Causal proteomic insights into drug target discovery for tension-type headache

The pathophysiology of tension-type headache (TTH) remains poorly understood, and current treatments are largely symptomatic. Identifying genetically supported, causally relevant proteins may provide insights into disease mechanisms and enable precision therapeutics. We conducted a proteome-wide Mendelian randomization (MR) analysis integrating large-scale plasma proteomic quantitative trait loci with genome-wide association study data for TTH. Phenome-wide MR, enrichment, protein-protein interaction (PPI), and mediation analyses were performed to identify druggable targets and clarify potential biological pathways. Thirteen plasma proteins exhibited significant causal associations with TTH (Bonferroni correction p < 2.76 × 10− 5). Enrichment analysis revealed ensheathment of neurons and cellular response to cholesterol and sterol as key pathways. Mediation analyses identified 3-methylglutaconate and 3-hydroxydecanoate as partial mediators of the proteomic effects on TTH, reflecting mitochondrial leucine catabolism and mitochondrial fatty acid beta oxidation, with mediation proportions of 7.5% to 15.2%. Phenome-wide MR analysis indicated that NRXN3, CCL22, CLEC1B, and LRIG1 were not associated with any major adverse effects. PPI analysis further showed that these proteins are functionally connected to proteins targeted by current TTH therapies, supporting their safety and translational potential. This integrative genetic analysis identified multiple plasma proteins with causal and pharmacologically relevant roles in NRXN3, CCL22, CLEC1B, and LRIG1 emerged as promising and potentially safe therapeutic targets.