TY - JOUR
T1 - Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases
AU - Asian Immune Diversity Atlas Network
AU - Tian, Chi
AU - Zhang, Yuntian
AU - Tong, Yihan
AU - Kock, Kian Hong
AU - Sim, Donald Yuhui
AU - Liu, Fei
AU - Dong, Jiaqi
AU - Jing, Zhixuan
AU - Wang, Wenjing
AU - Gao, Junbin
AU - Tan, Le Min
AU - Han, Kyung Yeon
AU - Tomofuji, Yoshihiko
AU - Nakano, Masahiro
AU - Buyamin, Eliora Violain
AU - Sonthalia, Radhika
AU - Ando, Yoshinari
AU - Hatano, Hiroaki
AU - Sonehara, Kyuto
AU - Moody, Jonathan
AU - Lin, Quy Xiao Xuan
AU - Venkatesh, Prasanna Nori
AU - Maitra, Arindam
AU - Lim, Jinyeong
AU - Kouno, Tsukasa
AU - Kojima, Miki
AU - Suzuki, Akari
AU - Oh, Jin Mi
AU - Myouzen, Keiko
AU - Inoue, Gyo
AU - Furukawa, Seiko
AU - Abe, Mai
AU - Thungsatianpun, Narita
AU - Sarkar, Sumanta
AU - Nguantad, Sarintip
AU - Jevapatarakul, Damita
AU - Ghosh, Supratim
AU - Chatterjee, Ankita
AU - Chantaraamporn, Juthamard
AU - Sankaran, Shvetha
AU - Rayan, Nirmala Arul
AU - Rajagopalan, Deepa
AU - Yamamoto, Kazuhiko
AU - Suktitipat, Bhoom
AU - Pithukpakorn, Manop
AU - Chambers, John C.
AU - Carninci, Piero
AU - Matangkasombut, Ponpan
AU - Majumder, Partha P.
AU - Park, Woong Yang
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85211588313
U2 - 10.1038/s41588-024-02019-8
DO - 10.1038/s41588-024-02019-8
M3 - Article
C2 - 39627432
AN - SCOPUS:85211588313
SN - 1061-4036
VL - 56
SP - 2739
EP - 2752
JO - Nature Genetics
JF - Nature Genetics
IS - 12
M1 - 122
ER -
SDG 3 Good Health and Well-being