Evidence for linkage of migraine in Rolandic epilepsy to known 1q23 FHM2 and novel 17q22 genetic loci

Abstract

Migraine headaches are a common comorbidity in Rolandic epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 [multipoint HLOD (heterogeneity LOD) 4.40, recessive, 99% penetrance], replicated in the second dataset (HLOD 2.61), and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (two-point LOD 3.00 and MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees were reanalyzed for linkage. In summary, we report a novel migraine susceptibility locus at 17q12-22, and a second locus that may contribute to migraine in the general population at 1q23.1-23.2. Comorbid migraine in RE appears genetically influenced, but we did not obtain evidence that the identified susceptibility loci are consistent with pleiotropic effects on other comorbidities in RE. Loci identified here should be fine-mapped in individuals from RE families with migraine, and prioritized for analysis in other types of epilepsy-associated migraine.