Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases
Article Type
Research Article
Publication Title
Nature Genetics
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.
First Page
2739
Last Page
2752
DOI
10.1038/s41588-024-02019-8
Publication Date
12-1-2024
Recommended Citation
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; Moody, Jonathan; Lin, Quy Xiao Xuan; Venkatesh, Prasanna Nori; Maitra, Arindam; Lim, Jinyeong; Kouno, Tsukasa; Kojima, Miki; Suzuki, Akari; Oh, Jin Mi; Myouzen, Keiko; Inoue, Gyo; Furukawa, Seiko; Abe, Mai; and Thungsatianpun, Narita, "Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases" (2024). Journal Articles. 5083.
https://digitalcommons.isical.ac.in/journal-articles/5083