{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:07:26Z","timestamp":1784700446470,"version":"3.55.0"},"reference-count":64,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171247"],"award-info":[{"award-number":["82171247"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371433"],"award-info":[{"award-number":["82371433"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["headachejournal.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Headache"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To identify genetic and phenotypic determinants of migraine susceptibility and progression using a large\u2010scale, hypothesis\u2010free approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Migraine is a common neurological disorder with a substantial individual and societal burden. While risk factors are known, hypothesis\u2010driven approaches may overlook contributors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed data from 502,364 UK Biobank participants (aged 37\u201373 years; recruited 2006\u20132010) to assess associations between migraine and 2824 phenotypes, including observational associations and associations with migraine polygenic risk scores. Time\u2010dependent associations were evaluated, and causality was assessed. Follow\u2010up extended from baseline through to November 30, 2024, with a median of ~14.7\u2009years.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our analyses identified 253 phenotypes significantly associated with migraine risk, 191 phenotypes associated with migraine PRS, and 87 overlapping between the two approaches. Cox regression analysis confirmed 84 robust time\u2010dependent associations and highlighted novel risk factors, such as oral ulcers (adjusted hazard ratio [aHR]\u2009=\u20091.14, 95% confidence interval [CI]: 1.02\u20131.28,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20092.54\u2009\u00d7\u200910\n                      <jats:sup>\u22122<\/jats:sup>\n                      ), lower limb obesity (aHR\u2009=\u20091.01, 95% CI: 1.00\u20131.02,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20093.52\u2009\u00d7\u200910\n                      <jats:sup>\u22124<\/jats:sup>\n                      ), and hormone replacement therapy (aHR\u2009=\u20091.39, 95% CI: 1.29\u20131.50,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20091.95\u2009\u00d7\u200910\n                      <jats:sup>\u221217<\/jats:sup>\n                      ). MR analysis also revealed causal associations with emotional fluctuations (inverse\u2010variance weighting odds ratio [IVW OR] 4.10, 95% CI\u2009=\u20091.76\u20139.53,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20091.00\u2009\u00d7\u200910\n                      <jats:sup>\u22122<\/jats:sup>\n                      ), neuroticism (IVW OR\u2009=\u20091.12, 95% CI\u2009=\u20091.07\u20131.08,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20091.24\u2009\u00d7\u200910\n                      <jats:sup>\u22125<\/jats:sup>\n                      ), general health ratings (IVW OR\u2009=\u20091.81, 95% CI\u2009=\u20091.43\u20132.29,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20093.30\u2009\u00d7\u200910\n                      <jats:sup>\u22122<\/jats:sup>\n                      ), and fatigue (IVW OR\u2009=\u20091.94, 95% CI\u2009=\u20091.35\u20132.79,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20095.73\u2009\u00d7\u200910\n                      <jats:sup>\u221236<\/jats:sup>\n                      ). However, the association with paracetamol use (IVW OR\u2009=\u20099.65\u2009\u00d7\u200910\n                      <jats:sup>4<\/jats:sup>\n                      , 95% CI\u2009=\u20091.67\u2009\u00d7\u200910\n                      <jats:sup>4<\/jats:sup>\n                      \u20135.57\u2009\u00d7\u200910\n                      <jats:sup>5<\/jats:sup>\n                      ,\n                      <jats:italic>q<\/jats:italic>\n                      \u2009=\u20095.73\u2009\u00d7\u200910\n                      <jats:sup>\u221236<\/jats:sup>\n                      ) had uncertain directionality on Steiger testing and should be interpreted cautiously. In total, 87 genetic and phenotypic determinants of migraine were identified, offering new therapeutic targets involving inflammatory and insulin\u2010like growth factor 1 (IGF\u20101) \u2010related pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This comprehensive analysis provides new insights into the genetic and phenotypic factors that influence migraine. The findings suggest new targets for therapeutic intervention and provide a basis for the development of precision prevention and clinical management strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.70079","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T10:35:34Z","timestamp":1781087734000},"page":"1474-1488","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A phenome\u2010wide association study reveals novel phenotypic determinants of migraine risk in the\n                    <scp>UK<\/scp>\n                    Biobank"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4843-0072","authenticated-orcid":false,"given":"Changhe","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Zhengzhou University, Zhengzhou University  Zhengzhou China"},{"name":"NHC Key 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