Yata Tomohiro, Sato Go, Ogawa Kotaro, Naito Tatsuhiko, Sonehara Kyuto, Saiki Ryunosuke, Edahiro Ryuya, Namba Shinichi, Watanabe Mitsuru, Shirai Yuya, Yamamoto Kenichi, NamKoong Ho, Nakanishi Tomoko, Yamamoto Yuji, Hosokawa Akiko, Yamamoto Mamoru, Oguro-Igashira Eri, Nii Takuro, Maeda Yuichi, Nakajima Kimiko, Nishikawa Rika, Tanaka Hiroaki, Nakayamada Shingo, Matsuda Koichi, Nishigori Chikako, Sano Shigetoshi, Kinoshita Makoto, Koike Ryuji, Kimura Akinori, Imoto Seiya, Miyano Satoru, Fukunaga Koichi, Mihara Masahito, Shimizu Yuko, Kawachi Izumi, Miyamoto Katsuichi, Tanaka Yoshiya, Kumanogoh Atsushi, Niino Masaaki, Nakatsuji Yuji, Ogawa Seishi, Matsushita Takuya, Kira Jun-Ichi, Mochizuki Hideki, Isobe Noriko, Okuno Tatsusada, Okada Yukinori
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan; Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Japan.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Tsurumi, Japan.
Cell Genom. 2025 Mar 12;5(3):100776. doi: 10.1016/j.xgen.2025.100776. Epub 2025 Feb 21.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by optic neuritis and transverse myelitis, with an unclear genetic background. A genome-wide meta-analysis of NMOSD in Japanese individuals (240 patients and 50,578 controls) identified significant associations with the major histocompatibility complex region and a common variant close to CCR6 (rs12193698; p = 1.8 × 10, odds ratio [OR] = 1.73). In single-cell RNA sequencing (scRNA-seq) analysis (25 patients and 101 controls), the CCR6 risk variant showed disease-specific expression quantitative trait loci effects in CD4 T (CD4T) cell subsets. Furthermore, we detected somatic mosaic chromosomal alterations (mCAs) in various autoimmune diseases and found that mCAs increase the risk of NMOSD (OR = 3.37 for copy number alteration). In scRNA-seq data, CD4T cells with 21q loss, a recurrently observed somatic event in NMOSD, showed dysregulation of type I interferon-related genes. Our integrated study identified novel germline and somatic mutations associated with NMOSD pathogenesis.
视神经脊髓炎谱系障碍（NMOSD）是一种罕见的自身免疫性疾病，其特征为视神经炎和横贯性脊髓炎，遗传背景尚不明确。一项针对日本人群（240例患者和50578例对照）的NMOSD全基因组荟萃分析确定了与主要组织相容性复合体区域以及靠近CCR6的一个常见变异（rs12193698；p = 1.8×10，优势比[OR]=1.73）存在显著关联。在单细胞RNA测序（scRNA-seq）分析（25例患者和101例对照）中，CCR6风险变异在CD4 T（CD4T）细胞亚群中显示出疾病特异性表达数量性状位点效应。此外，我们在各种自身免疫性疾病中检测到体细胞镶嵌染色体改变（mCAs），并发现mCAs会增加NMOSD的风险（拷贝数改变的OR = 3.37）。在scRNA-seq数据中，21号染色体缺失的CD4T细胞是NMOSD中反复观察到的体细胞事件，显示出I型干扰素相关基因的失调。我们的综合研究确定了与NMOSD发病机制相关的新的种系和体细胞突变。
