Multiancestry genome-wide association and multiomics analyses elucidate spatiocellular features of multiple sclerosis genetics

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination disseminated in space and time. Here we performed a genome-wide association study (GWAS) using 688 MS cases and 205,199 controls from the Japanese population and identified significant associations in the major histocompatibility complex region and a population-specific risk variant in 11q24. Through cross-population GWAS meta-analyses using a total of 29,374 cases and 1,843,563 controls from 4 ancestral populations, we identified 22 novel susceptibility loci. Integration of GWAS and single-cell and single-nucleus RNA sequencing of peripheral blood mononuclear cells and subcortical lesions from patients with MS revealed enrichment of genetic risk factors for MS in CD4+ T helper cell lineage and regulatory T cells, as well as in endothelial cells. Furthermore, spatial transcriptomics of subcortical lesions demonstrated spatial and temporal heterogeneity in associations with MS genetic risk. Our study demonstrates the value of investigation of spatiocellular features of disease genetics across diverse populations and omics modalities. Multiancestry genome-wide association analyses of multiple sclerosis integrated with single-cell, single-nucleus and spatial transcriptomics data yield insights into the cellular, spatial and temporal heterogeneity underlying disease risk.

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Publication Details

Journal
Nature Genetics
Published
2026-09-07
DOI
https://doi.org/10.1038/s41588-026-02741-5
Primary Topic
Multiple Sclerosis Research Studies
Type
article
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article

Multiancestry genome-wide association and multiomics analyses elucidate spatiocellular features of multiple sclerosis genetics

Izumi Kawachi, Yuji Yamamoto, Noriko Isobe, Tatsusada Okuno et al.
Nature Genetics
Multiple Sclerosis Research Studies
article

Multiancestry genome-wide association and multiomics analyses elucidate spatiocellular features of multiple sclerosis genetics

Izumi Kawachi, Yuji Yamamoto, Noriko Isobe, Tatsusada Okuno, Masaaki Niino, Mitsuru Watanabe, Masayuki Nakamori, Tatsuhiko Naito, Kotaro Ogawa, Atsushi Kumanogoh, Yukinori Okada, Shinichi Namba, Fumitaka Shimizu, Hideki Mochizuki, Ryuya Edahiro, Tomohiro Yata, Chifune Kai, Katsuichi Miyamoto, Yosuke Ogawa, Yuya Shirai, Masahito Mihara, Kyuto Sonehara, Yuji Nakatsuji, Mamoru Yamamoto, Akiko Hosokawa, Go Sato, the BioBank Japan Project, Koichi Matsuda, Japan MS/NMOSD Biobank, Rintaro Fujimoto, Jun-ichi Kira, Makoto Kinoshita, Shiori Tagawa, Yuko Shimizu, Takuya Matsushita
article en

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination disseminated in space and time. Here we performed a genome-wide association study (GWAS) using 688 MS cases and 205,199 controls from the Japanese population and identified significant associations in the major histocompatibility complex region and a population-specific risk variant in 11q24. Through cross-population GWAS meta-analyses using a total of 29,374 cases and 1,843,563 controls from 4 ancestral populations, we identified 22 novel susceptibility loci. Integration of GWAS and single-cell and single-nucleus RNA sequencing of peripheral blood mononuclear cells and subcortical lesions from patients with MS revealed enrichment of genetic risk factors for MS in CD4+ T helper cell lineage and regulatory T cells, as well as in endothelial cells. Furthermore, spatial transcriptomics of subcortical lesions demonstrated spatial and temporal heterogeneity in associations with MS genetic risk. Our study demonstrates the value of investigation of spatiocellular features of disease genetics across diverse populations and omics modalities. Multiancestry genome-wide association analyses of multiple sclerosis integrated with single-cell, single-nucleus and spatial transcriptomics data yield insights into the cellular, spatial and temporal heterogeneity underlying disease risk.

Nature Genetics
Osaka Gakuin University (JP), Kyushu University (JP), Yamaguchi University (JP), Kawasaki Medical School (JP), Wakayama Medical University (JP), Wellcome Sanger Institute (GB), Fukuoka International University (JP), Fukuoka Hospital (JP), National Hospital Organization Hokkaido Medical Center (JP), Toneyama National Hospital (JP), Suita Municipal Hospital (JP), Niigata University Medical and Dental Hospital (JP), Tokyo Women's Medical University (JP), National Hospital Organization (JP), RIKEN Center for Integrative Medical Sciences (JP), Kouseiren Takaoka Hospital (JP), University of Toyama (JP), Niigata University (JP), The University of Tokyo (JP), Kōchi University (JP), International University of Health and Welfare (JP), The University of Osaka (JP)
Good health and well-being
Openalex Percentile: Top 11%
Multiple Sclerosis Research Studies
DOIOpen Access PDFOpenAlex
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