HGG Advances (Jan 2023)
High-quality read-based phasing of cystic fibrosis cohort informs genetic understanding of disease modification
- Scott Mastromatteo,
- Angela Chen,
- Jiafen Gong,
- Fan Lin,
- Bhooma Thiruvahindrapuram,
- Wilson W.L. Sung,
- Joe Whitney,
- Zhuozhi Wang,
- Rohan V. Patel,
- Katherine Keenan,
- Anat Halevy,
- Naim Panjwani,
- Julie Avolio,
- Cheng Wang,
- Guillaume Côté-Maurais,
- Stéphanie Bégin,
- Damien Adam,
- Emmanuelle Brochiero,
- Candice Bjornson,
- Mark Chilvers,
- April Price,
- Michael Parkins,
- Richard van Wylick,
- Dimas Mateos-Corral,
- Daniel Hughes,
- Mary Jane Smith,
- Nancy Morrison,
- Elizabeth Tullis,
- Anne L. Stephenson,
- Pearce Wilcox,
- Bradley S. Quon,
- Winnie M. Leung,
- Melinda Solomon,
- Lei Sun,
- Felix Ratjen,
- Lisa J. Strug
Affiliations
- Scott Mastromatteo
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Angela Chen
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Jiafen Gong
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Fan Lin
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Bhooma Thiruvahindrapuram
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Wilson W.L. Sung
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Joe Whitney
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Zhuozhi Wang
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Rohan V. Patel
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Katherine Keenan
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Anat Halevy
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Naim Panjwani
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Julie Avolio
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Cheng Wang
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Guillaume Côté-Maurais
- Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Stéphanie Bégin
- Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Damien Adam
- Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Emmanuelle Brochiero
- Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Candice Bjornson
- Alberta Children’s Hospital, Calgary, AB, Canada
- Mark Chilvers
- British Columbia Children’s Hospital, Vancouver, BC, Canada
- April Price
- The Children’s Hospital, London Health Science Centre, London, ON, Canada
- Michael Parkins
- University of Calgary, Department of Medicine, Calgary, AB, Canada
- Richard van Wylick
- Kingston Health Sciences Centre, Kingston, ON, Canada
- Dimas Mateos-Corral
- IWK Health Centre, Halifax, NS, Canada
- Daniel Hughes
- IWK Health Centre, Halifax, NS, Canada
- Mary Jane Smith
- Memorial University of Newfoundland, Faculty of Medicine, St. John’s, NL, Canada
- Nancy Morrison
- Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
- Elizabeth Tullis
- St. Michael’s Hospital, Toronto, ON, Canada
- Anne L. Stephenson
- St. Michael’s Hospital, Toronto, ON, Canada
- Pearce Wilcox
- St. Paul’s Hospital, Vancouver, BC, Canada
- Bradley S. Quon
- St. Paul’s Hospital, Vancouver, BC, Canada
- Winnie M. Leung
- University of Alberta Hospital, Edmonton, AB, Canada
- Melinda Solomon
- Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada
- Lei Sun
- Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Felix Ratjen
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada
- Lisa J. Strug
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada; Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Department of Computer Science, University of Toronto, Toronto, ON, Canada; Corresponding author
- Journal volume & issue
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Vol. 4,
no. 1
p. 100156
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.
