The Cumulative Effects of Known Susceptibility Variants to Predict Primary Biliary Cirrhosis Risk

Multiple genetic variants influence the risk for development of primary biliary cirrhosis (PBC). To explore the cumulative effects of known susceptibility loci on risk, we utilized a weighted genetic risk score (wGRS) to evaluate whether genetic information can predict susceptibility. The wGRS was created using twenty-six known susceptibility loci and investigated in 1840 UK PBC and 5164 controls. Our data indicate that the wGRS was significantly different between PBC and controls (P=1.61E-142). Moreover, we assessed predictive performance of wGRS on disease status by calculating the area under the receiver operator characteristic curve (AUC). The AUC for the purely genetic model was 0.72 and for gender plus genetic model was 0.82, with confidence limits substantially above random predictions. The risk of PBC using logistic regression was estimated after dividing individuals into quartiles. Individuals in the highest risk group disclosed demonstrated a substantially increased risk for PBC, compared to the lowest risk group (OR: 9.3, P=1.91E-084). Finally, we validated our findings in an analysis of an Italian PBC cohort. Our data suggested that the wGRS utilizing genetic variants was significantly associated with increased risk for PBC with consistent discriminant ability. Our study is a first step toward risk prediction for PBC.