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GPR37L1 is an orphan G-protein coupled receptor that has emerged as a promising candidate in the pathogenesis of migraine disorder. Recent analyses of large-scale exome sequencing data involving 51,289 individuals have revealed that rare coding variants in GPR37L1 are statistically associated with migraine, providing a new avenue for understanding the genetic underpinnings of this common neurological condition (PMID:37461723). In these studies, the authors employed sequence kernel association testing to correlate the burden of rare variants with diagnostic codes of migraine, thus establishing initial genetic evidence for the association.
The genetic evidence is further supported by the identification of multiple rare coding variants, one of which is the variant c.925C>G (p.Arg309Gly). This variant, along with several others catalogued in the cohort, underscores the heterogeneous nature of GPR37L1 disruptions in affected individuals. These observations were made in an unbiased computational framework that binned variants according to predicted pathogenicity, with the rare variant burden reaching statistical significance in the DiscovEHR cohort (PMID:37461723).
Functional studies provide additional support for the role of GPR37L1 in migraine pathobiology. In vitro assessments using SK-N-MC cells demonstrated that receptor variants can significantly alter signaling pathways including reductions in cyclic AMP levels and aberrant activation of the MAPK pathway. These changes are consistent with a dysfunction that could influence neuronal excitability and migraine susceptibility (PMID:37461723).
In vivo experiments using knockout mouse models further bolster the clinical relevance of these genetic findings. Although the knockout animals did not fully recapitulate an acute migraine phenotype, they exhibited sex-specific alterations in behavioral assays that parallel some aspects of migraine-related disorders. Additionally, the altered receptor function in animal models supports the observed cellular phenotype, thereby linking the genetic variation to functional outcomes (PMID:38106084).
While specific familial segregation data for migraine symptoms were not reported, the integration of large-scale case-control exome data with robust functional assays provides a compelling case for the association. The lack of detailed segregation information is offset by the quantitative burden of rare variants and the reproducibility of signaling differences in model systems.
In conclusion, the association between GPR37L1 and migraine disorder is underpinned by strong genetic evidence and moderate experimental support. The results advocate for the potential clinical utility of screening rare GPR37L1 variants in migraine diagnosis and suggest that targeting the receptor’s signaling pathway may offer novel therapeutic approaches. Key take‑home: Understanding GPR37L1’s role in migraine paves the way for improved diagnostic and treatment strategies in neuropsychiatric disorders.
Gene–Disease AssociationStrongAnalysis of 51,289 exomes revealed a significant burden of rare GPR37L1 variants associated with migraine disorder (PMID:37461723), with findings replicated in independent studies (PMID:38569927). Genetic EvidenceStrongMultiple rare coding variants, including c.925C>G (p.Arg309Gly), were identified using sequence kernel association testing, providing statistically robust evidence from a large patient cohort (PMID:37461723). Functional EvidenceModerateCellular assays demonstrated altered cAMP and MAPK signaling, and knockout mouse models exhibited sex-specific changes relevant to migraine pathophysiology, thus supporting a mechanistic role for GPR37L1 in disease (PMID:37461723, PMID:38106084). |