Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus

Richard K Perez; M Grace Gordon; Meena Subramaniam; Min Cheol Kim; George C Hartoularos; Sasha Targ; Yang Sun; Anton Ogorodnikov; Raymund Bueno; Andrew Lu; Mike Thompson; Nadav Rappoport; Andrew Dahl; Cristina M Lanata; Mehrdad Matloubian; Lenka Maliskova; Serena S Kwek; Tony Li; Michal Slyper; Julia Waldman; Danielle Dionne; Orit Rozenblatt-Rosen; Lawrence Fong; Maria Dall'Era; Brunilda Balliu; Aviv Regev; Jinoos Yazdany; Lindsey A Criswell; Noah Zaitlen; Chun Jimmie Ye

doi:10.1126/science.abf1970

Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus

Science. 2022 Apr 8;376(6589):eabf1970. doi: 10.1126/science.abf1970. Epub 2022 Apr 8.

Authors

Richard K Perez^#¹, M Grace Gordon^#^{2

3

4

5}, Meena Subramaniam^#^{2

4}, Min Cheol Kim^{1

3

4

6

7}, George C Hartoularos^{2

3

4}, Sasha Targ^{1

2

6}, Yang Sun^{3

4}, Anton Ogorodnikov^{3

4}, Raymund Bueno^{3

4}, Andrew Lu⁸, Mike Thompson⁹, Nadav Rappoport¹⁰, Andrew Dahl¹¹, Cristina M Lanata^{3

12}, Mehrdad Matloubian^{3

12}, Lenka Maliskova^{4

13}, Serena S Kwek¹⁴, Tony Li¹⁴, Michal Slyper¹⁵, Julia Waldman¹⁵, Danielle Dionne¹⁵, Orit Rozenblatt-Rosen¹⁵, Lawrence Fong¹⁴, Maria Dall'Era¹, Brunilda Balliu¹⁶, Aviv Regev^{15

17

18}, Jinoos Yazdany³, Lindsey A Criswell^{3

4

12}, Noah Zaitlen¹⁹, Chun Jimmie Ye^{3

4

12

13

20

21

22}

Affiliations

¹ School of Medicine, University of California, San Francisco, CA, USA.
² Biological and Medical Informatics Graduate Program, University of California, San Francisco, CA, USA.
³ Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA.
⁴ Institute for Human Genetics, University of California, San Francisco, CA, USA.
⁵ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
⁶ Medical Scientist Training Program, University of California, San Francisco, CA, USA.
⁷ UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA, USA.
⁸ UCLA-Caltech Medical Scientist Training Program, Los Angeles, CA, USA.
⁹ Department of Computer Science, University of California, Los Angeles, CA, USA.
¹⁰ Department of Software and Information Systems Engineering, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
¹¹ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
¹² Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, CA, USA.
¹³ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
¹⁴ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA.
¹⁵ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
¹⁶ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹⁷ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁸ Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁹ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
²⁰ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
²¹ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
²² Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA.

^# Contributed equally.

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4⁺ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH⁺ CD8⁺ T cells. Cell type-specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type-specific cis-expression quantitative trait loci and to link SLE-associated variants to cell type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.

MeSH terms

CD8-Positive T-Lymphocytes / metabolism
Case-Control Studies
Humans
Interferon Type I* / metabolism
Leukocytes, Mononuclear
Lupus Erythematosus, Systemic* / genetics
RNA-Seq
Transcription, Genetic

Substances

Interferon Type I

Abstract

MeSH terms

Substances

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