title: Genome-wide analysis of blood gene expression in migraine implicates immune-inflammatory pathways.
abstract: Background Typical migraine is a frequent, debilitating and painful headache disorder with an estimated heritability of about 50%. Although genome-wide association (GWA) studies have identified over 40 single nucleotide polymorphisms associated with migraine, further research is required to determine their biological role in migraine susceptibility. Therefore, we performed a study of genome-wide gene expression in a large sample of 83 migraine cases and 83 non-migraine controls to determine whether altered expression levels of genes and pathways could provide insights into the biological mechanisms underlying migraine. Methods We assessed whole blood gene expression data for 17994 expression probes measured using IlluminaHT-12 v4.0 BeadChips. Differential expression was assessed using multivariable logistic regression. Gene expression probes with a nominal p value < 0.05 were classified as differentially expressed. We identified modules of co-regulated genes and tested them for enrichment of differentially expressed genes and functional pathways using a false discovery rate <0.05. Results Association analyses between migraine and probe expression levels, adjusted for age and gender, revealed an excess of small p values, but there was no significant single-probe association after correction for multiple testing. Network analysis of pooled expression data identified 10 modules of co-expressed genes. One module harboured a significant number of differentially expressed genes and was strongly enriched with immune-inflammatory pathways, including multiple pathways expressed in microglial cells. Conclusions These data suggest immune-inflammatory pathways play an important role in the pathogenesis, manifestation, and/or progression of migraine in some patients. Furthermore, gene-expression associations are measurable in whole blood, suggesting the analysis of blood gene expression can inform our understanding of the biological mechanisms underlying migraine, identify biomarkers, and facilitate the discovery of novel pathways and thus determine new targets for drug therapy.
authors.affiliation: 1 Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Zachary F
authors.initials: ZF
authors.lastname: Gerring
authors.affiliation: 2 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.|3 The Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Powell
authors.affiliation: 2 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: 1 Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics* / Q000503:physiopathology*; D059467:Transcriptome
keywords: Migraine; blood; expression; gene; inflammation