Contribution of germline and somatic mutations to risk of neuromyelitis optica spectrum disorder
Cell Genomics, 2025
Yata T., Sato G., Ogawa K., Naito T., Sonehara K., Saiki R., Edahiro R., Namba S., Watanabe M., Shirai Y., Yamamoto K., NamKoong H., Nakanishi T., Yamamoto Y., Hosokawa A., Yamamoto M., Oguro-Igashira E., Nii T., Maeda Y., Nakajima K., Nishikawa R., Tanaka H., Nakayamada S., Matsuda K., Nishigori C., Sano S., Kinoshita M., Koike R., Kimura A., Imoto S., Miyano S., Fukunaga K., Mihara M., Shimizu Y., Kawachi I., Miyamoto K., Tanaka Y., Kumanogoh A., Niino M., Nakatsuji Y., Ogawa S., Matsushita T., Kira J., Mochizuki H., Isobe N., Okuno T., Okada Y.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Plasma | O Olink Explore 3072/384 |
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.