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. 2022 Nov 21;23(1):147.
doi: 10.1186/s10194-022-01517-6.

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

Shih-Pin Chen  1   2   3   4   5 , Chia-Lin Hsu  6 , Yen-Feng Wang  1   2   5 , Fu-Chi Yang  7 , Ting-Huei Chen  8   9 , Jia-Hsin Huang  10 , Li-Ling Hope Pan  1   2 , Jong-Ling Fuh  1   2   5 , Hsueh-Chen Chang  1   2 , Yi-Lun Lee  10 , Hung-Ching Chang  10 , Ko-Han Lee  10 , Yu-Chuan Chang  10 , Cathy Shen-Jang Fann  11 , Shuu-Jiun Wang  12   13   14
Affiliations

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

Shih-Pin Chen et al. J Headache Pain. .

Abstract

Background: Cluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan.

Methods: We conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed.

Results: We enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10-16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10-13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10-8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache.

Conclusions: This study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

Keywords: CAPN2; Cluster headache; Genome-wide association study; MERTK; STAB2.

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Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Fig. 1
Fig. 1
Manhattan plots for the GWAS and gene-based analysis. A Manhattan plot for the associations of SNPs with cluster headache. The horizontal axis shows the chromosomal position, and the vertical axis shows the significance of tested markers. The threshold for genome wide significance (p < 5 × 10–8) is indicated by a red dash line. B Manhattan plot of the gene-based test as computed by Multimarker Analysis of GenoMic Annotation (MAGMA). The input SNPs were mapped to 18,460 protein coding genes. The red dash line indicates the genome wide significance defined at p = 0.05/18,460 = 2.709 × 10–6
Fig. 2
Fig. 2
Regional association plots of the two genome-wide significant cluster headache loci (A) CAPN2, (B) MERTK, and (C) SATB2. Each dot represents a single nucleotide polymorphism (SNP) derived from the fine-mapped imputation data. The horizontal axis gives the genomic coordinate and the vertical axis the significance level (-log10 p value). The top SNP for each locus is marked with a purple diamond (CRCh38/hg19). SNPs are colored based on their correlation (r2) with the labeled lead SNP according to the legend. The solid blue line shows the recombination rate from 1000 Genomes EAS data (right vertical axis). The gray dash line corresponds to p = 5 × 10−8. Figures were obtained from LocusZoom
Fig. 3
Fig. 3
Genome-wide polygenic risk score (PRS) for cluster headache. The density distributions of polygenic score for cluster headache in testing dataset. The x-axis represents polygenic score, with values scaled to a mean of 0 and standard deviation of 1. Cases: blue; Controls: yellow
See this image and copyright information in PMC

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