Genome sequencing reveals the Adgrl3 (ADGRL3) gene as a possible cause of cephalic hypersensitivity in the STA rat and migraine in humans

BackgroundMigraine is a common primary headache disorder with a significant genetic component influencing its pathophysiology, in which the trigeminal system plays a central role. The spontaneous trigeminal allodynia (STA) inbred rat strain is a validated migraine model that exhibits a chronic cephalic hypersensitive phenotype, responsive to specific migraine treatments. The heritable STA trait presents a unique opportunity to dissect the genetic component of migraine.MethodsSTA rats were backcrossed twice with wild-type (WT) Sprague-Dawley (SD) rats and whole-genome sequencing was performed on 47 rats exhibiting either the STA or WT phenotype. mRNA and protein expression analyses were conducted in the trigeminovascular system of both rats and humans. Based on data from the STA rats, we performed an F-SKAT (i.e. sequence kernel association test for family data) analysis to investigate a potential link between families with clustering of migraine and our findings from the STA rats.ResultsSequencing of STA rats revealed a risk locus near the gene for adhesion G protein-coupled receptor L3 (Adgrl3). In humans, the ADGRL3 gene showed an increased burden of rare variants segregating with migraine in families with a clustering of the condition (p = 0.046). We found similar associations between migraine and the ADGRL3 when expanding the analyses to a genome-wide analysis including rare variants from more than one million individuals with migraine. Expression analyses of rat and human tissues confirmed that Adgrl3 is expressed in the migraine-associated trigeminovascular system.ConclusionsIn this translational study, ADGRL3 was associated with both cephalic hypersensitivity in STA rats and an increased burden of rare variants in humans with migraine. The gene was expressed in the trigeminovascular system, a central pathophysiological component of cephalic pain. ADGRL3 provides novel insights into the pathophysiology of chronic cephalic pain in migraine.