Genome Wide Meta-analysis of Parent-of-origin Effects of Asthma, Atopy and Airway Hyperresponsiveness in Four Cohorts

Eslami A1, Akhabir L1, Ellis G1, Vonk JM2, Becker AB3, Kozyrskyj AL4, Paré PD1, Sandford AJ1, Koppelman GH2, Laprise C5,6, Daley D1

1. University of British Columbia, Vancouver, BC, Canada; 2. Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen; 3. Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, MB; 4. Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB; 5. Université du Québec à Chicoutimi, Saguenay, QC; 6. Centre intégré universitaire de santé et de services sociaux de Saguenay (CIUSSSS), QC

Background: Asthma is a complex disease caused by a combination of genetic and environmental factors. The main genetic effects of the common SNPs identified by Genome-Wide Association Studies (GWAS) do not fully explain the heritability of asthma. Genetic effects related to parent-of-origin, such as genomic imprinting, are potential mechanisms which may help us to better understand the etiology of asthma. Imprinting is an epigenetic phenomenon where the expression of genes depends on their parental origin. Silencing of the imprinted allele is caused by DNA methylation. Imprinting effects have been reported in the development of a variety of complex diseases including asthma and atopy.

Aim: Identify candidate genomic regions for imprinting in asthma and related phenotypes (atopy and airway hyperresponsiveness (AHR)) by using existing GWAS data from four family-based studies.

Methods: To identify candidate genomic regions for imprinting we used GWAS data from four family-based studies (two parents and one asthmatic child). These studies are: 1) the Canadian Asthma Primary Prevention Study (CAPPS), a high-risk asthma birth cohort, 2) the Study of Asthma Genes and Environment (SAGE), a population-based asthma birth cohort, 3) the Saguenay-Lac-Saint-Jean Québec Familial Collection (SLSJ), a founder population of French-Canadians, and 4) The Dutch Asthma GWAS (DAG), a cohort from the Netherlands. We used a likelihood-based variant of the Transmission Disequilibrium Test. Parent-of-origin effects were analyzed by including parental sex as a modifier in the analysis, which determines whether the asthma risk is modified by the parental origin of the allele. An odds ratio for parent-of-origin effects is determined by dividing maternal odds ratio by paternal odds ratio. Meta-analysis was conducted using the parent-of-origin effects results of SLSJ, DAG, and the joint analysis of CAPPS and SAGE (CAPPS/SAGE), weighted by the number of informative transmissions for each study.

Results: Meta-analysis for asthma, using results of SLSJ (251 trios), DAG (316 trios), and CAPPS/SAGE (141 trios), resulted in 5 independent SNPs with significant parent-of-origin effects with P ≤1.49×10-5. Meta-analysis for atopy, using results of SLSJ (229 trios), DAG (312 trios) and CAPPS/SAGE (217 trios) resulted in 2 independent SNPs. Meta-analysis for AHR using results of SLSJ (132 trios), DAG (260 trios) and CAPPS/SAGE (219 trios) resulted in 7 independent SNPs. Of the significant results, 11 out of 14 of the SNPs were in or near long non-coding (lnc)RNA genes.

Conclusion: Meta-analysis of four family-based studies yielded several SNPs with significant parent-of-origin effects (P ≤1.49×10-5) for asthma and the related phenotypes. These SNPs were mostly located in or near lncRNA genes. LncRNAs are known to be involved in genomic imprinting and gene regulation.