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

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

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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 il barone wine 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 iphone 14 price san francisco 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.