High-quality read-based phasing of cystic fibrosis cohort informs genetic understanding of disease modification.

Phasing of heterozygous alleles is critical for interpretation of cis -effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using linked-read sequencing, which display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, demonstrating its utility for understanding complex CF alleles. These are visualized in a Web app, CFTbaRcodes, that enables interactive exploration of CFTR haplotypes present in this cohort. We perform fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus, an intestinal obstruction at birth associated with more severe CF outcomes and pancreatic disease. A 20-kb deletion polymorphism and a PRSS2 missense variant p.Thr8Ile (rs62473563) are shown to independently contribute to meconium ileus risk (p = 0.0028, p = 0.011, respectively) and are PRSS2 pancreas eQTLs (p = 9.5 × 10 ^-7 and p = 1.4 × 10 ^-4 , respectively), suggesting the mechanism by which these polymorphisms contribute to CF. The phase information from linked reads provides a putative causal explanation for variation at a CF-relevant locus, which also has implications for the genetic basis of non-CF pancreatitis, to which this locus has been reported to contribute.
Competing Interests: D.M.-C. received an honorarium for teaching module development for Vertex Pharmaceuticals. N.M. is doing contract research trials for Vertex Phaemaceuticals and Abbvie. A.L.S. has received speaking fees for educational programs sponsored by Vertex Pharmaceuticals. B.S.Q. has received speaker fees from Vertex Pharmaceuticals and has served as site principal investigator for several Vertex-sponsored clinical trials. W.M.L. is a study investigator for Vertex Pharmaceuticals. E.T. and F.R. act as consultants for Vertex Pharmaceuticals. M.S. participated in Vertex clinical trials and received payment for education modules. S.M., A.C., J.G., F.L., B.T., W.W.L.S., J.W., Z.W., R.V.P., K.K., A.H., N.P., J.A., C.W., G.C.M., S.B., D.A., E.B., C.B., M.C., A.P., M.P., R.V.W., D.H., M.J.S., E.T., P.W., L.S., F.R., and L.J.S. declare no competing interests.
(© 2022 The Authors.)