Investigating Imprinting as a Mechanism for the Development of Asthma in Two Canadian Birth Cohorts
1. Centre for Heart Lung Innovation, Faculty of Medicine, University of British Columbia, Vancouver, BC; 2. Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, MB; 3. Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB
Background: Asthma is a complex disease caused by a combination of genetic and environmental factors. To date, 37 genome-wide association studies (GWAS) have been completed for asthma-related traits, including childhood onset and treatment response. Among these studies, 23 considered asthma as the primary phenotype of interest (http://www.genome.gov/26525384). Combined, these 23 asthma studies have identified 44 SNPs at a p value <1x10-6. The consensus is that main genetic effects of these common SNPs (with modest effects) do not fully explain the heritability of asthma. This has led to further studies of more complex interaction (gene-gene and gene-environment) models to identify the missing heritability in asthma. Genomic imprinting is an alternative mechanism, which may explain some of the ‘missing heritability’. Imprinting is an epigenetic phenomenon where the expression of genes depends on their parental origin (parent-of origin effect). To date, about 100 imprinted genes have been described in humans. Imprinting effects have been reported in the development of variety of complex diseases including asthma.
Hypothesis: Imprinting is involved in the etiology of asthma.
Methods: To identify candidate genomic regions for imprinting we used GWAS data from two family-based studies (two parents and one offspring). These studies are: 1) the Canadian Asthma Primary Prevention Study (CAPPS), a high-risk asthma birth cohort and, 2) the Study of Asthma Genes and Environment (SAGE), a population-based asthma birth cohort. To identify candidate genomic regions for imprinting, we used a likelihood-based variant of the Transmission Disequilibrium Test. Parent-of-origin effects are tested by including a modifier (the sex of parents) in the analysis, which determines whether the asthma risk is modified by the parental origin of the allele. The analysis was performed in two stages: 1) analysis of CAPPS and SAGE separately; 2) combined analysis.
Results: Preliminary results from 148 CAPPS and SAGE asthma complete trios are available. In the separate analyses, CAPPS did not show any significant parent-of-origin effects; whereas there were 5 significant SNPs in SAGE. In the joint analysis, 13 SNPs were found significant with p<10-5. Empirical p values were obtained (100,000 permutations). Notably, we showed a parent-of-origin effect at a known imprinted gene, CTNNA3 on 10q22. Six of our identified SNPs were in or near Long non-coding (lnc)RNA genes. In the last decade, lncRNAs have been increasingly implicated in imprinting by modulating imprinting control regions or being imprinted themselves. In the SAGE separate analysis, we found evidence of a parent-of-origin effect for rs1510881 in SMARCA5 located on 4q31. Of note is the presence of the marker D4S426 on 4q35; this marker was differentially linked with atopy and serum IgE levels depending on the parental origin of the alleles.
Conclusion: Epigenetic effects play a role in asthma susceptibility. Uncovering the extent of the genetic imprinting effects and the potential role of non coding RNA will increase the resolution of our understanding of the etiology of this disease.