title: Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.
abstract: Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored.
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Emond
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Tin
authors.initials: T
authors.lastname: Louie
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, United States of America; Center for Clinical and Translational Medicine, Seattle Children's Research Institute Seattle, Washington, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Emerson
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, United States of America; Trueman-Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Holly K
authors.initials: HK
authors.lastname: Tabor
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lung
authors.initials: L
authors.lastname: Go
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, United States of America; Division of Pulmonary Medicine, Seattle Children's Hospital, Seattle, Washington, United States of America.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Gibson
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, United States of America; Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
mesh_terms: D000293:Adolescent; D051243:Caveolin 2 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications / Q000175:diagnosis / Q000382:microbiology*; D059472:Exome; D005260:Female; D060045:Genes, Modifier; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011552:Pseudomonas Infections / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D011550:Pseudomonas aeruginosa
chemical_list: C495544:CAV2 protein, human; D051243:Caveolin 2; D008565:Membrane Proteins; C470314:TMC6 protein, human