart failure and ischemic heart disease: Mendelian randomization analysis confirmed increased risk with genetically elevated BMI.
• Atrial fibrillation: Genetically elevated BMI was causally associated with this heart rhythm condition in the MR analysis.
• Chronic renal failure: MR analysis supported a causal association between elevated BMI and kidney failure.
• Respiratory failure and asthma: Elevated BMI was causally associated with both conditions in MR analysis.
• Musculoskeletal and dermatologic conditions: These categories were identified as part of the broader BMI-associated disease network, though variant-specific effect sizes were not reported.

Evidence quality Evidence draws from a large-scale meta-GWAS including approximately 1.1 million European ancestry participants and 100,000 African ancestry participants, with Mendelian randomization conducted using a 2,446-variant BMI risk score across 316 clinical diagnoses in the Million Veteran Program biobank. The finding that 96.5% of diagnoses show increased risk is a summary statistic covering all 316 conditions, not a finding specific to rs111357538 as an individual SNP. The provided study does not report a variant-level effect size, p-value, or allele frequency for rs111357538 itself, so conclusions about this particular SNP relative to the broader locus remain limited.

Lifestyle considerations No lifestyle considerations on file for this variant.