Large Danish Cohort Study Reveals No Significant Association Between HLA Alleles and Migraine

Lisette Kogelman, MSc

(Credit: LinkedIn)

A recent analysis of nearly 100,000 individuals from the Danish Blood Donor Study (DBDS) reported no significant genetic associations between migraine and the human leukocyte antigen (HLA) system, including across sex-specific or clinically defined migraine subtypes. The study, published in Headache by the DBDS Genomic consortium group, could add to further evidence against the hypothesis that HLA alleles contribute to migraine pathophysiology.¹

The analysis, which comprised 13,210 migraine cases and 86,738 controls, investigated the relationship between migraine and 111 HLA alleles across 15 HLA genes. Despite initial exploration of sex-specific associations and migraine subtypes, including migraine with aura (MA), migraine without aura (MO), and chronic migraine (CM), no statistically significant associations were reported by the researchers. This included no positive associations between HLA alleles and the occurrence of migraine, nor any differences when examining distinct migraine subtypes.

Conducted by senior author Lisette Kogelman, MSc, senior researcher in the Department of Neurology at Copenhagen University Hospital, and colleagues, the study population of 99,948 participants was recruited from the ongoing DBDS, which is a nationwide research platform leveraging Danish blood banks. Migraine status was assessed using a comprehensive questionnaire sent to 47,365 participants, providing an extensive dataset for analysis. Coming into the analysis, the prevalence of migraine was significantly higher among women (19.2%) than men (7.3%).

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An analysis of HLA allele frequency in the DBDS cohort showed a high correlation with a healthy Danish reference panel, confirming the reliability of the data. However, despite this robust analysis, no significant associations were observed between the 111 HLA alleles and migraine. When the study focused specifically on a subset of 47,365 participants who had answered a detailed migraine questionnaire known as the DaMP cohort², no significant associations between HLA alleles and migraine were reported by the authors. Additionally, analysis of sex-specific differences revealed no meaningful findings.

In examining migraine subtypes, the study did identify some weak associations between specific HLA alleles and MO. These included F01:03, which was positively associated with MO, and F01:01 and DOB*01:05, which were negatively associated with MO. However, these associations were not replicated in an Icelandic cohort, suggesting they were likely false positives. No significant associations were revealed for MA or CM. Even after excluding less polymorphic, nonclassical HLA genes and adjusting for the remaining 77 HLA alleles, the study still had not observed significant associations with migraine or its subtypes.

The study, which analyzed nearly 100,000 participants from the DBDS cohort, revealed no evidence supporting a connection between the HLA system and migraine susceptibility, including across migraine subtypes and sex-specific analyses. Despite initial weak associations in a subset of participants, authors noted that these were not replicated in an independent cohort and may be likely false positives. Therefore, the results suggest that this comprehensive study did not support the hypothesis that HLA alleles contribute to the development of migraine.

REFERENCES
1. Tummoszeit IZ, Olofsson IA, Chalmer MA, et al. No association between migraine and HLA alleles in a cohort of 13,210 individuals with migraine from the Danish Blood Donor Study. Headache. 2025;65(1):124-131. doi:10.1111/head.14784
2. Chalmer MA, Kogelman LJA, Callesen I, et al. Sex differences in clinical characteristics of migraine and its burden: a population-based study. Eur J Neurol. 2023;30(6):1774-1784. doi:10.1111/ene.15778