Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies

Background: There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 populationmatched controls. Methods: Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated (p<5×10^-8; thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs. Results: Significant heterogeneity of SNP effects (p<inf>het</inf><1.4×10^-3) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genomewide SNP effects to be in the same direction across the subgroups. Conclusions: Any differences in common genetic risk across these subgroups are outweighed by the similarities. Metaanalysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.

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