{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:57:34Z","timestamp":1791413854934,"version":"4.3.3"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The purpose of this study was to identify disease relevant genes and explore underlying immunological mechanisms that contribute to early and late onset forms of myasthenia gravis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a novel genomic methodology to integrate genomewide association study (GWAS) findings in myasthenia gravis with cell\u2010type specific information, such as gene expression patterns and promotor\u2010enhancer interactions, in order to identify disease\u2010relevant genes. Subsequently, we conducted additional genomic investigations, including an expression quantitative analysis of 313 healthy people to provide mechanistic insights.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified several genes that were specifically linked to early onset myasthenia gravis including\n                      <jats:italic>TNIP1<\/jats:italic>\n                      ,\n                      <jats:italic>ORMDL3<\/jats:italic>\n                      ,\n                      <jats:italic>GSDMB<\/jats:italic>\n                      , and\n                      <jats:italic>TRAF3<\/jats:italic>\n                      . We showed that regulators of toll\u2010like receptor 4 signaling were enriched among these early onset disease genes (fold enrichment\u00a0=\u00a03.85,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a06.4\u2009\u00d7\u200910\n                      <jats:sup>\u22123<\/jats:sup>\n                      ). In contrast, T\u2010cell regulators\n                      <jats:italic>CD28<\/jats:italic>\n                      and\n                      <jats:italic>CTLA4<\/jats:italic>\n                      were exclusively linked to late onset disease. We identified 2 causal genetic variants (rs231770 and rs231735; posterior probability\u00a0=\u00a00.98 and 0.91) near the\n                      <jats:italic>CTLA4<\/jats:italic>\n                      gene. Subsequently, we demonstrated that these causal variants result in low expression of\n                      <jats:italic>CTLA4<\/jats:italic>\n                      (rho\u00a0=\u00a0\u22120.66,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a01.28\u2009\u00d7\u200910\n                      <jats:sup>\u221238<\/jats:sup>\n                      and rho\u00a0=\u00a0\u22120.52,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a07.01\u2009\u00d7\u200910\n                      <jats:sup>\u221222<\/jats:sup>\n                      , for rs231735 and rs231770, respectively).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>The disease\u2010relevant genes identified in this study are a unique resource for many disciplines, including clinicians, scientists, and the pharmaceutical industry. The distinct immunological pathways linked to early and late onset myasthenia gravis carry important implications for drug repurposing opportunities and for future studies of drug development. ANN NEUROL 2021;90:455\u2013463<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26169","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T05:31:24Z","timestamp":1626672684000},"page":"455-463","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Genomic Insights into Myasthenia Gravis Identify Distinct Immunological Mechanisms in Early and Late Onset Disease"],"prefix":"10.1002","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8242-3722","authenticated-orcid":false,"given":"Lahiru","family":"Handunnetthi","sequence":"first","affiliation":[{"name":"Wellcome Centre for Human Genetics University of Oxford  Oxford UK"},{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Knezevic","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Genetics University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silva","family":"Kasela","sequence":"additional","affiliation":[{"name":"Estonian Genome Centre, Institute of Genomics University of Tartu  Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie L.","family":"Burnham","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Milani","sequence":"additional","affiliation":[{"name":"Estonian Genome Centre, Institute of Genomics University of Tartu  Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-9748","authenticated-orcid":false,"given":"Sarosh R.","family":"Irani","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford 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