| Summary: | Abstract Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes. Patients with simple steatosis typically experience a benign course, whereas those with more advanced liver injury, nonalcoholic steatohepatitis (NASH), and advanced stage fibrosis suffer increased risk for complications such as cirrhosis, hepatic decompensation, and liver cancer. Genetic variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) and clinical factors including diabetes, obesity, and older age increase a patient's risk for NASH, advanced fibrosis, and worse outcomes. Despite substantial investigation and identification of some common variants associated with NAFLD and advanced fibrosis, the genetics and functional mechanisms remain poorly understood. This study aimed to identify genetic variants by whole‐exome sequencing of NAFLD phenotypes to provide novel insights into mechanisms behind NAFLD pathogenesis and variability. We sequenced 82 patients with liver biopsy–confirmed NAFLD and 4455 population controls. NAFLD patients were divided into extreme phenotypes based on liver fibrosis stage and clinical risk factors to investigate rare variants that might predispose to or protect from advanced NAFLD fibrosis. We compared NAFLD extremes to each other and individually to population controls, exploring genetic variation at both the single‐variant and gene‐based level. We replicated known associations with PNPLA3 and TM6SF2 and advanced fibrosis, despite sample‐size limitations. We also observed enrichment of variation in distinct genes for progressor or protective NAFLD phenotypes, although these genes did not reach statistical significance. Conclusion: We report the first whole‐exome sequencing study of genetic variation in liver biopsy–confirmed NAFLD susceptibility and severity, using a small cohort of extreme NAFLD phenotypes and a large cohort of population controls.
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