Mapping the Cellular Etiology of Schizophrenia and Diverse Brain Phenotypes

Psychiatric disorders account for a substantial fraction of the world’s disease burden ¹ , and yet the development of novel therapeutics has been notoriously slow ² . Likely contributing factors include the complexity of the human brain and the high polygenicity of psychiatric disorders ^3–5 , meaning that thousands of genetic factors contribute to disease risk. Fortunately, technological advances have enabled comprehensive surveys of human brain cell types using transcriptomes from single nuclei (snRNAseq) ^6–8 . Additionally, genome-wide association studies (GWAS) have linked thousands of risk loci to psychiatric disorders ^9–11 . Here, we combined these two landmark data resources to infer the cell types involved in the etiology of schizophrenia and comparison phenotypes. This work demonstrated: 1) cell types that are concordant with prior findings about schizophrenia, 2) novel cell type associations for schizophrenia, 3) greater molecular specificity regarding schizophrenia-associated cell types than was previously available, 4) evidence that well powered genome-wide and brain-wide datasets are required for these analyses, 5) distinct cellular profiles for five brain-related phenotypes, 6) a prototype for a cell-type based classification system for psychiatric and other brain disorders, and 7) a roadmap toward drug repurposing, novel drug development, and personalized treatment recommendations. Thus, this work formalizes a data-driven, cellular and molecular model of complex brain disorders.