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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年12月3日

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  • Chi Tian,
  • Yuntian Zhang,
  • Yihan Tong,
  • Kian Hong Kock,
  • Donald Yuhui Sim,
  • Fei Liu,
  • Jiaqi Dong,
  • Zhixuan Jing,
  • Wenjing Wang,
  • Junbin Gao,
  • Le Min Tan,
  • Kyung Yeon Han,
  • Yoshihiko Tomofuji,
  • Masahiro Nakano,
  • Eliora Violain Buyamin,
  • Radhika Sonthalia,
  • Yoshinari Ando,
  • Hiroaki Hatano,
  • Kyuto Sonehara,
  • Varodom Charoensawan,
  • Partha P. Majumder,
  • Ponpan Matangkasombut,
  • Piero Carninci,
  • John C. Chambers,
  • Manop Pithukpakorn,
  • Bhoom Suktitipat,
  • Kazuhiko Yamamoto,
  • Deepa Rajagopalan,
  • Nirmala Arul Rayan,
  • Shvetha Sankaran,
  • Juthamard Chantaraamporn,
  • Ankita Chatterjee,
  • Supratim Ghosh,
  • Damita Jevapatarakul,
  • Sarintip Nguantad,
  • Sumanta Sarkar,
  • Narita Thungsatianpun,
  • Mai Abe,
  • Seiko Furukawa,
  • Gyo Inoue,
  • Keiko Myouzen,
  • Jin-Mi Oh,
  • Akari Suzuki,
  • Miki Kojima,
  • Tsukasa Kouno,
  • Jinyeong Lim,
  • Arindam Maitra,
  • Prasanna Nori Venkatesh,
  • Quy Xiao Xuan Lin,
  • Jonathan Moody,
  • Xin Jin,
  • Marie Loh,
  • John Chambers,
  • Chung-Chau Hon,
  • Murim Choi,
  • Jong-Eun Park,
  • Kazuyoshi Ishigaki,
  • Tomohisa Okamura,
  • Keishi Fujio,
  • Yukinori Okada,
  • Woong-Yang Park,
  • Jay W. Shin,
  • Xavier Roca,
  • Shyam Prabhakar,
  • Boxiang Liu

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 ~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.