Polygenic heritability estimates in pharmacogenetics: focus on asthma and related phenotypes

Abstract

Although accurate measures of heritability are required to understand the pharmacogenetic basis of drug treatment response, these are generally not available, as it is unfeasible to give medications to individuals for which treatment is not indicated. Using a polygenic linear mixed modeling approach, we estimated lower bounds on the heritability of asthma and the heritability of two related drug-response phenotypes, bronchodilator response and airway hyperreactivity, using genome-wide single nucleotide polymorphism (SNP) data from existing asthma cohorts. Our estimate of the heritability for bronchodilator response is 28.5% (SE 16%, P=0.043) and airway hyperresponsiveness is 51.1% (SE 34%, P=0.064), whereas we estimate asthma genetic liability at 61.5% (SE 16%, P<0.001). Our results agree with the previously published estimates of the heritability of these traits, suggesting that the linear mixed modeling method is useful for computing the heritability of other pharmacogenetic traits. Furthermore, our results indicate that multiple SNP main effects, including SNPs as yet unidentified by genome-wide association study methods, together explain a sizable portion of the heritability of these traits.

Figure 1

Heritability of Asthma, BDR, and AHR by different numbers of genotype principal components included. Heritability values above 1.0 represent model convergence failures, and do not represent stable estimates of true heritability. This figure shows that the heritability estimates of each phenotype can vary with the number of included genotype PCs, but remain mostly stable for a range of PCs between 10 and 35.