FHL5 – Migraine Disorder

This summary details the association between FHL5 (HGNC:17371) and migraine disorder (MONDO_0005277). Two independent GWAS meta‐analyses have robustly implicated common regulatory variants in FHL5 as risk factors for migraine without aura. In one study, 1042 patients in the discovery stage and 842 patients in the replication stage were analyzed (PMID:33762637), while a second study evaluated 6139 migraine-first patients, reinforcing the association (PMID:39333847).

The genetic evidence is bolstered by significant association findings that survived replication across large, multi‑cohort samples. Although classical familial segregation data are lacking, the consistency of the association in case‑control settings suggests that the FHL5 signal, particularly centered on the common regulatory variant rs7775721, is unlikely to be a chance finding (PMID:33762637).

While a formal Mendelian inheritance pattern is not applicable to the etiology of migraine, which is complex in nature, the evidence supports an autosomal dominant model of risk contribution given the allele’s relatively high prevalence and consistent replication in independent studies. No specific coding variant in HGVS format was provided from the data; thus, the reported variants list remains empty.

Functional assessments have revealed that the identified risk allele is associated with significant eQTL signals in relevant tissues, providing experimental support for a regulatory mechanism that may modulate FHL5 expression and influence migraine pathogenesis (PMID:33762637). These functional data are congruent with the genetic findings and help bridge the gap between statistical association and biological effect.

Integrating the genetic and functional evidence, we conclude that the association between FHL5 and migraine disorder is strong. The convergent evidence from large cohorts, replication across independent studies, and supporting eQTL data argues for the utility of this association in diagnostic decision‑making and the potential development of targeted interventions.

Key take‑home sentence: The robust and reproducible association of FHL5 with migraine without aura supports its clinical utility as a contributory risk factor in the multifactorial etiology of migraine.

References

• Scientific Reports • 2021 • Common variants in KCNK5 and FHL5 genes contributed to the susceptibility of migraine without aura in Han Chinese population PMID:33762637
• The Journal of Headache and Pain • 2024 • Improved polygenic risk prediction in migraine-first patients PMID:39333847

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