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.