Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization

Area of Science:

• Cardiovascular Genetics
• Epidemiology
• Obesity Research

Background:

• Observational studies suggest a link between body mass index (BMI) and atrial fibrillation (AF), but causality is uncertain due to potential biases.
• Mendelian randomization is employed to overcome limitations of observational data and infer causal relationships.

Purpose of the Study:

• To investigate the causal association between body mass index (BMI) and the incidence of atrial fibrillation (AF) using genetic variants as instrumental variables.

Main Methods:

• Utilized data from 51,646 European ancestry individuals across 7 prospective cohorts.
• Employed Mendelian randomization with instrumental variable analysis using FTO genotype and a 39-SNP BMI gene score.
• Combined cohort-specific estimates via random-effects, inverse variance-weighted meta-analysis for incident AF over a median follow-up of 7.4–19.2 years.

Main Results:

• Both genetic instruments (FTO and BMI gene score) were significantly associated with higher BMI and increased risk of incident AF.
• Instrumental variable analysis revealed a causal association: a 1 kg/m² increase in BMI was associated with a 1.11-1.15 hazard ratio for AF.
• Findings were consistent with observational data and robust to multivariable adjustments.

Conclusions:

• The study provides strong evidence for a causal relationship between higher BMI and incident AF.
• Public health strategies focused on obesity prevention may be effective in reducing the burden of AF.