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High-quality read-based phasing of cystic fibrosis cohort informs genetic understanding of disease modification
- Source :
- HGG Advances, Vol 4, Iss 1, Pp 100156- (2023)
- Publication Year :
- 2023
- Publisher :
- Elsevier, 2023.
-
Abstract
- 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.
- Subjects :
- meconium ileus
cystic fibrosis
phasing
trypsinogen
CFTR
PRSS2
Genetics
QH426-470
Subjects
Details
- Language :
- English
- ISSN :
- 26662477
- Volume :
- 4
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- HGG Advances
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.000a1d3c634e4c91b0e728e58acc8bdb
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.xhgg.2022.100156