Development of a Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease Prediction in UK...

Area of Science:

• Genetics and Genomics
• Hepatology
• Medical Imaging

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of liver morbidity and mortality.
• Liver biopsy is invasive; MRI-PDFF offers non-invasive assessment of treatment response.
• Genetic predisposition to MASLD requires further investigation for improved prediction.

Purpose of the Study:

• To develop a Polygenic Risk Score (PRS) for predicting MASLD.
• To enhance the predictive accuracy of Magnetic Resonance Imaging-derived Proton Density Fat Fraction (MRI-PDFF) for MASLD.
• To assess the utility of PRS in predicting MASLD genetic liability using UK Biobank data.

Main Methods:

• Utilized UK Biobank data with GWAS summary statistics and raw genotype data.
• Employed PRSice2 to derive PRS candidates and generated SNP sets based on frequency cutoffs.
• Validated the optimal PRS on a Greek nonalcoholic fatty liver disease (NAFLD) cohort.

Main Results:

• An optimal PRS comprising 75 SNPs was identified, significantly improving prediction (incremental R² = 0.025, p=0.00145).
• 43 of the selected SNPs mapped to known MASLD-related genes.
• The PRS successfully predicted related traits (LDL cholesterol, diastolic blood pressure) and disease outcomes in different cohorts.

Conclusions:

• PRS demonstrates significant potential as a predictive model for MASLD.
• The developed PRS is applicable across diverse ethnic populations.
• This genetic approach enhances non-invasive MASLD assessment and prediction.