Migraine is the world’s most common neurological disorder, affecting ~14% of the adult population. The largest migraine GWAS comprising 102,084 migraine cases and 771,257 controls identified 170 independent genetic risk variants (SNPs) associated with migraine (P < 5×10-8). However, the functional mechanisms of these SNPs remain unclear.
We used an imputation-based methylome-wide association study (MeWAS) approach that integrates GWAS and DNA methylation (meQTL) data to identify genetically regulated DNA methylation CpG sites associated with the trait. We used the MetaMeth R package and prediction models from blood tissue to impute differential methylation associated with migraine for 86,518 CpGs, of which 2,360 were significantly associated with migraine at the Benjamini-Hochberg false discovery rate (FDR) < 0.05. Using COLOC, we investigated which of these 2,360 CpGs (meQTLs) co-localised with a GWAS risk variant associated with migraine (i.e., the same causal variant underlies the meQTL and migraine risk locus). COLOC analyses identified 981 CpGs co-localised with a migraine risk locus (post posterior probability [PP4] > 0.5).
Of the 981 CpGs, 777 CpGs were mapped to 409 genes using the Illumina Human Methylation 450k Array manifest file, while 204 CpGs did not map to any genes. Of these 204 CpGs, 198 CpGs mapped to within 250kb of a gene transcription start site. Given these 975 CpG-gene annotations are solely based on genomic location, to more robustly characterise the CpG-gene relationship associated with migraine, we tested for co-localisation between the CpGs (meQTLs) associated (and co-localised) with migraine and gene expression (eQTLs) associated (and co-localised) with migraine. Of the 975 CpGs associated with migraine, 759 CpGs co-localised (PP4 > 0.5) with differential gene expression (eQTLs) associated with migraine.
In this multi-omic study, we provide important insight into CpG-gene annotations and identify the first DNA methylation CpG sites and their putative target genes associated with migraine risk.