Cortical gene expression architecture links healthy neurodevelopment to the imaging, transcriptomics and genetics of autism and schizophrenia
Linking Healthy Neurodevelopment with Imaging, Transcriptomic, and Genetic Associations in Autism Spectrum Disorder and Schizophrenia: A Study of Cortical Gene Expression Patterns
Background: How does the complex anatomy and functional organization of the human brain develop from the expression of more than 20,000 genes? And how does this process go awry in neurodevelopmental disorders? Over the past decade, whole-brain, whole-genome transcriptomic atlases (such as the Allen Human Brain Atlas) have suggested that the organization of the healthy brain may rely on coordinated “transcriptional programs” involving the concerted expression of many genes. The first principal component may represent a key neurodevelopmental transcriptional program, but the biological significance of higher-order components remains unclear.
Authors and Publication: This study was conducted by Richard Dahl, Conrad Waddington, Jacob Seidlitz, and others, and published in the journal Nature Neuroscience in 2024. The authors are affiliated with the University of Cambridge, University College London, the University of Pennsylvania, McGill University, Monash University, Yale University, and the National Institutes of Health.
Research Workflow:
a) The researchers optimized the processing pipeline for the Allen Human Brain Atlas data, using diffusion embedding rather than principal component analysis, to identify three generalizable principal components of human cortical gene expression (C1, C2, and C3).
b) They found that C1 was related to the known “neuronal patterning” component, while C2 and C3 were enriched for metabolic, epigenetic, and immune-related genes, and genes related to synaptic plasticity, learning, and memory, respectively.
c) Through analysis with other datasets (such as single-cell RNA sequencing and developmental gene expression), the researchers found that C1-C3 represent coordinated transcriptional programs within cells, with distinct developmental trajectories in the fetal and infant periods.
d) By integrating imaging, differential expression, and genome-wide association study data, they found that autism spectrum disorder was associated with C1/C2, while schizophrenia was associated with C3.
e) C3 was related to white matter development and intelligence, and was manifest as abnormal transmodal cortical connectivity in schizophrenia patients.
Key Findings:
The human cortical gene expression landscape comprises three distinct principal components (C1, C2, and C3), enriched for different biological processes and cell type-specific genes.
C1-C3 represent transcriptional programs related to neuronal patterning, metabolic regulation, and adolescent synaptic plasticity, respectively.
C1 and C2 are established early in embryonic and infant development, while C3 matures gradually after adolescence.
Autism spectrum disorder is associated with abnormal development of C1/C2, while schizophrenia is associated with abnormal development of C3.
C3 mediates adolescent brain maturation, and its dysregulation leads to abnormal transmodal cortical connectivity in schizophrenia patients.
Significance: This study unveils multiple key components of the human brain’s transcriptomic architecture, elucidating their roles in brain development and disease pathogenesis, providing new insights into the pathophysiological mechanisms underlying neurodevelopmental disorders. These findings not only have important scientific value but may also offer new avenues for early diagnosis and treatment of these disorders.