Nature genetics · 2024
Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.
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Tian Chi, Zhang Yuntian, Tong Yihan, Kock Kian Hong, Sim Donald Yuhui, Liu Fei, Dong Jiaqi, Jing Zhixuan, Wang Wenjing, Gao Junbin, Tan Le Min, Han Kyung Yeon, Tomofuji Yoshihiko, Nakano Masahiro, Buyamin Eliora Violain, Sonthalia Radhika, Ando Yoshinari, Hatano Hiroaki, Sonehara Kyuto, Asian Immune Diversity Atlas Network, Jin Xin, Loh Marie, Chambers John, Hon Chung-Chau, Choi Murim, Park Jong-Eun, Ishigaki Kazuyoshi, Okamura Tomohisa, Fujio Keishi, Okada Yukinori, Park Woong-Yang, Shin Jay W, Roca Xavier, Prabhakar Shyam, Liu Boxiang
Аннотация
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.