Abstract
A goal of psychiatric research is to determine the molecular basis of human brain health and illness. One way to achieve this goal is through studies of gene expression in human brain tissue. Due to the unavailability of brain tissue from living people, most such studies are performed using tissue from postmortem brain donors. An assumption underlying this practice is that gene expression in the postmortem human brain is an accurate representation of gene expression in the living human brain. This assumption - which, until now, had not been adequately tested - was tested by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples. Expression levels differed significantly for nearly 80% of genes, and a systematic examination of alternative explanations for this observation determined that these differences are not explained by cell type composition, RNA quality, postmortem interval, age, medication, morbidity, symptom severity, tissue pathology, sample handling, batch effects, or computational methods utilized. Using gene expression data from two independent cohorts, the differences identified between living and postmortem samples were replicated and shown to be present in all brain cell types. Analyses integrating the data generated for this study with data from earlier studies that used tissue from postmortem brain donors showed that postmortem brain gene expression signatures of psychiatric and neurological illnesses, as well as of normal traits such as aging, may not always be accurate representations of these gene expression signatures in the living brain. By using tissue safely obtained from large cohorts of living people, future studies of the human brain have the potential to (1) determine the biomedical research questions that can be addressed using postmortem tissue as a proxy for living tissue and (2) expand the scope of medical research to include questions about the molecular basis of human brain health and illness that can only be addressed in living people (e.g., "What happens in the brain at the molecular level as a person experiences an emotion?").