Contribution of germline and somatic mutations to risk of neuromyelitis optica spectrum disorder.

IF 11.1 Q1 CELL BIOLOGY

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-02-21 DOI:10.1016/j.xgen.2025.100776

Tomohiro Yata, Go Sato, Kotaro Ogawa, Tatsuhiko Naito, Kyuto Sonehara, Ryunosuke Saiki, Ryuya Edahiro, Shinichi Namba, Mitsuru Watanabe, Yuya Shirai, Kenichi Yamamoto, Ho NamKoong, Tomoko Nakanishi, Yuji Yamamoto, Akiko Hosokawa, Mamoru Yamamoto, Eri Oguro-Igashira, Takuro Nii, Yuichi Maeda, Kimiko Nakajima, Rika Nishikawa, Hiroaki Tanaka, Shingo Nakayamada, Koichi Matsuda, Chikako Nishigori, Shigetoshi Sano, Makoto Kinoshita, Ryuji Koike, Akinori Kimura, Seiya Imoto, Satoru Miyano, Koichi Fukunaga, Masahito Mihara, Yuko Shimizu, Izumi Kawachi, Katsuichi Miyamoto, Yoshiya Tanaka, Atsushi Kumanogoh, Masaaki Niino, Yuji Nakatsuji, Seishi Ogawa, Takuya Matsushita, Jun-Ichi Kira, Hideki Mochizuki, Noriko Isobe, Tatsusada Okuno, Yukinori Okada

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Abstract

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^-8, 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.

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生殖系和体细胞突变对视神经脊髓炎谱系障碍风险的贡献。

视神经脊髓炎（NMOSD）是一种罕见的自身免疫性疾病，以视神经炎和横切性脊髓炎为特征，遗传背景不清楚。一项针对日本个体（240例患者和50578名对照）的NMOSD全基因组荟萃分析发现，NMOSD与主要组织相容性复合体区域和一种接近CCR6的常见变异(rs12193698；p = 1.8 × 10-8，优势比[OR] = 1.73)。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定量性状位点效应。此外，我们在各种自身免疫性疾病中检测了体细胞镶嵌染色体改变（mCAs），发现mCAs增加了NMOSD的风险（拷贝数改变的OR = 3.37）。在scRNA-seq数据中，21q缺失的CD4T细胞（NMOSD中反复观察到的体细胞事件）显示I型干扰素相关基因的失调。我们的综合研究发现了与NMOSD发病机制相关的新型种系和体细胞突变。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell genomics

CiteScore

7.10

自引率

0.00%

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