Age-Specific Associations of Polygenic Risk Scores With Advanced Fibrosis and Histological Activity in Biopsy-Proven...

The genetic susceptibility to MASLD histological severity remains incompletely defined. We assessed the associations between recently developed genome-wide association studies-derived polygenic risk scores (PRSs) and advanced fibrosis in MASLD. We also evaluated PRSs' associations with histological activity and selected PRSs' predictive ability for advanced fibrosis.

We analysed 2149 adults and 900 children with biopsy-proven MASLD from the NASH Clinical Research Network studies. Genotyping was performed by the Regeneron Genetics Center using whole-exome sequencing with targeted genotyping. Associations between seven published PRSs (Chen, Emdin, Whitfield, Schwantes-An, Vujkovic, and Ghouse) and MASLD histological features were examined using linear and logistic regression models. Penalized regression models were used to select top PRSs associated with MASLD traits.

The Schwantes-An PRS in adults (OR 1.29, 95% CI 1.17-1.42, p < 0.01) and the Chen PRS in children (OR 1.46, 95% CI 1.17-1.82, p < 0.01) were associated with higher risk of advanced fibrosis versus other PRSs. The Chen PRS in adults (OR 1.29, 95% CI 1.18-1.41, p < 0.01) and Schwantes-An PRS in children (OR 1.39, 95% CI 1.20-1.61, p < 0.05) were associated with higher risk with MASLD activity. Although highest PRSs quartiles were associated with advanced fibrosis risk versus bottom quartiles, neither PRS had good diagnostic discrimination for advanced fibrosis (AUROC < 60%).

In this large biopsy-proven MASLD cohort, two distinct PRSs were associated with disease histological severity and activity in adults versus children. Findings suggest current PRSs may improve personalized risk stratification for advanced fibrosis but not its diagnosis.