meQTL analysis of asthma GWAS loci and DNA methylation

Background: Asthma is characterized as a chronic inflammation disease and has increased in prevalence over the decades. Genome-wide association studies (GWAS) have implicated several single nucleotide polymorphisms (SNPs) with varying risk estimates for asthma, but the etiology is still not fully understood. Objective: To investigate the association between genetic and epigenetic (methylation) variations in six common GWAS asthma genes - ORMDL3, GSDMB, IL1RL1, IL4R, TSLP and WDR36, we explored the cis and trans-regulatory effects to identify SNPs associated with altered DNA methylation (meQTL) in 500kb buffer region and how top GWAS SNPs relate with resulting SNP-CpG hits. Methods: Using peripheral blood of 231 eight-year-old children with a doctor's diagnosis of asthma ever and 233 controls, from the BAMSE study, DNA methylation was measured on Illumina 450K beadchip and SNPs were assessed on Illumina610-Quad beadchip, imputed on 1000 Genomes reference panels. To identify meQTLs, CpG methylation values were regressed on SNP dosages with sex, asthma status and population stratification eigenvalues as covariates. Results: After applying genome-wide Bonferroni significance thresholds, we had significant SNP-CpG pair hits. The top hits for ORMDL3/GSDMB was cg26162295-rs8081462 (p=4.89x10-50) while LD with GWAS top SNP rs7216389 is r2=0.46. Similarly for IL1RL1, cg09003973-rs11902044 was top hit (p=5.76x10-32) and for TSLP, cg13681701-rs35188965 was top hit (p=4.47x10-71), with no LD to their top GWAS SNPs ( r2<0.05) Conclusion: Our results indicate that most CpG sites were associated with SNPs manifesting cis-effects. Thus, studying these meQTLs can help us disentangle some of the molecular mechanisms of asthma better