Combining phenomics with transcriptomics reveals cell-type-specific morphological and molecular signatures of the 22q11.2 deletion.

Neuropsychiatric disorders remain difficult to treat due to complex and poorly understood mechanisms. NeuroPainting is a high-content morphological profiling assay based on Cell Painting and optimized for human stem cell-derived neural cell types, including neurons, progenitors, and astrocytes. The assay quantifies over 4000 features of cell structure and organelle organization, generating a dataset suitable for phenotypic screening in neural models. Here, we show that, in studies of the 22q11.2 deletion-a strong genetic risk factor for schizophrenia-we observe cell-type-specific effects, particularly in astrocytes, including mitochondrial disruption, altered endoplasmic reticulum organization, and cytoskeletal changes. Transcriptomic analysis shows reduced expression of cell adhesion genes in deletion astrocytes, consistent with post-mortem brain data. Integration of RNA and morphology data suggests a link between adhesion gene dysregulation and mitochondrial abnormalities. These results illustrate how combining image-based profiling with gene expression analysis can reveal cellular mechanisms associated with genetic risk in neuropsychiatric disease.