DOAJ Open Access 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 +31 lainnya

Abstrak

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.

Topik & Kata Kunci

Genetics

Penulis (36)

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

Format Sitasi

APA MLA BibTeX

Mastromatteo, S., Chen, A., Gong, J., Lin, F., Thiruvahindrapuram, B., Sung, W.W. et al. (2023). High-quality read-based phasing of cystic fibrosis cohort informs genetic understanding of disease modification. https://doi.org/10.1016/j.xhgg.2022.100156

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Informasi Jurnal

Tahun Terbit: 2023
Sumber Database: DOAJ
DOI: 10.1016/j.xhgg.2022.100156
Akses: Open Access ✓