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.
Highlights
Cystic fibrosis (CF) (MIM219700) is a life shortening, monogenic condition caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR) [1]
We used exome sequencing to identify variants in CAV2 and TMC6 that modify the age-of-onset of chronic Pseudomonas aeruginosa infection among children with cystic fibrosis, and validated our findings in a large cohort of children with cystic fibrosis
We employed an alternative design that compares genetic frequencies in exomes sampled from one extreme to that among exomes from a large set of controls. We show that this design confers substantially greater statistical power for discovery of CAV2 and TMC6 and provide general conditions under which this single extreme versus control design is more powerful than the extreme phenotypes design
Summary
Cystic fibrosis (CF) (MIM219700) is a life shortening, monogenic condition caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR) [1]. P. aeruginosa airway infection in individuals with CF is associated with increased morbidity and reduced survival [4,5,6]. In a large registry-based study, any history of P. aeruginosa airway infection at or before age 2 years was associated with reduced lung function, increased frequency of pulmonary exacerbations and reduced survival [4,5,6]. Onset of mucoid P. aeruginosa is associated with a sharp decline in lung function [7,8] and even higher mortality [9]. These observations support a causal relationship between frequent P. aeruginosa infection and morbidity and mortality in CF. Aggressive acute and maintenance antibiotic treatment of P. aeruginosa infection in individuals with CF in the U.S has coincided with a rise in the median predicted survival from 28 to 38 years [11]
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