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


Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders1. 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 large2. 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 alleles3. 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.

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Figure 1: Primary results for DCTN4 from exome discovery and validation phases.


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We thank the families for their participation and the EPIC study site investigators and research coordinators (Supplementary Note) for their assistance. We thank A. Bigham, S. Leal, M. Rosenfeld, B. Ramsey, N. Hamblett, K. Buckingham, M. McMillin, S. McNamara and S. Ruuska for technical assistance and helpful discussion. The authors wish to acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (Lung GO) and RC2 HL-102924 (Women's Health Initiative Sequencing Project (WHISP)). Exome sequencing was performed with support from NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Our work was supported in part by grants from the Cystic Fibrosis Foundation (to R.L.G. (GIBSON07K0) and to M. Rosenfeld and R.L.G. (CFF EPIC09K0)), the US National Institutes of Health/National Human Genome Research Institute (5RO1 HG004316 to H.K.T.), and the Life Sciences Discovery Fund (2065508 and 0905001). K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program.

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The project was conceived and experiments planned by M.J.B., M.J.E., M.R.K., K.C.B. and R.L.G. Review of phenotypes and sample collection were performed by M.J.B., M.J.E., R.L.G., J.E. and M.R.K. Experiments were performed by M.J.R. and D.A.N. Regulatory review and guidance was provided by H.K.T. Data analysis was performed by M.J.E., J.E., T.L., F.A.W., W.Z. and R.A.M. The manuscript was written by M.J.B., M.J.E. and R.L.G. All aspects of the study were supervised by M.J.B., M.J.E. and R.L.G.

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Correspondence to Mary J Emond or Michael J Bamshad.

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The authors declare no competing financial interests.

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A full list of members and their affiliations is provided in the Supplementary Note.

A full list of members and their affiliations is provided in the Supplementary Note.

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Supplementary Tables 1–5, Supplementary Figures 1–16 and Supplementary Note (PDF 657 kb)

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Emond, M., Louie, T., Emerson, J. et al. Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nat Genet 44, 886–889 (2012).

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