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

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<sup>-10</sup>). Subtype-stratified GWASs show stronger signals for generalized MG (gMG; OR = 1.38, P = 1.6×10<sup>-12</sup>), anti AChR antibody-positive gMG (g-AChR-Ab(+)MG; OR= 1.49, P = 2.1×10<sup>-15</sup>), and thymoma-associated gMG (g-TAMG; OR = 1.92, P = 1.1×10<sup>-15</sup>). 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.

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Journal
Nature Communications
Published
2026-03-12
DOI
https://doi.org/10.1038/s41467-026-70376-5
Primary Topic
Myasthenia Gravis and Thymoma
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article
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article

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

Jun Takayama, Naoko Ose, Tatsusada Okuno, Tatsuhiko Naito et al.
Nature Communications
Myasthenia Gravis and Thymoma
article

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

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

Abstract

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<sup>-10</sup>). Subtype-stratified GWASs show stronger signals for generalized MG (gMG; OR = 1.38, P = 1.6×10<sup>-12</sup>), anti AChR antibody-positive gMG (g-AChR-Ab(+)MG; OR= 1.49, P = 2.1×10<sup>-15</sup>), and thymoma-associated gMG (g-TAMG; OR = 1.92, P = 1.1×10<sup>-15</sup>). 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.

Nature Communications
Hiroshima University (JP), Osaka Gakuin University (JP), Toho University (JP), Tokyo Medical University (JP), Chiba University (JP), Tohoku University (JP), Keio University (JP), Japan Agency for Medical Research and Development (JP), Juntendo University (JP), Toho University Ohashi Medical Center (JP), National Hospital Organization Hokkaido Medical Center (JP), Toneyama National Hospital (JP), Kindai University Sakai Hospital (JP), Tokyo Metropolitan Neurological Hospital (JP), Hiroshima University Hospital (JP), RIKEN Center for Advanced Intelligence Project (JP), National Hospital Organization Hanamaki Hospital (JP), Chiba Hospital (JP), Tohoku Medical Megabank Organization (JP), National Hospital Organization (JP), Aso Iizuka Hospital (JP), RIKEN Center for Integrative Medical Sciences (JP), Shonan Kamakura General Hospital (JP), Social Insurance Saitama Chuo Hospital (JP), Toranomon Hospital (JP), The University of Tokyo (JP), International University of Health and Welfare (JP), Nippon Medical School (JP), Hyogo University (JP), Saitama Medical University (JP), The University of Osaka (JP)
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