Jaclyn R Stonebraker, Rhonda G Pace, Paul J Gallins, Hong Dang, Melis A Aksit, Anna V Faino, William W Gordon, Sonya MacParland, Michael J Bamshad, Ronald L Gibson, Garry R Cutting, Peter R Durie, Fred A Wright, Yi-Hui Zhou, Scott M Blackman, Wanda K O'Neal, Simon C Ling, Michael R Knowles
BACKGROUND AND AIMS: It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF (pwCF). We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. APPROACH AND RESULTS: Whole genome sequencing was available in 4,082 pwCF with pancreatic insufficiency (n=516 with severe CFLD; n=3,566 without CFLD). We tested ~15.9 million SNPs for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including: 1) genetic variant (SERPINA1; Z-allele) previously associated with severe CFLD; 2) candidate SNPs (n=205) associated with non-CF liver diseases; 3) genome-wide association study (GWAS) of common/rare SNPs; 4) transcriptome-wide association (TWAS); and 5) gene-level and pathway analyses...
March 27, 2024: Hepatology: Official Journal of the American Association for the Study of Liver Diseases