Effect of genetic liability to visceral adiposity on stroke and its subtypes: A Mendelian randomization study

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization study, genetic variants (221 single nucleotide polymorphisms; P < 5 × 10⁻⁸) using as instrumental variables for Mendelian randomization analysis was obtained from a genome-wide association study of visceral adipose tissue. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). Mendelian randomization standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analyses (Mendelian randomization-Egger, weighted median, Mendelian randomization-pleiotropy residual sum and outlier) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable Mendelian randomization analysis was employed to adjust potential confounders. Results: In the standard Mendelian randomization analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio (OR) 1.30; 95% confidence interval (CI) 1.21–1.41, P = 1.48× 10⁻¹¹), ischemic stroke (OR 1.30; 95% CI 1.20–1.41, P = 4.01 × 10⁻¹⁰) and large artery stroke (OR 1.49; 95% CI 1.22–1.83, P = 1.16 × 10⁻⁴). The significant association was also found in sensitivity analysis and multi-variable Mendelian randomization analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.