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

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.

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Publication Details

Journal
Nature Genetics
Published
2024-12-01
DOI
https://doi.org/10.1038/s41588-024-02019-8
Citations
24
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
5.61

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article

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

Murim Choi, Woong‐Yang Park, Tomohisa Okamura, Jay W. Shin et al.
24 citations
Nature Genetics
Single-cell and spatial transcriptomics
5.61
article

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

Murim Choi, Woong‐Yang Park, Tomohisa Okamura, Jay W. Shin, Jiaqi Dong, Chi Tian, Kian Hong Kock, Chung-Chau Hon, Shyam Prabhakar, Le Min Tan, Marie Chiew Shia Loh, John C. Chambers, Yukinori Okada, Hiroaki Hatano, Yuntian Zhang, Yoshinari Ando, Boxiang Liu, Yoshihiko Tomofuji, Xavier Roca, Kazuyoshi Ishigaki, Donald Yuhui Sim, Keishi Fujio, Zefan Jing, Kyung Yeon Han, Xin Jin, Junbin Gao, Yihan Tong, Kyuto Sonehara, Eliora Violain Buyamin, Radhika Sonthalia, Wenjing Wang, Jong-Eun Park, Masahiro Nakano, Fei Liu
article en
24 citations

Abstract

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.

Nature GeneticsVol. 56(12)
BGI Group (China) (CN), Hiroshima University (JP), Agency for Science, Technology and Research (SG), Siriraj Hospital (TH), Seoul National University (KR), Korea Advanced Institute of Science and Technology (KR), National University of Singapore (SG), Nanyang Technological University (SG), Shanxi Medical University (CN), Mahidol University (TH), Samsung Medical Center (KR), Human Technopole (IT), RIKEN Center for Integrative Medical Sciences (JP), National Institute of Biomedical Genomics (IN), BGI Research (CN), Imperial College London (GB), Indian Statistical Institute (IN), Genome Institute of Singapore (SG), The University of Tokyo (JP), Suranaree University of Technology (TH), South China University of Technology (CN), The University of Osaka (JP)
Silicon Valley Community Foundation, Japan Agency for Medical Research and Development, Imperial College London, National Research Foundation, Ministry of Education - Singapore, Nanyang Technological University, Israel Science Foundation, Mahidol University, Ministry of Education, India, National Healthcare Group, National Supercomputing Centre Singapore, Medical Research Council, National Medical Research Council, Japan Society for the Promotion of Science, Lee Kong Chian School of Medicine, Nanyang Technological University, Moonshot Research and Development Program
Zero hunger
Openalex Percentile: Top 3%
Single-cell and spatial transcriptomics
5.61
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