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<p>Myasthenia gravis (MG) is an autoimmune disorder characterized by impaired neuromuscular transmission and motor symptoms. Its genetic background remains unclear, particularly beyond specific subtypes reported in European populations. Here, we perform a genome-wide association study (GWAS) of 1,434 MG cases covering all disease subtypes and 42,913 controls of Japanese, which newly identify the <i>TERT</i> locus (odds ratio [OR] = 1.31, <i>P</i> = 1.7×10<sup>-10</sup>). Subtype-stratified GWASs show stronger signals for generalized MG (gMG; OR = 1.38, <i>P</i> = 1.6×10<sup>-12</sup>), anti AChR antibody-positive gMG (g-AChR-Ab(+)MG; OR= 1.49, <i>P</i> = 2.1×10<sup>-15</sup>), and thymoma-associated gMG (g-TAMG; OR = 1.92, <i>P</i> = 1.1×10<sup>-15</sup>). Fine-mapping of the major histocompatibility complex region reveal distinct associations of <i>HLA-DRB1</i> with late onset gMG (g-LOMG) and <i>HLA-A</i> with early onset gMG (g-EOMG). The MG risk <i>TERT</i> lead variant rs2736099 is associated with poor treatment response, especially in g-AChR-Ab(+)MG and g-EOMG (<i>P</i> &lt; 0.0042). The biobank-based phenome-wide association study identify pleiotropic effects on lung cancer, hematological traits, and telomere length. Single cell transcriptomics and immunohistochemistry identified immature lymphocyte-specific <i>TERT</i> expression in thymoma specimens. Full-length transcriptomics reveal allele-specific decreasing effect of rs2736099-A on <i>TERT</i> expression. Our study unveils genetics of MG distinctly across disease subtypes, and involvement of <i>TERT</i> in its pathogenesis.</p>

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Elucidating genetic backgrounds of myasthenia gravis in Japanese by genome-wide association studies and multi-omics analyses of thymoma

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  • 发表日期：

    2026年3月12日

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  • Hiroyuki Ueda,
  • Tomoya Kubota,
  • Risa Goto,
  • Akari Suzuki,
  • Takafumi Ojima,
  • Kotaro Ogawa,
  • Kyuto Sonehara,
  • Shinichi Namba,
  • Tatsuhiko Naito,
  • Qingbo Wang,
  • Shingo Konno,
  • Makoto Samukawa,
  • Naoki Kawaguchi,
  • Takashi Kimura,
  • Takamichi Sugimoto,
  • Hiroyuki Murai,
  • Takemori Yamawaki,
  • Kenichi Kaida,
  • Daiki Tokuyasu,
  • Manato Yasuda,
  • Hiroyuki Akamine,
  • Yosuke Onishi,
  • Yosuke Ogawa,
  • Yuya Shirai,
  • Ryuya Edahiro,
  • Kenichi Yamamoto,
  • Hideki Nagata,
  • Naoko Ose,
  • Jun Takayama,
  • Ken Suzuki,
  • Shinichi Higashiue,
  • Shuzo Kobayashi,
  • Hiroki Yamaguchi,
  • Yasushi Okazaki,
  • Naoyuki Matsumoto,
  • Kenta Motomura,
  • Hidenobu Koga,
  • Koichi Matsuda,
  • Gen Tamiya,
  • Masayuki Yamamoto,
  • Toshimasa Yamauchi,
  • Takashi Kadowaki,
  • Kazuhiko Yamamoto,
  • Akiko Ohno,
  • Tatsusada Okuno,
  • Eiichi Morii,
  • Hideki Mochizuki,
  • Yuriko Nagane,
  • Naoya Minami,
  • Akiyuki Uzawa,
  • Masayuki Masuda,
  • Shigeaki Suzuki,
  • Iichiro Shimomura,
  • Yasushi Shintani,
  • Kimiaki Utsugisawa,
  • Masanori P. Takahashi,
  • Yukinori Okada

摘要

Myasthenia gravis (MG) is an autoimmune disorder characterized by impaired neuromuscular transmission and motor symptoms. Its genetic background remains unclear, particularly beyond specific subtypes reported in European populations. Here, we perform a genome-wide association study (GWAS) of 1,434 MG cases covering all disease subtypes and 42,913 controls of Japanese, which newly identify the TERT locus (odds ratio [OR] = 1.31, P = 1.7×10-10). Subtype-stratified GWASs show stronger signals for generalized MG (gMG; OR = 1.38, P = 1.6×10-12), anti AChR antibody-positive gMG (g-AChR-Ab(+)MG; OR= 1.49, P = 2.1×10-15), and thymoma-associated gMG (g-TAMG; OR = 1.92, P = 1.1×10-15). Fine-mapping of the major histocompatibility complex region reveal distinct associations of HLA-DRB1 with late onset gMG (g-LOMG) and HLA-A with early onset gMG (g-EOMG). The MG risk TERT lead variant rs2736099 is associated with poor treatment response, especially in g-AChR-Ab(+)MG and g-EOMG (P < 0.0042). The biobank-based phenome-wide association study identify pleiotropic effects on lung cancer, hematological traits, and telomere length. Single cell transcriptomics and immunohistochemistry identified immature lymphocyte-specific TERT expression in thymoma specimens. Full-length transcriptomics reveal allele-specific decreasing effect of rs2736099-A on TERT expression. Our study unveils genetics of MG distinctly across disease subtypes, and involvement of TERT in its pathogenesis.