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

被引：1

作者：

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

Jin, Xin ^{[11
,12
,13
,14
]}

Loh, Marie ^{[15
,16
]}

Chambers, John ^{[15
]}

Hon, Chung-Chau ^{[17
]}

Choi, Murim ^{[18
]}

Park, Jong-Eun ^{[19
]}

Ishigaki, Kazuyoshi ^{[9
]}

Okamura, Tomohisa ^{[20
]}

Fujio, Keishi ^{[20
]}

Okada, Yukinori ^{[6
,7
,8
,21
,22
]}

Park, Woong-Yang ^{[5
]}

Shin, Jay W. ^{[3
,10
,23
]}

Roca, Xavier ^{[4
]}

Prabhakar, Shyam ^{[3
,15
]}

Liu, Boxiang ^{[1
,2
,3
,24
,25
,26
]}

机构：

[1] Natl Univ Singapore, Fac Sci, Dept Pharm & Pharmaceut Sci, Singapore, Singapore

[2] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biomed Informat, Singapore, Singapore

[3] ASTAR, Genome Inst Singapore GIS, Singapore, Singapore

[4] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore

[5] Samsung Med Ctr, Samsung Genome Inst, Seoul, South Korea

[6] RIKEN Ctr Integrat Med Sci, Lab Syst Genet, Yokohama, Japan

[7] Osaka Univ, Dept Stat Genet, Grad Sch Med, Suita, Japan

[8] Univ Tokyo, Grad Sch Med, Dept Clin Genome Informat, Tokyo, Japan

[9] RIKEN Ctr Integrat Med Sci, Lab Human Immunogenet, Yokohama, Japan

[10] RIKEN Ctr Integrat Med Sci, Lab Adv Genom Circuit, Yokohama, Japan

[11] BGI Res, Shenzhen, Peoples R China

[12] South China Univ Technol, Innovat Ctr, Sch Med, Minist Educ Dev & Dis, Guangzhou, Peoples R China

[13] Shanxi Med Univ, BGI Collaborat Ctr Future Med, Taiyuan, Peoples R China

[14] BGI Res, Shenzhen Key Lab Trans Biotechnol, Shenzhen, Peoples R China

[15] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore

[16] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[17] Hiroshima Univ, RIKEN Ctr Integrat Med Sci, Grad Sch Integrated Sci Life, Lab Genome Informat Anal, Hiroshima, Japan

[18] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea

[19] KAIST Daejeon, Grad Sch Med Sci & Engn, Daejeon, South Korea

[20] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Tokyo, Japan

[21] Osaka Univ, Immunol Frontier Res Ctr WPI IFReC, Lab Stat Immunol, Suita, Japan

[22] Osaka Univ, Premium Res Inst Human Metaverse Med WPI PRIMe, Suita, Japan

[23] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore

[24] Natl Univ Singapore, Yong Loo Lin Sch Med, Precis Med Translat Res Programme, Singapore, Singapore

[25] Natl Univ Singapore, NUS Ctr Canc Res, Yong Loo Lin Sch Med, Singapore, Singapore

[26] Natl Univ Singapore, Yong Loo Lin Sch Med, Cardiovasc Metab Dis Translat Res Programme, Singapore, Singapore

来源：

NATURE GENETICS | 2024年

基金：

新加坡国家研究基金会; 英国医学研究理事会;

关键词：

ANALYSES IDENTIFY; GENE-EXPRESSION; SEQ; ASSOCIATION; THOUSANDS; SYSTEM; LOCI; GWAS; CD45; EQTL;

D O I：

10.1038/s41588-024-02019-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 similar to 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.

引用

页码：2739 / 2752

页数：34

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