Whole-genome association study in migraine without aura and functional characterization of disease associated alleles

Coordinator:    Prof. Dr. Martin Dichgans
Institution: LMU München, Klinikum Großhadern, Neurologische Klinik und Poliklinik
Migraine, a severe primary headache disorder, is among the most common neurological disorders (prevalence 15%). More than 2/3 of patients have migraine without aura (MO), i.e. without associated neurological disturbances. An important genetic component of migraine has long been known, however no robust genetic risk factors for the common, genetically complex forms of the disease had been established. In TP1, by means of a genome-wide association study (GWAS), which was conducted in the context of the International Headache Genetics Consortium (IHGC), the first risk variant for migraine with aura (MA) was identified (Anttila et al., Nat. Genet. 2010), which seems to play role in cerebral glutamate homeostasis. A population-based study, the replication phase of which included data from TP1 and TP2, revealed three further risk variants for general migraine (Chasman et al., Nat. Genet. 2011). TP2 aimed at analyzing genetic susceptibility to MO, i.e. the clinically most prevalent migraine subtype.
In the context of the IHGC two large clinic-based and carefully phenotyped MO cohorts from Germany and the Netherlands (n=2360) were GWA-typed with Illumina chips. Available GWAS datasets from population-based cohorts were used as controls (n=4580). Raw data were imputed to HapMap3 and subjected to a genomewide logistic regression analysis. The most promising signals of the first study phase (loci with ? 2 SNPs with P < 1 x 10-5) were taken forward to replication analysis in four further clinic-based European MO cohorts (from Finland, the Netherlands, Spain and Norway).
In a meta-analysis of the entire dataset (including the replication phase) we identified four genome-wide significant (P < 5 x 10-8) susceptibility loci for MO in or near the genes MEF2D, PHACTR1, ASTN2 and TGFBR2. In addition, SNPs in two further loci (TRPM8 and LRP1), which had been identified in the population-based study (Chasman et al. 2011), were replicated in our clinic-based MO cohort. The identified genes highlight the significance of cerebral hyperexcitability as well as vascular mechanisms in the pathophysiology of MO.

Freilinger et al. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet. 2012;44(7):777-82.
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