Identification of common genetic and molecular signatures in migraine and comorbid conditions

Abstract Background Migraine is a very common chronic neurological disorder associated with severe disability and significant social burden worldwide. Beyond recurrent headache attacks, increasing evidence indicates that migraine often coexists with a broad range of systemic disorders, forming complex and often bidirectional relationships. These overlapping conditions complicate clinical management and suggest the presence of shared pathophysiological mechanisms extending beyond the central nervous system. Main findings Epidemiological studies have consistently shown strong associations between migraine and multiple comorbidities, including epilepsy, psychiatric disorders, sleep disturbances, cardio-cerebrovascular diseases, multiple sclerosis, asthma, other chronic pain syndromes, gastrointestinal disorders, and metabolic‒endocrine abnormalities. The presence of these conditions is generally associated with increased disease severity, higher rates of migraine chronification, poorer treatment responses, and increased healthcare utilization. Emerging mechanistic evidence indicates that migraine and its comorbidities share common biological pathways, including dysregulation of neurovascular signaling, neuroinflammation, central sensitization, alteration in autonomic nervous system and brain function, and disturbances in immune and metabolic homeostasis. Importantly, the presence of comorbid conditions may affect the efficacy, tolerance and safety of treatment, highlighting the limitations of symptom-oriented treatment strategies that fail to address these shared mechanisms. Conclusions This review synthesizes current evidence on the epidemiological associations, shared pathophysiological mechanisms, and clinical implications of migraine and its common comorbidities. By elucidating these interrelated pathways, we aim to inform the development of comprehensive, personalized management strategies that transcend symptom-oriented treatment towards mechanism-based, comorbidity-informed approaches. Future research should prioritize the identification of biomarkers and the refinement of patient stratification tools to facilitate precision medicine in migraine and its associated conditions.