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

被引：240

作者：

Perez, Richard K. ^{[1
]}

Gordon, M. Grace ^{[2
,3
,4
,5
]}

Subramaniam, Meena ^{[2
,4
,23
]}

Kim, Min Cheol ^{[1
,3
,4
,6
,7
]}

Hartoularos, George C. ^{[2
,3
,4
]}

Targ, Sasha ^{[1
,2
,6
]}

Sun, Yang ^{[3
,4
]}

Ogorodnikov, Anton ^{[3
,4
]}

Bueno, Raymund ^{[3
,4
]}

Lu, Andrew ^{[8
]}

Thompson, Mike ^{[9
]}

Rappoport, Nadav ^{[10
]}

Dahl, Andrew ^{[11
]}

Lanata, Cristina M. ^{[3
,12
,24
]}

Matloubian, Mehrdad ^{[3
,12
]}

Maliskova, Lenka ^{[4
,13
]}

Kwek, Serena S. ^{[14
]}

Li, Tony ^{[14
]}

Slyper, Michal ^{[15
,25
]}

Waldman, Julia ^{[15
]}

Dionne, Danielle ^{[15
]}

Rozenblatt-Rosen, Orit ^{[15
,25
]}

Fong, Lawrence ^{[14
]}

Dall'Era, Maria ^{[1
]}

Balliu, Brunilda ^{[16
]}

Regev, Aviv ^{[15
,17
,18
,25
]}

Yazdany, Jinoos ^{[3
]}

Criswell, Lindsey A. ^{[3
,4
,12
,26
]}

Zaitlen, Noah ^{[19
]}

Ye, Chun Jimmie ^{[3
,4
,12
,13
,20
,21
,22
]}

机构：

[1] Univ Calif San Francisco, Sch Med, San Francisco, CA USA

[2] Univ Calif San Francisco, Biol & Med Informat Grad Program, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Dept Med, Div Rheumatol, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[6] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94143 USA

[7] UC Berkeley UCSF Grad Program Bioengn, San Francisco, CA USA

[8] Univ Calif Los Angeles, Caltech Med Scientist Training Program, Los Angeles, CA USA

[9] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90024 USA

[10] Ben Gurion Univ Negev, Dept Software & Informat Syst Engn, Beer Sheva, Israel

[11] Univ Chicago, Dept Med, Sect Genet Med, Chicago, IL 60637 USA

[12] Univ Calif San Francisco, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA

[13] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94110 USA

[14] Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA

[15] Broad Inst, Klarman Cell Observ, Cambridge, MA USA

[16] Univ Calif Los Angeles, David Geffen Sch Med, Dept Computat Med, Los Angeles, CA 90095 USA

[17] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[18] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[19] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA

[20] Parker Inst Canc Immunotherapy, San Francisco, CA 94129 USA

[21] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

[22] Univ Calif San Francisco, Bakar Computat Hlth Sci Inst, San Francisco, CA 94110 USA

[23] Immunai Inc, New York, NY USA

[24] NHGRI, Bethesda, MD 20892 USA

[25] Genentech Inc, 460 Point San Bruno Blvd, San Francisco, CA 94080 USA

[26] NHGRI, Genom Autoimmune Rheumat Dis Sect, Bethesda, MD 20892 USA

来源：

SCIENCE | 2022年 / 376卷 / 6589期

关键词：

GENOME-WIDE ASSOCIATION; DISEASE-ACTIVITY; GRANZYME-B; EXPRESSION; ERYTHEMATOSUS; RISK; AUTOIMMUNE; INTERFERON; PATHOGENESIS; METAANALYSIS;

D O I：

10.1126/science.abf1970

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 naive 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.

引用

页码：153 / +

页数：52

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