Genetic evidence for the causal relationship between NAFLD and brain functional connectivity

Abstract

Liver disease is responsible for approximately 2 million deaths each year worldwide [1]. As one of the most prevalent liver diseases, Non-Alcoholic Fatty Liver Disease (NAFLD) is a term for a range of liver conditions affecting patients who drink little or no alcohol, but have over-storage of fat in their liver cells. The correlation existing between NAFLD and the brain has been well established by past studies. NAFLD has been found to be associated with cerebral risk factors including brain lesions, alterations in cerebral perfusion and activity [2], as well as certain brain phenotypes, such as cerebral brain volume [3] and White Matter Hyperintensities (WMH) [4]. A better knowledge of the association could lead to an improved management of risk, or at least lay a foundation for finding explanations for those correlation between the two, implying possible practical implications. In this study, we integrated two Genome-wide Association Studies (GWAS) datasets of Magnetic Resonance Imaging (MRI) of brain traits and NAFLD through Mendelian Randomization (MR), aiming to determine causal relationship as well as the direction of causality between NAFLD and certain brain phenotypes. We found that the functional connectivity between the brain region responsible for vision and that associated with emotional responses is significantly reduced by a higher risk of NAFLD (b≈-0.13, pval≈2.3E-05). The enrichment analysis also shows that the functional connectivity between brain regions is more likely to be affected by NAFLD, while the structural connectivity (measured by dMRI) is less likely to be influenced. Together our result provides a systematic evaluation for the association between NAFLD and brain phenotypes, and prioritizes the functional connectivity that tends to be affected by NAFLD, which could offer insight for the clinical diagnosis and treatment of NAFLD-induced cerebral disorders.