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Background <p>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.</p> Methods <p>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.</p> Results <p>We identified five genome-wide significant loci, including variants near <i>LRP1</i> (rs11172113, <i>p</i> = 2.27 × 10<sup>–17</sup>), <i>TRPM8</i> (rs6724624, <i>p</i> = 9.20 × 10<sup>–11</sup>), <i>PHACTR1</i> (rs9349379, <i>p</i> = 8.63 × 10<sup>–10</sup>), <i>LINC01765</i> (rs12134493, <i>p</i> = 1.39 × 10<sup>–8</sup>), and <i>UFL1-AS1</i> (rs145859244, <i>p</i> = 2.33 × 10<sup>–8</sup>). Sex-stratified GWAS analyses revealed four loci including <i>TRPM8</i> (rs758276, <i>p</i> = 5.37 × 10<sup>–11</sup>), <i>STAT6</i>/<i>LRP1</i> (rs4759275, <i>p</i> = 1.36 × 10<sup>–10</sup>), <i>SLITRK6</i> (rs192920620, <i>p</i> = 7.71 × 10<sup>–9</sup>), and <i>PHACTR1</i>(rs9349379, <i>p</i> = 1.25 × 10<sup>–8</sup>) specific to females and one locus with <i>LRP1</i> (rs11172113,<i> p</i> = 2.10 × 10<sup>–8</sup>) 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.</p> Conclusions <p>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.</p>

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

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  • 发表日期：

    2026年4月1日

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  • Yiwen Tao,
  • Qi Pan,
  • Sen Lin,
  • Tengda Cai,
  • Luning Yang,
  • Mainul Haque,
  • Hua Zheng,
  • Huadong Ni,
  • Longsheng Xu,
  • Ming Yao,
  • Holger Husi,
  • Victoria Chapman,
  • Weihua Meng

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.