Introduction
Asthma is a complex, multifactorial disease with numerous reported genetic and environmental risk factors.(1) It is estimated that genetic factors contribute to approximately 55-74% of asthma heritability, which is the proportion of the phenotypic variability attributed to genetic differences.(2,3) Genetic studies of asthma to date have reported hundreds of genes associated with asthma and related respiratory outcomes such as lung function, however, these genetic loci account for only a small fraction of the estimated heritability.(4) For example, Vicente at al. reported that 31 well-replicated asthma variants collectively explain for only 2.5% of asthma heritability. Moreover, this study estimated that all common genetic variants (i.e. single nucleotide polymorphisms or SNPs) account for only 14% of asthma heritability.(5) The difference between the estimated asthma heritability and that explained by known genetic variants is referred to as the missing heritability .
In this manuscript, we test the hypothesis that the missing heritability of asthma may be explained in part by polygenic effects of multiple genetic factors as well as interactions with environmental exposures. Genetics studies of asthma to date have focused on associations of single variants, with few evaluating the polygenic or additive effects of multiple genetic factors.(6) Such polygenic effects are assessed as genetic risk scores (GRS), which is calculated as the total number of risk alleles multiplied by their individual weights or allelic effect sizes.(7,8) Moreover, we investigate the potential interactions between genetic risk and environmental exposures during early infancy on risk of developing childhood-onset asthma.(9) Previous studies have reported interactions between a well-established locus on chromosome 17q21 and exposures to rhinovirus infection and cigarette smoke.(10–14)
This is the first genetic study of asthma using data from the Canadian CHILD Cohort Study (N=3,455) and the first study to determine GRS using results from the largest genome-wide association study (GWAS) of childhood-onset asthma to date.(15) Furthermore, we test for interactions between the GRS and modifiable exposures (e.g., breastfeeding, pet ownership, cigarette smoke, traffic air pollution) on respiratory outcomes including recurrent wheeze and asthma by age 5. Recurrent wheeze between ages 2-5 years is the primary outcome of this study given that clinical diagnosis of asthma during early childhood is known to be difficult due to heterogeneity of asthma phenotypes.(16) In addition, standard assessments of lung health for the diagnosis of asthma such as spirometry measures and methacholine challenge tests are not typically used for children before age 7.(17)
In addition to determining the polygenic effects of multiple genetic variants associated with childhood-onset asthma, this manuscript is one of few studies to assess genetic interactions with environmental exposures on respiratory outcomes during infancy. The GRS may be used to assess genetic risk of developing recurrent wheeze and asthma early in childhood, when disease risk may be modified by exposures.