Claustrum Transcriptome Alterations in Schizophrenia
Dominique Arion, John F. Enwright, Kelly M. Rogers, Kyle D. Ketchesin, Colleen A. McClung, Jill R. Glausier, David A. LewisImportance
Schizophrenia (SZ) is associated with transcriptome alterations in the dorsolateral prefrontal cortex (dlPFC) and anterior cingulate cortex (ACC), key regions in a distributed network that mediates cognitive functions impaired in the illness. The subcortical dorsal claustrum (dCLA) is structurally densely interconnected with the ACC and dlPFC and functionally coactivated with these regions during certain cognitive tasks.
Objective
To identify SZ-associated transcriptome alterations in the dCLA.
Design, Settings, and Participants
This case-control study used RNA sequencing data for dCLA homogenates from postmortem human brain of individuals with SZ and unaffected comparison (UC) individuals. Brain donations were obtained from the Allegheny County Office of the Medical Examiner, Pittsburgh, Pennsylvania. Data analysis was performed from January 12, 2024, through May 22, 2026.
Exposure
Schizophrenia.
Main Outcomes and Measures
Gene expression differences in the dCLA between individuals with SZ and UC individuals were the primary outcome. Secondary outcomes included gene set enrichment in the dCLA and comparisons of gene expression differences across the dCLA, ACC, dlPFC, putamen, and caudate between individuals with SZ and UC individuals, including rank-rank hypergeometric overlap (RRHO) analyses.
Results
In the final dCLA samples from 96 individuals, including 47 individuals with SZ (10 [21.3%] female; mean [SD] age, 49.0 [13.3] years) and 49 UC individuals (10 [20.4%] female; mean [SD] age, 49.9 [14.2] years), there were 1717 differentially expressed genes (DEGs) between individuals with SZ and UC individuals, with 1149 (66.9%) of the DEGs upregulated in SZ. Many upregulated DEGs were associated with immune response or transcription regulation, and many downregulated DEGs were associated with mitochondrial activity or oxidative phosphorylation. In comparisons between individuals with SZ and UC individuals with data from the dCLA, ACC, and dlPFC, the number of DEGs detected was 4 to 12 times greater in the dCLA (1242 DEGs) than in the ACC (289 DEGs) or dlPFC (102 DEGs). However, threshold-free RRHO analyses revealed a conserved pattern of SZ-associated gene expression alterations across all 3 regions. In comparison, concordance of gene expression alterations was lower with the putamen and caudate, subcortical regions with weaker connections to the dCLA.
Conclusions and Relevance
The results of this case-control study suggest that the dCLA is a prominent site of molecular alterations in SZ. These alterations might reflect the dCLA’s extensive connectivity with affected cortical regions, distinctive intrinsic circuitry, and/or enrichment of vulnerable cell types.