Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort

Abstract

Background: Childhood wheezing and asthma vary greatly in clinical presentation and time course. The extent to which phenotypic variation reflects heterogeneity in disease pathways is unclear.

Objective: We sought to assess the extent to which single nucleotide polymorphisms (SNPs) associated with childhood asthma in a genome-wide association study are predictive of asthma-related phenotypes.

Methods: In 8365 children from a population-based birth cohort, the Avon Longitudinal Study of Parents and Children, allelic scores were derived based on between 10 and 215,443 SNPs ranked according to the inverse of the P value for their association with physician-diagnosed asthma in an independent genome-wide association study (6176 cases and 7111 control subjects). We assessed the predictive value of allelic scores for asthma-related outcomes at age 7 to 9 years (physician's diagnosis, longitudinal wheezing phenotypes, and measurements of pulmonary function, bronchial responsiveness, and atopy).

Results: Scores based on the 46 highest-ranked SNPs were associated with the symptom-based phenotypes early onset persistent wheeze (P< 10(-11); area under the receiver operating characteristic curve [AUC], 0.59) and intermediate-onset wheeze (P< 10(-3); AUC, 0.58). Among lower-ranked SNPs (ranks, 21,545-46,416), there was evidence for associations with diagnosed asthma (P< 10(-4); AUC, 0.54) and atopy (P< 10(-5); AUC, 0.55). We found little evidence of associations with transient early wheezing, reduced pulmonary function, or nonasthma phenotypes.

Conclusion: The genetic origins of asthma are diverse, and some pathways are specific to wheezing syndromes, whereas others are shared with atopy and bronchial hyperresponsiveness. Our study also provides evidence of etiologic differences among wheezing syndromes.

Figure 1. Manhattan plot of pooled results for physician diagnosed asthma in GABRIEL childhood cohorts excluding ALSPAC

Horizontal lines represent genetic prediction scores with varying number (shown to the right of each line) of included SNPs. All SNPs with P-values above a line are included in the respective score.

Figure 2. Comparison of predictive value of allelic log-odds scores for the defined outcomes in mid-childhood

Data: area under ROC curve (AUC) (sub-figures A), inter-quartile odds ratio (IQOR) (B) and P-values for association (C). Outcomes: outcomes based on a physician’s diagnosis (A1-C1), phenotypes of wheeze in the first seven years of life (A2-C2), physiological measurements (A3-C3), and non-asthma outcomes (A4-C4). SNPs included in inverse order of their P-values in an independent GWAS for physician diagnosed asthma.