NCOR2 is a novel candidate gene for migraine-epilepsy phenotype

Abstract

Hypothesis To identify genetic factors predisposing to migraine-epilepsy phenotype utilizing a multi-generational family with known linkage to chr12q24.2-q24.3. Methods We used single nucleotide polymorphism (SNP) genotyping and next-generation sequencing technologies to perform linkage, haplotype, and variant analyses in an extended Finnish migraine-epilepsy family (n = 120). In addition, we used a large genome-wide association study (GWAS) dataset of migraine and two biobank studies, UK Biobank and FinnGen, to test whether variants within the susceptibility region associate with migraine or epilepsy related phenotypes in a population setting. Results The family showed the highest evidence of linkage (LOD 3.42) between rs7966411 and epilepsy. The haplotype shared among 12 out of 13 epilepsy patients in the family covers almost the entire NCOR2 and co-localizes with one of the risk loci of the recent GWAS on migraine. The haplotype harbors nine low-frequency variants with potential regulatory functions. Three of them, in addition to two common variants, show nominal associations with neurological disorders in either UK Biobank or FinnGen. Conclusion We provide several independent lines of evidence supporting association between migraine-epilepsy phenotype and NCOR2. Our study suggests that NCOR2 may have a role in both migraine and epilepsy and thus would provide evidence for shared pathophysiology underlying these two diseases.

Genetic mechanisms underlying local spontaneous brain activity in episodic migraine

“…This gene was higher in brain regions with a higher ReHo increment. NCOR2 mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access to basal transcription (Lee et al, 2022) and is a novel candidate gene for the migraine-epilepsy phenotype (Nuottamo et al, 2022). The higher expression level of NCOR2 may lead to a ReHo increment by having a more inhibitory effect on gene transcription in migraine.…”

Migraine genetics: Status and road forward

“…A few recent studies in the field of migraine used NGS for a different approach. First, SNP genotyping followed by NGS was used for linkage, haplotype, and variant analyses within a single large Finnish migraine-epilepsy family and found an association between the epilepsy phenotype and the NCOR2 gene that colocalises with one of the migraine risk loci (53). Second, in a WES of 16 individuals, who developed numerous neurological- and concussion-related symptoms following minor head injuries of which seven had developed migraines following the injury, revealed possible mutations in various ion channel, neurotransmitter, and ubiquitin-related genes, but causality of any of them needs to be established (51).…”

Diagnosis of comorbid migraine without aura in patients with idiopathic/genetic epilepsy based on the gray zone approach to the International Classification of Headache Disorders 3 criteria

“…The clinical, pathophysiological, and symptomatic overlaps are held responsible at the forefront of the underlying mechanisms of this comorbidity since there is a hypothesis that both diseases are likely to be explained by cortical hyperexcitability. In addition, the fact that both migraine and epilepsy are strongly heritable disorders points out the importance of the genetic variants, leading to susceptibility to these disorders ( 6 , 11 – 13 ). Also, the fact that both disorders are often responsive and can be treated with antiseizure medications (ASMs) is another supportive factor of the presence of common underlying mechanisms ( 14 ).…”