Alberts R, et al. – Here, the authors identify genetic variants associated with primary sclerosing cholangitis (PSC) disease progression and development of complications. They perform a large international PSC cohort and report genetic loci correlated with PSC disease progression. They identify a genome–wide significant signal and demonstrate expression of the candidate gene RSPO3 in key liver–resident effector cells for liver transplant–free survival. This warrants additional assessments of the role of this potential key PSC modifier gene.