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

https://doi.org/10.1016/j.xhgg.2022.100156Get rights and content
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Summary

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.

Keywords

meconium ileus
cystic fibrosis
phasing
trypsinogen
CFTR
PRSS2
pancreatitis
linked-reads
colocalization
eQTL

Data and code availability

The CGMS genotype data and 10XG data reported in this study are available at the Canadian CF registry at https://www.cysticfibrosis.ca/our-programs/cf-registry/requesting-canadian-cf-registry-data. The GTEx RNA-seq data and GTEx v8 variant calls are available at dbGaP: phs000424.v8.p and the GTEx Portal at https://www.gtexportal.org/home/datasets/, respectively. The source code for the CFTbaRcodes tool generated during this study is available at https://github.com/strug-hub/CFTbaRcodes with documentation available at https://cftbarcode.readthedocs.io/en/latest/.

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