Genome-Wide Associations Identified in Cluster Headache Open Door to Future Research

Andrea C. Belin, PhD

A recently conducted genome-wide association study (GWAS) has identified several significant genetic associations with cluster headache (CH), supporting the theory of a genetic predisposition for this patient population.

The analysis, which compared 852 UK and 591 Swedish cluster headache cases with 5614 and 1134 controls, identified 4 loci with genome-wide significance (GWS), 2 of which had significant independent association with CH in both cohorts. The locus with the strongest association, 2q33 with lead single nucleotide protein (SNP) rs113658130 (OR, 1.51 [95% Cim 1.37-1.66]; P = 1.92 x 10-17), was located in a long intergenic noncoding RNA LINC01877 with the closest protein coding gene being SATB2. SNP rs4519530, an intronic variant at 2q13 located in the MERTK gene, represented the second locus observed (OR, 1.47 [95% CI, 1.34-1.61]; P = 6.98 x 10-17).

The third locus, lead SNP rs11153082 (OR, 1.30 [95% CI, 1.19-1.42]; P = 1.85 x 10-8), corresponded to the 1 identified on 6q16 in the UK cohort and was located in the FHL5 gene. A new locus, the fourth of the study, was identified on chromosome 1q41 with lead SNP rs12121134 (OR, 1.36 [95% CI, 1.22-1.52]; P = 1.66 x 10-8). This region did not contain any known genes, with the closest being LINC01705, a long noncoding RNA, located 11kb upstream from rs12121134. The nearest coding gene to this region was DUSP10.

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Single variant association testing was performed using Scalable and Accurate Implementation of Generalized Mixed Model (SAIGE), fitting a null logistic model. Gene windows were extended 35kb upstream and 10kb downstream of the annotated gene start and end sites to include regulatory regions.

When evaluating migraine GWAS overlap, 3 of the 4 loci showed no association with migraine, which was confirmed using colocalization analysis. The findings showed that for the loci on chromosomes 1 and 2 (rs12121134, rs113658130, and rs45194530), only CH had a genetic association within the tested region. The lead SNP rs11153082 at the chromosome 6 locus showed overlap with migraine. This was confirmed from the same causal variant as in the migraine GWAS from the UK Biobank GWAS database (posterior probability for shared causal variant at chr6q16 = 97.4%).

A total of 74 pathways were significantly enriched for 46 genes in candidate regions (P < .05), the most significant being cytokine-cytokine receptor interaction (KEGG 04060; P = 3.97 x 10-4). Following that, interleukin(IL)-1 family signaling (REAC R-HAS-446652; P = 6.66 x 10-5), growth factor receptor binding (GO 0070851; P = 4.64 x 10-5), IL-36 pathway (REAC R-HAS-9014826; P = 4.21 x 10-5) and IL-1 receptor binding (GO 0005149; P = 1.30 x 10-10), were the other most significantly enriched pathways.

Senior author Andrea C. Belin, PhD, Department of Neuroscience, Karolinska Institut, and colleagues concluded that, “replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache.”

REFERENCE

O’Connor E, Fourier C, Ran C, et al. Genome-wide association study identifies risk loci for cluster headache. Ann Neurol. Published online June 29, 2021. doi: 10.1002/ana.26150