Genetic associations between obesity and brain cortical thickness: combined genetic correlation, multi-trait meta- analysis and Mendelian randomization

Introduction: Obesity may lead to cognitive impairment and neuropsychiatric disorders, which are associated with changes in the brain cortical structure, particularly in cortical thickness. However, the exact genetic association between obesity and brain cortical thickness remains inconclusive. We aimed to identify the relationship between obesity-related traits [body mass index (BMI), waist-hip ratio (WHR), and waist-hip ratio adjusted for BMI (WHRadjBMI)] and brain cortical thickness. Methods: Leveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on BMI(N=806,834), WHR(N=697,734), WHRadjBMI (N=694,649), and brain cortex thickness (N=33,709), we performed GWAS combining genetic correlation, multi-trait meta-analysis and Mendelian randomization analysis. Results: Our findings revealed a strong genetic correlation between BMI and brain cortical thickness(rg=-0.0542, P=0.0435), and a significant result was also observed for WHR and brain thickness (rg=-0.0744, P=0.009). In addition, we identified three loci between obesity-related traits. MR analysis supported the causal role of BMI (IVW beta=-0.006, 95% CI=-0.011– -3.85E-04；weighted median beta=-0.006, 95% CI=-0.013– -0.002), WHR (IVW beta=-0.011, 95% CI=-0.018– -0.005; weighted median beta=-0.008, 95% CI=-0.018– -0.003) and WHRadjBMI (IVW beta =0.011 95% CI=-0.018– -0.005; weighted median beta=-0.008, 95% CI=-0.018– -0.002) in brain cortical thickness. Conclusion: This study has shown that genetically predicted obesity-related traits have a causal relationship with reduced cortical thickness. These findings provide genetic evidence for a link between obesity and structural changes in the brain, and suggest that obesity may be associated with neuropsychiatric disorders by affecting brain structure, particularly cortical thickness.