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

ABSTRACT: 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.

SUBMITTER: Mastromatteo S

PROVIDER: S-EPMC9647008 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Mastromatteo Scott S Chen Angela A Gong Jiafen J Lin Fan F Thiruvahindrapuram Bhooma B Sung Wilson W L WWL Whitney Joe J Wang Zhuozhi Z Patel Rohan V RV Keenan Katherine K Halevy Anat A Panjwani Naim N Avolio Julie J Wang Cheng C Côté-Maurais Guillaume G Bégin Stéphanie S Adam Damien D Brochiero Emmanuelle E Bjornson Candice C Chilvers Mark M Price April A Parkins Michael M van Wylick Richard R Mateos-Corral Dimas D Hughes Daniel D Smith Mary Jane MJ Morrison Nancy N Tullis Elizabeth E Stephenson Anne L AL Wilcox Pearce P Quon Bradley S BS Leung Winnie M WM Solomon Melinda M Sun Lei L Ratjen Felix F Strug Lisa J LJ

HGG advances 20221020 1

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</i ...[more]

PMID: 36386424

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Project description:BackgroundLung disease as major cause for morbidity in patients with cystic fibrosis (CF) starts early in life. Its large phenotypic heterogeneity is partially explained by the genotype but other contributing factors are not well delineated. The close relationship between mucus, inflammation and infection, drives morpho-functional alterations already early in pediatric CF disease, The TRACK-CF cohort has been established to gain insight to disease onset and progression, assessed by lung function testing and imaging to capture morpho-functional changes and to associate these with risk and protective factors, which contribute to the variation of the CF lung disease progression.Methods and designTRACK-CF is a prospective, longitudinal, observational cohort study following patients with CF from newborn screening or clinical diagnosis throughout childhood. The study protocol includes monthly telephone interviews, quarterly visits with microbiological sampling and multiple-breath washout and as well as a yearly chest magnetic resonance imaging. A parallel biobank has been set up to enable the translation from the deeply phenotyped cohort to the validation of relevant biomarkers. The main goal is to determine influencing factors by the combined analysis of clinical information and biomaterials. Primary endpoints are the lung clearance index by multiple breath washout and semi-quantitative magnetic resonance imaging scores. The frequency of pulmonary exacerbations, infection with pro-inflammatory pathogens and anthropometric data are defined as secondary endpoints.DiscussionThis extensive cohort includes children after diagnosis with comprehensive monitoring throughout childhood. The unique composition and the use of validated, sensitive methods with the attached biobank bears the potential to decisively advance the understanding of early CF lung disease.Ethics and trial registrationThe study protocol was approved by the Ethics Committees of the University of Heidelberg (approval S-211/2011) and each participating site and is registered at clinicaltrials.gov (NCT02270476).

Project description:ContextA subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.ObjectiveTo assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.Design, setting, and participantsTwo-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.Main outcome measuresDifferences in distribution of genotypes in patients with CFLD vs patients without CFLD.ResultsThe initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).ConclusionsThe SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Dataset Information

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

Publications

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

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