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

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2025-02-17 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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Cell genomics

CiteScore

7.10

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0.00%

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