A genome-wide association study identifies genetic loci associated with non-migraine headache in the UK Biobank (N = 120,504)

Non-migraine headache, defined by broadly headache excluding migraine in our study, represents a substantial yet understudied public health concern with high global prevalence and significant impact on quality of life. In this study, we conducted a comprehensive genome-wide association study (GWAS) using data from the UK Biobank 2019 pain questionnaire, including 25,460 cases and 95,044 controls, to identify loci associated with non-migraine headache. We identified five genome-wide significant loci, including variants near LRP1 (rs11172113, p = 2.27 × 10–17), TRPM8 (rs6724624, p = 9.20 × 10–11), PHACTR1 (rs9349379, p = 8.63 × 10–10), LINC01765 (rs12134493, p = 1.39 × 10–8), and UFL1-AS1 (rs145859244, p = 2.33 × 10–8). Sex-stratified GWAS analyses revealed four loci including TRPM8 (rs758276, p = 5.37 × 10–11), STAT6/LRP1 (rs4759275, p = 1.36 × 10–10), SLITRK6 (rs192920620, p = 7.71 × 10–9), and PHACTR1(rs9349379, p = 1.25 × 10–8) specific to females and one locus with LRP1 (rs11172113, p = 2.10 × 10–8) in males. Transcriptome-wide association studies revealed significant tissue-specific expression of associated genes in vascular, neural, and endocrine tissues. Phenome-wide association studies further connected key variants to neurological, cardiovascular, metabolic, and medication-use traits, providing insight into pleiotropic effects and comorbid pathways. These findings advance our understanding of the genetic basis of non-migraine headache and lay the groundwork for future research into its pathophysiology and potential precision medicine approaches.