Gene expression in transformed lymphocytes reveals variation in endomembrane and HLA pathways modifying cystic fibrosis pulmonary phenotypes

Wanda K O'Neal; Paul Gallins; Rhonda G Pace; Hong Dang; Whitney E Wolf; Lisa C Jones; XueLiang Guo; Yi-Hui Zhou; Vered Madar; Jinyan Huang; Liming Liang; Miriam F Moffatt; Garry R Cutting; Mitchell L Drumm; Johanna M Rommens; Lisa J Strug; Wei Sun; Jaclyn R Stonebraker; Fred A Wright; Michael R Knowles

doi:10.1016/j.ajhg.2014.12.022

Gene expression in transformed lymphocytes reveals variation in endomembrane and HLA pathways modifying cystic fibrosis pulmonary phenotypes

Am J Hum Genet. 2015 Feb 5;96(2):318-28. doi: 10.1016/j.ajhg.2014.12.022. Epub 2015 Jan 29.

Authors

Wanda K O'Neal¹, Paul Gallins², Rhonda G Pace³, Hong Dang³, Whitney E Wolf³, Lisa C Jones³, XueLiang Guo³, Yi-Hui Zhou⁴, Vered Madar⁵, Jinyan Huang⁶, Liming Liang⁷, Miriam F Moffatt⁸, Garry R Cutting⁹, Mitchell L Drumm¹⁰, Johanna M Rommens¹¹, Lisa J Strug¹², Wei Sun¹³, Jaclyn R Stonebraker³, Fred A Wright¹⁴, Michael R Knowles³

Affiliations

¹ Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: wanda_o'neal@med.unc.edu.
² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA.
⁵ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁷ Department of Biostatistics, Harvard University, Boston, MA 02115, USA.
⁸ National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
⁹ McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁰ Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
¹¹ Program in Genetics and Genome Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X8, Canada.
¹² Program in Child Health Evaluative Sciences, The Hospital for Sick Children, and Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, ON M5G 1X8, Canada.
¹³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁴ Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA; Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA.

Abstract

Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P. aeruginosa) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. LPAR6, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent P. aeruginosa infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cystic Fibrosis / genetics*
Cystic Fibrosis / pathology*
Endoplasmic Reticulum Stress / genetics
Gene Expression Profiling
Genes, MHC Class I / genetics*
Genetic Variation*
Humans
Linear Models
Phenotype*
Receptors, Lysophosphatidic Acid / genetics*
Sequence Deletion / genetics

Substances

LPAR6 protein, human
Receptors, Lysophosphatidic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding