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The cumulative effects of known susceptibility variants to predict primary biliary cirrhosis risk

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An Erratum to this article was published on 23 April 2015

Abstract

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 26 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. The area under curve 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 disclosed risk group demonstrated a substantially increased risk for PBC compared with the lowest risk group (odds ratio: 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.

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Acknowledgements

We are grateful to all the subjects of this study for their participation. The Italian GWAS data set used in this manuscript was obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000444.v1.p1. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. The study was sponsored by Foundation for the Author of National Excellent Doctoral Dissertation of PR China (201325 to R.T) and awards from the National Natural Science Foundation of China (81170380 and 81325002 to XM). This work was supported in part by grants from the National Institutes of Health (R01AR065174 and K08AR057763 to WL and R01DK091823 to MEG and MFS).

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Correspondence to M E Gershwin, W Liao or X Ma.

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Tang, R., Chen, H., Miao, Q. et al. The cumulative effects of known susceptibility variants to predict primary biliary cirrhosis risk. Genes Immun 16, 193–198 (2015). https://doi.org/10.1038/gene.2014.76

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