NAFLD’s Predisposion: insight from phenome-wide association and Mendelian Randomization

Genome-wide association studies (GWAS) meta-analysis have unveiled common single nucleotide polymorphisms (SNPs) associated with the increased risk of Non-alcoholic fatty liver disease (NAFLD). We conducted a phenome-wide association study (PheWAS) using data from the UK Biobank to further elucidate NAFLD-associated phenotypes and investigate the disease's underlying biology. A significant enrichment was found in 31 of 778 traits examined using 17 known NAFLD-risk SNPs along with 4:1 matched control SNPs. We explored genetic correlations and causal relationships by employing bidirectional Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC). Notably, strong positive genetic correlations with NAFLD were observed for BMI (r _g = 0.73), Trunk fat mass (r _g = 0.67), Type 2 diabetes (r _g = 0.86), and weight (r _g = 0.57), while whole-body impedance (r _g = -0.31) and neutrophil count (r _g = -0.28) exhibited negative correlations. Our MR analysis demonstrated unidirectional effects of BMI (OR = 1.57), Trunk fat mass (OR = 1.40), Weight (OR = 1.22), whole-body Impedance (OR = 0.83), and Type 2 diabetes (OR = 1.42) on NAFLD risk. Intriguingly, bidirectional causal effects were identified between Alcohol intake frequency and NAFLD (OR _{Alcohol intake frequency → NAFLD} = 1.42; OR _{NAFLD → Alcohol intake frequency} = 1.02), suggesting a complex interplay. Furthermore, through intermediary MR analyses, we uncovered pathways mediated by FGF21 and IL-10RB, linking BMI and Trunk fat mass, respectively, to NAFLD development. These findings provide novel insights into the multifaceted genetic landscape of NAFLD, highlighting the importance of body composition, metabolic health, and lifestyle factors in its pathogenesis.