Single-cell multi-cohort dissection of the schizophrenia transcriptome

被引：26

作者：

Ruzicka, W. Brad ^{[1
,2
,3
]}

Mohammadi, Shahin ^{[3
,4
,11
]}

Fullard, John F. ^{[5
,6
,7
,8
]}

Davila-Velderrain, Jose ^{[3
,4
,9
]}

Subburaju, Sivan ^{[1
,2
]}

Tso, Daniel Reed ^{[1
]}

Hourihan, Makayla ^{[1
]}

Jiang, Shan ^{[6
,7
]}

Lee, Hao-Chih ^{[6
,7
]}

Bendl, Jaroslav ^{[5
,6
,7
,8
]}

Voloudakis, Georgios ^{[5
,6
,7
,8
]}

Haroutunian, Vahram ^{[8
,10
]}

Hoffman, Gabriel E. ^{[5
,6
,7
,8
]}

Roussos, Panos ^{[5
,6
,7
,8
,9
]}

Kellis, Manolis ^{[3
,4
]}

机构：

[1] McLean Hosp, Lab Epigen Human Psychopathol, Belmont, MA 02478 USA

[2] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA

[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[4] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA

[5] Icahn Sch Med Mt Sinai, Ctr Dis Neurogenom, New York, NY 10029 USA

[6] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[7] Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA

[8] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[9] Human Technopole, Neurogenom Res Ctr, I-20157 Milan, Italy

[10] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY 10468 USA

[11] Insitro, San Francisco, CA 94080 USA

来源：

SCIENCE | 2024年 / 384卷 / 6698期

基金：

美国国家卫生研究院;

关键词：

PREFRONTAL CORTEX; GENE-EXPRESSION; SYNAPTIC PLASTICITY; GABAERGIC NEURONS; POLYGENIC RISK; NEURODEVELOPMENT; HIPPOCAMPUS; DEFICITS; IMPACT; LOCI;

D O I：

10.1126/science.adg5136

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：

The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked by expression of specific excitatory and inhibitory neuronal cell states. This single-cell atlas links transcriptomic changes to etiological genetic risk factors, contextualizing established knowledge within the human cortical cytoarchitecture and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.

引用

页数：13

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