Mapping the cellular etiology of schizophrenia and complex brain phenotypes

Laramie E Duncan; Tayden Li; Madeleine Salem; Will Li; Leili Mortazavi; Hazal Senturk; Naghmeh Shahverdizadeh; Sam Vesuna; Hanyang Shen; Jong Yoon; Gordon Wang; Jacob Ballon; Longzhi Tan; Brandon Scott Pruett; Brian Knutson; Karl Deisseroth; William J Giardino

doi:10.1038/s41593-024-01834-w

Mapping the cellular etiology of schizophrenia and complex brain phenotypes

Nat Neurosci. 2025 Jan 20. doi: 10.1038/s41593-024-01834-w. Online ahead of print.

Authors

Laramie E Duncan^#^{1

2}, Tayden Li^#³, Madeleine Salem⁴, Will Li⁴, Leili Mortazavi^{5

6}, Hazal Senturk⁷, Naghmeh Shahverdizadeh⁸, Sam Vesuna⁸, Hanyang Shen⁹, Jong Yoon^{8

5

10}, Gordon Wang^{8

5}, Jacob Ballon⁸, Longzhi Tan^{5

11}, Brandon Scott Pruett¹², Brian Knutson^{5

6}, Karl Deisseroth^{8

5

13}, William J Giardino^{8

5}

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. [email protected].
² Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. [email protected].
³ Department of Statistics, Stanford University, Stanford, CA, USA.
⁴ Vice Provost for Undergraduate Education, Stanford University, Stanford, CA, USA.
⁵ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
⁶ Department of Psychology, Stanford University, Stanford, CA, USA.
⁷ Department of Computer Science, University of San Francisco, San Francisco, CA, USA.
⁸ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
⁹ Department of Epidemiology, Stanford University, Stanford, CA, USA.
¹⁰ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹¹ Department of Neurobiology, Stanford University, Stanford, CA, USA.
¹² School of Medicine, University of Alabama at Birmingham, Birmingham, CA, USA.
¹³ Department of Bioengineering, Stanford University, Stanford, CA, USA.

^# Contributed equally.

PMID: 39833308
DOI: 10.1038/s41593-024-01834-w

Abstract

Psychiatric disorders are multifactorial and effective treatments are lacking. Probable contributing factors to the challenges in therapeutic development include the complexity of the human brain and the high polygenicity of psychiatric disorders. Combining well-powered genome-wide and brain-wide genetics and transcriptomics analyses can deepen our understanding of the etiology of psychiatric disorders. Here, we leverage two landmark resources to infer the cell types involved in the etiology of schizophrenia, other psychiatric disorders and informative comparison of brain phenotypes. We found both cortical and subcortical neuronal associations for schizophrenia, bipolar disorder and depression. These cell types included somatostatin interneurons, excitatory neurons from the retrosplenial cortex and eccentric medium spiny-like neurons from the amygdala. In contrast we found T cell and B cell associations with multiple sclerosis and microglial associations with Alzheimer's disease. We provide a framework for a cell-type-based classification system that can lead to drug repurposing or development opportunities and personalized treatments. This work formalizes a data-driven, cellular and molecular model of complex brain disorders.

Abstract

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