Exome sequencing of extreme phenotypes

Individuals with cystic fibrosis are at high risk for Pseudomonas aeruginosa infection, which is associated with worse long-term pulmonary disease and survival. A study published online this week in Nature Genetics reports genetic variants associated with susceptibility to P. aeruginosa infection.

In order to identify host genetic factors that influence risk of P. aeruginosa infection, Michael Bamshad, Mary Emond and colleagues used an extreme phenotype study design, selecting individuals who are at the extreme ends of a phenotype distribution, combined with exome sequencing. Exome sequencing of forty-three individuals with early age of onset of chronic P. aeruginosa infection and 48 older individuals who had not reached chronic P. aeruginosa infection was performed as part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP). This analysis identified variants in DCTN4 that are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis. They validated the finding in 696 additional individuals with cystic fibrosis.