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Single-cell RNA-seq reveals cell type–specific molecular and genetic associations to lupus
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4 08 2022
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Source: Science. 376(6589):eabf1970
[PDF-1.60 MB]
Details:
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Alternative Title:Science
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Personal Author:
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Description:INTRODUCTION:
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with elevated prevalence in women and individuals of Asian, African, and Hispanic ancestry. Bulk transcriptomic profiling has implicated increased type 1 interferon signaling, dysregulated lymphocyte activation, and failure of apoptotic clearance as hallmarks of disease. Many genes participating in these processes are proximal to the ~100 loci associated with SLE. Despite this progress, a comprehensive census of circulating immune cells in SLE remains incomplete, and annotating the cell types and contexts that mediate genetic associations remains challenging.
RATIONALE:
Historically, flow cytometry and bulk transcriptomic analyses were used to profile the composition and gene expression of circulating immune cells in SLE. However, flow cytometry is biased by its use of a limited set of known markers, whereas bulk transcriptomic profiling does not have sufficient power to detect cell type–specific expression differences. Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) holds potential as a comprehensive and unbiased approach to simultaneously profile the composition and transcriptional states of circulating immune cells. However, application of scRNA-seq to population cohorts has been limited by sample throughput, cost, and susceptibility to technical variability. To overcome these limitations, we previously developed multiplexed scRNA-seq (mux-seq) to enable systematic and cost-effective scRNA-seq of population cohorts.
RESULTS:
We used mux-seq to profile more than 1.2 million PBMCs from 162 SLE cases and 99 healthy controls of either Asian or European ancestry. SLE cases exhibited differences in both the composition and state of PBMCs. Analysis of lymphocyte composition revealed a reduction in naïve CD4+ T cells and an increase in repertoire-restricted GZMH+ CD8+ T cells. Analysis of transcriptomic profiles across eight cell types revealed that classical monocytes expressed the highest levels of both pan–cell type and myeloid-specific type 1 interferon-stimulated genes (ISGs). The expression of ISGs in monocytes was inversely correlated with naïve CD4+ T cell abundance. Cell type–specific expression features accurately predicted case-control status and stratified patients into molecular subtypes. By integrating genotyping data and using a novel matrix decomposition method, we mapped shared and cell type–specific cis–expression quantitative trait loci (cis-eQTLs) across eight cell types. Cell type–specific cis-eQTLs were enriched for regions of open chromatin specific to the same or related cell types. Joint analysis of cis-eQTLs and genome-wide association study results enabled identification of cell types relevant to immune-mediated diseases, fine-mapping of disease-associated loci, and discovery of novel SLE associations. Interaction analysis identified variants whose effects on gene expression are further modified by interferon activation across patients.
CONCLUSION:
SLE remains challenging to diagnose and treat. The heterogeneity of disease manifestations and treatment response highlight the need for improved molecular characterization. In a large multiethnic cohort, we demonstrate mux-seq as a systematic approach to characterize cellular composition, identify cell type–specific transcriptomic signatures, and annotate genetic variants associated with SLE.
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Pubmed ID:35389781
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Pubmed Central ID:PMC9297655
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Volume:376
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Issue:6589
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