Robust evidence that cluster headache has a genetic basis

A combined analysis of 2 genome-wide association studies (GWAS) identified 4 risk loci for cluster headache. The discovery of these risk loci provides robust evidence that the disease has a genetic basis [1].

In the pathophysiology of cluster headache, the hypothalamus, calcitonin gene-related peptide (CGRP), and possibly neuroinflammation are involved. “Evidence on its molecular basis is still limited,” said Dr Bendik S. Winsvold (Oslo University Hospital, Norway). Investigating cluster headache is challenging due to its low prevalence (1–1.5 per 1,000 persons, compared with 140 per 1,000 for migraine). Evidence of a possible genetic basis of cluster headache is premature. “Twin studies are not suitable due to the low prevalence of cluster headache, but a clear familial aggregation has been shown previously,” explained Dr Winsvold [2]. Most genetic studies in cluster headache have evaluated individual candidate genes. Currently, only 1 GWAS for cluster headache has been performed, which suggested variants involvement of genes encoding neprilysin and the PACAP receptor [3].

Dr Winsvold presented data from 2 independent studies, both recently published in the Annals of Neurology [4,5]. These studies were the basis of the International Consortium for Cluster Headache Genetics (CCG, www.clusterheadachegenetics.org). Therein, 2 parallel GWAS of cluster headache were conducted based on:

• 984 cluster headache cases and 3,257 controls from the Netherlands and Norway; and
• 1,443 cluster headache cases and 6,748 controls from Sweden and the United Kingdom [1].

“The 2 studies are strikingly concordant,” Dr Winsvold found. “In fact, they identified the same 4 genetic risk loci (P<5 x 10^-8)”:

• on chromosome 1 near the gene DUSP10;
• on chromosome 2 near MERTK;
• on chromosome 2 near SATB2; and
• on chromosome 6 near FHL5.

Based on both studies, a meta-analysis was conducted, which found 3 additional loci:

• on chromosome 7 near ASZ1;
• on chromosome 10 near PLC1; and
• on chromosome 19 near KIR3DX1.

This concordance implies that these are true causal genetic risk factors for cluster headache, according to Dr Winsvold. The effect sizes were larger than what is usually observed in GWAS in complex disorders. “Usually, odds ratios are 1.1 or 1.2, here they are ~1.5 (range 1.30–1.61). This could suggest that cluster headache is genetically driven by a handful of high-impact variants,” explained Dr Winsvold.

The main purpose of GWAS is to understand the pathophysiology. “These first studies are not adequately powered for this purpose,” Dr Winsvold acknowledged, “but we still gained some preliminary insight. For example, one of the loci (FHL5) is a well-known risk locus for migraine. This suggests that cluster headache and migraine have a partly shared and a partly distinct genetic and molecular basis.”

1. Winsvold BS, et al. International Consortium for Cluster Headache Genetics: two initiatives report first genome-wide association hits. AL070, IHC 2021, 8–12 September.
2. O'Connor E, et al. J Headache Pain. 2020;21(1):37.
3. Bacchelli E, et al. J Headache Pain. 2016;17(1):114.
4. Harder AVE, et al. Ann Neurol. 2021;90(2):203–16.
5. O'Connor E, et al. Ann Neurol. 2021;90:193–202.

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Posted on 8 November 202128 March 2024