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

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 WaldmanDanielle Dionne, Orit Rozenblatt-Rosen, Lawrence Fong, Maria Dall'Era, Brunilda Balliu, Aviv Regev, Jinoos Yazdany, Lindsey A. Criswell, Noah Zaitlen, Chun Jimmie Ye

Department of Software and Information Systems Engineering

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166 Scopus citations

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 repertoirerestricted 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.

Original language	English
Article number	abf1970
Journal	Science
Volume	376
Issue number	6589
DOIs	https://doi.org/10.1126/science.abf1970
State	Published - 8 Apr 2022

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Perez, R. K., Gordon, M. G., Subramaniam, M., Kim, M. C., Hartoularos, G. C., Targ, S., Sun, Y., Ogorodnikov, A., Bueno, R., Lu, A., Thompson, M., Rappoport, N., Dahl, A., Lanata, C. M., Matloubian, M., Maliskova, L., Kwek, S. S., Li, T., Slyper, M., ... Ye, C. J. (2022). Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus. Science, 376(6589), Article abf1970. https://doi.org/10.1126/science.abf1970

@article{f16b97fdd3354710968fbb811a597c4e,

title = "Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus",

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 na{\"i}ve CD4+ T cells that correlated with monocyte ISG expression, and expansion of repertoirerestricted 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.",

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

year = "2022",

month = apr,

day = "8",

doi = "10.1126/science.abf1970",

language = "English",

volume = "376",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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Perez, RK, Gordon, MG, Subramaniam, M, Kim, MC, Hartoularos, GC, Targ, S, Sun, Y, Ogorodnikov, A, Bueno, R, Lu, A, Thompson, M, Rappoport, N, Dahl, A, Lanata, CM, Matloubian, M, Maliskova, L, Kwek, SS, Li, T, Slyper, M, Waldman, J, Dionne, D, Rozenblatt-Rosen, O, Fong, L, Dall'Era, M, Balliu, B, Regev, A, Yazdany, J, Criswell, LA, Zaitlen, N & Ye, CJ 2022, 'Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus', Science, vol. 376, no. 6589, abf1970. https://doi.org/10.1126/science.abf1970

TY - JOUR

T1 - Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus

AU - Perez, Richard K.

AU - Gordon, M. Grace

AU - Subramaniam, Meena

AU - Kim, Min Cheol

AU - Hartoularos, George C.

AU - Targ, Sasha

AU - Sun, Yang

AU - Ogorodnikov, Anton

AU - Bueno, Raymund

AU - Lu, Andrew

AU - Thompson, Mike

AU - Rappoport, Nadav

AU - Dahl, Andrew

AU - Lanata, Cristina M.

AU - Matloubian, Mehrdad

AU - Maliskova, Lenka

AU - Kwek, Serena S.

AU - Li, Tony

AU - Slyper, Michal

AU - Waldman, Julia

AU - Dionne, Danielle

AU - Rozenblatt-Rosen, Orit

AU - Fong, Lawrence

AU - Dall'Era, Maria

AU - Balliu, Brunilda

AU - Regev, Aviv

AU - Yazdany, Jinoos

AU - Criswell, Lindsey A.

AU - Zaitlen, Noah

AU - Ye, Chun Jimmie

PY - 2022/4/8

Y1 - 2022/4/8

N2 - 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 repertoirerestricted 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.

AB - 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 repertoirerestricted 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.

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U2 - 10.1126/science.abf1970

DO - 10.1126/science.abf1970

M3 - Article

C2 - 35389781

AN - SCOPUS:85127918245

SN - 0036-8075

VL - 376

JO - Science

JF - Science

IS - 6589

M1 - abf1970

ER -

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

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