Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis

被引:174
作者
Emond, Mary J. [1 ]
Louie, Tin [1 ]
Emerson, Julia [2 ,3 ]
Zhao, Wei [1 ]
Mathias, Rasika A. [4 ]
Knowles, Michael R. [5 ]
Wright, Fred A. [6 ]
Rieder, Mark J. [7 ]
Tabor, Holly K. [2 ,8 ]
Nickerson, Deborah A. [7 ]
Barnes, Kathleen C. [4 ]
Go, Lung
Gibson, Ronald L. [2 ,9 ]
Bamshad, Michael J. [2 ,7 ,10 ]
机构
[1] Univ Washington, Dept Biostat, Seattle, WA 98195 USA
[2] Univ Washington, Dept Pediat, Seattle, WA 98195 USA
[3] Seattle Childrens Res Inst, Ctr Clin & Translat Med, Seattle, WA USA
[4] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[5] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC USA
[6] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA
[7] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
[8] Seattle Childrens Res Inst, Trueman Katz Ctr Pediat Bioeth, Seattle, WA USA
[9] Seattle Childrens Hosp, Div Pulm Med, Seattle, WA USA
[10] Seattle Childrens Hosp, Div Med Genet, Seattle, WA USA
基金
美国国家卫生研究院;
关键词
GENOME-WIDE ASSOCIATION; CF PATIENTS; DISEASE; ACQUISITION; DISCOVERY; AUTOPHAGY; CHILDREN;
D O I
10.1038/ng.2344
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders(1). 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(2). 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(3). 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.
引用
收藏
页码:886 / +
页数:6
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