CLUSTER HEADACHE GENOME-WIDE ASSOCIATION STUDY AND META-ANALYSIS IDENTIFIES EIGHT LOCI AND IMPLICATES SMOKING AS CAUSAL RISK FACTOR 139 7 Introduction Cluster headache (CH) is a primary headache disorder that affects 0.1% of the population and is four times more common in men than in women.1 It is characterized by episodes of excruciating unilateral pain centered around the eye or the temple.2 The large majority of patients are either current or previous smokers and there is a higher prevalence of illicit drug use, depression and sleep disorders among patients with CH than in the general population.1, 3 Much is unknown about the pathophysiology of CH, but hypothalamic, trigeminovascular, and autonomic nervous system dysfunction are likely involved.1, 4 Previous twin- and family-based studies have suggested the involvement of genetic factors,5 and two recent genome-wide association studies (GWAS) in individuals of European ancestry6, 7 demonstrated robust genetic associations for CH, independently identifying four genetic risk loci on chromosome 1 (near the gene DUSP10), chromosome 2 (within MERTK and near SATB2), and chromosome 6 (within FHL5), with odds ratios (ORs) ranging from 1.30 to 1.61. A third GWAS in Han Chinese individuals replicated two of these loci (MERTK and SATB2) and reported an additional locus in the gene CAPN2.8 To identify additional genetic factors and increase power for functional interpretation of the genetic signals, we established the International Consortium for Cluster Headache Genetics (CCG) and analyzed data from ten European and one East Asian CH cohorts; those used in the four previous GWASs of CH6, 7, 9 and five additional cohorts, increasing the sample size for analysis 3.2-fold compared to the largest previous CH GWAS.7 Methods Cohorts and phenotyping For reference, acronyms are listed in Table S1. Data were obtained from ten European and one East Asian cohorts (Table 1), with a combined sample size of 4,777 patients with CH (3,348 men and 1,429 women) and 31,575 controls, of which 4,043 patients (85%) were of European and 734 (15%) of East Asian ancestry. Cases were recruited between 2005 and 2022 through specialized headache clinics and diagnosed according to standardized ICHD criteria.2, 10 Details on the recruitment and phenotyping in each cohort is provided in Table S1. All studies were approved by local research ethics committees, and written informed consent was obtained from each study participant. GWAS and meta-analysis A standardized quality control (QC) and analysis protocol was applied to each individual GWAS, while allowing for adaptations to comply with local data sharing regulations and analysis pipelines. Details are given in Table S3. Samples in each cohort were genotyped on genome-wide arrays,
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