I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Fox Foundation (Grant 18232), National Institute of Mental Health (R01MH109897).

National Institute of Aging (R01AG069976). The authors have declared no competing interest. By using tissue from large cohorts living people, future observational studies of human brain biology have the potential to (1) determine the medical 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 at the molecular level in the brain as a person experiences an emotion?”). Analyses integrating the data generated for this study with data from earlier landmark studies that used tissue from postmortem brain donors showed that postmortem brain gene expression signatures of neurological and mental illnesses, as well as of normal traits such as aging, may not be accurate representations of these gene expression signatures in the living brain. 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 a consequence of cell type composition, RNA quality, postmortem interval, age, medication, morbidity, symptom severity, tissue pathology, sample handling, batch effects, or computational methods utilized. Here, this assumption – which, until now, had not been adequately tested – is tested by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples.

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. Due to the unavailability of brain tissue from living people, most such studies are performed using tissue from postmortem brain donors. One way to achieve this goal is through observational studies of gene expression in human brain tissue. A goal of medical research is to determine the molecular basis of human brain health and illness.

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