Mapping the Cellular Etiology of Schizophrenia and Diverse Brain Phenotypes

Abstract

Psychiatric disorders account for a substantial fraction of the world's disease burden, and yet the development of novel therapeutics has been notoriously slow. Likely contributing factors include the complexity of the human brain and the high polygenicity of psychiatric disorders, 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). Additionally, genome-wide association studies (GWAS) have linked thousands of risk loci to psychiatric disorders. 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.