Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.

Autor: Tian C; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore., Zhang Y; Department of Biomedical Informatics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Tong Y; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore., Kock KH; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Sim DY; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Liu F; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore., Dong J; Department of Biomedical Informatics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Jing Z; Department of Biomedical Informatics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Wang W; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore.; Department of Biomedical Informatics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Gao J; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore., Tan LM; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Han KY; Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea., Tomofuji Y; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Nakano M; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.; Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan., Buyamin EV; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Sonthalia R; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Ando Y; Laboratory for Advanced Genomics Circuit, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.; Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan., Hatano H; Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan., Sonehara K; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Jin X; BGI Research, Shenzhen, China.; The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China.; Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China.; Shenzhen Key Laboratory of Transomics Biotechnologies, BGI Research, Shenzhen, China., Loh M; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., Chambers J; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore., Hon CC; Laboratory for Genome Information Analysis, RIKEN Center for Integrative Medical Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan., Choi M; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea., Park JE; Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea., Ishigaki K; Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan., Okamura T; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Fujio K; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Okada Y; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Japan., Park WY; Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea., Shin JW; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Laboratory for Advanced Genomics Circuit, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Roca X; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Prabhakar S; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore., Liu B; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore. boxiangliu@nus.edu.sg.; Department of Biomedical Informatics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. boxiangliu@nus.edu.sg.; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. boxiangliu@nus.edu.sg.; Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. boxiangliu@nus.edu.sg.; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. boxiangliu@nus.edu.sg.; Cardiovascular-Metabolic Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. boxiangliu@nus.edu.sg.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 Dec; Vol. 56 (12), pp. 2739-2752. Date of Electronic Publication: 2024 Dec 03.
DOI: 10.1038/s41588-024-02019-8
Abstrakt: Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5' splice site of TCHP exon 4 that putatively modulates the risk of Graves' disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution.
Competing Interests: Competing interests: X.J. is an employee of BGI Research. Y. Tong is undertaking a PhD scholarship partially supported by BGI Research. The other authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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