title: Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis.
abstract: Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.
authors: Department of Biostatistics, University of Washington, Seattle, Washington, USA. mbamshad@u.washington.edu
authors: Mary J
authors: MJ
authors: Emond
authors: Tin
authors: T
authors: Louie
authors: Julia
authors: J
authors: Emerson
authors: Wei
authors: W
authors: Zhao
authors: Rasika A
authors: RA
authors: Mathias
authors: Michael R
authors: MR
authors: Knowles
authors: Fred A
authors: FA
authors: Wright
authors: Mark J
authors: MJ
authors: Rieder
authors: Holly K
authors: HK
authors: Tabor
authors: Deborah A
authors: DA
authors: Nickerson
authors: Kathleen C
authors: KC
authors: Barnes
authors: Ronald L
authors: RL
authors: Gibson
authors: Michael J
authors: MJ
authors: Bamshad
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications* / Q000235:genetics*; D000072159:Dynactin Complex; D059472:Exome; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011552:Pseudomonas Infections / Q000209:etiology* / Q000235:genetics*; D011550:Pseudomonas aeruginosa
chemical_list: C000606363:DCTN4 protein, human; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins