Mechanisms of allergy and clinical immunology
Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort

https://doi.org/10.1016/j.jaci.2012.06.002Get rights and content

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.

Section snippets

Methods

More detail is provided in the Methods section of this article’s Online Repository at www.jacionline.org.

Results

Genetic data were available for 8365 unrelated white European ALSPAC children. Of these, 5748 (68.7%) replied to the questionnaire at age 7 years, and 6128 (73.3%) and 5621 (67.2%) participated in study clinics at ages 7 to 8 and 8 to 9 years, respectively. Wheezing phenotypes based on repeated assessment of current wheeze throughout the first 7 years of life3 were available in 7176 (85.8%) children. Of these, 506 (7.1%) had persistent, 338 (4.7%) had late-onset, 168 (2.3%) had

Main findings

We used SNPs associated with asthma in the GABRIEL GWAS16 to construct genome-wide prediction scores and evaluated their performance in an independent population-based birth cohort study. Prediction scores were most strongly associated with the persistent and intermediate-onset wheezing phenotypes, which were defined previously by using latent class analysis.3 We found associations with asthma among the lower-ranked SNPs with P values for association that did not reach genome-wide thresholds in

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    The UK Medical Research Council and the Wellcome Trust (grant reference 092731) and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children. B.D.S. is the recipient of a European Respiratory Society/Marie Curie Joint Research Fellowship (no. MC 1614-2010). The research leading to these results has received funding from the European Respiratory Society and the European Community’s Seventh Framework Programme FP7/2007-2013–Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571. R.G. was supported by the UK Medical Research Council (grant no. 0401540). The GABRIEL project was supported by a contract from the European Commission (018996) and grants from the French Ministry of Research, the Wellcome Trust (WT084703MA), and Asthma UK.

    Disclosure of potential conflict of interest: J. Henderson, G. D. Smith, and J. A. C. Sterne receive research support from the Medical Research Council and the Wellcome Trust. R. Granell receives research support from the Medical Research Council. The rest of the authors declare that they have no relevant conflicts of interest.

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