Genome-wide Interrogation of Longitudinal FEV_1 in Children with Asthma

摘要

Rationale: Most genomic studies of lung function have used phenotypic data derived from a single time-point (e.g., presence/absence of disease) without considering the dynamic progression of a chronic disease. Objectives: To characterize lung function change over time in subjects with asthma and identify genetic contributors to a longitudinal phenotype. Methods: We present a method that models longitudinal FEV_1 data, collected from 1,041 children with asthma who participated in the Childhood Asthma Management Program. This longitudinal progression model was built using population-based nonlinear mixed-effects modeling with an exponential structure and the determinants of age and height. Measurements and Main Results: We found ethnicity was a key covariate for FEV_1 level. Budesonide-treated children with asthma had a slight but significant effect on FEV_1 when compared with those treated with placebo or nedocromil (P ＜ 0.001). A genome-wide association study identified seven single-nucleotide polymorphisms nominally associated with longitudinal lung function phenotypes in 581 white Childhood Asthma Management Program subjects (P ＜ 10~(-4) in the placebo ["discovery"] and P ＜ 0.05 in the nedocromil treatment ["replication"] group). Using ChIP-seq and RNA-seq data, we found that some of the associated variants were in strong enhancer regions in human lung fibroblasts and may affect gene expression in human lung tissue. Genetic mapping restricted to genome-wide enhancer single-nucleotide polymorphisms in lung fibroblasts revealed a highly significant variant (rs6763931; P = 4 × 10~(-6); false discovery rate ＜ 0.05). Conclusions: This study offers a strategy to explore the genetic determinants of longitudinal phenotypes, provide a comprehensive picture of disease pathophysiology, and suggest potential treatment targets.