Liharska Lora E, Park You Jeong, Ziafat Kimia, Wilkins Lillian, Silk Hannah, Linares Lisa M, Vornholt Eric, Sullivan Brendan, Cohen Vanessa, Kota Prashant, Feng Claudia, Cheng Esther, Moya Emily, Thompson Ryan C, Johnson Jessica S, Rieder Marysia-Kolbe, Huang Jia, Scarpa Joseph, Hashemi Alice, Polanco Jairo, Levin Matthew A, Nadkarni Girish N, Sebra Robert, Crary John, Schadt Eric E, Beckmann Noam D, Kopell Brian H, Charney Alexander W
medRxiv. 2023 Aug 1:2023.04.21.23288916. doi: 10.1101/2023.04.21.23288916.
A goal of medical research is to determine the molecular basis of human brain health and illness. One way to achieve this goal is through observational 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. 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. 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. 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. 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?").
医学研究的一个目标是确定人类大脑健康与疾病的分子基础。实现这一目标的一种方法是通过对人类脑组织中的基因表达进行观察性研究。由于无法获取活人脑组织，大多数此类研究是使用死后脑捐赠者的组织进行的。这种做法背后的一个假设是，死后人类大脑中的基因表达是活人脑中基因表达的准确反映。在此，通过比较275个活体样本和243个死后样本之间的人类前额叶皮质基因表达，对这一此前未得到充分验证的假设进行了检验。近80%的基因表达水平存在显著差异，对这一观察结果的其他解释进行系统检查后确定，这些差异不是细胞类型组成、RNA质量、死后间隔、年龄、药物治疗、发病率、症状严重程度、组织病理学、样本处理、批次效应或所使用的计算方法造成的。将本研究生成的数据与早期具有里程碑意义的研究（使用死后脑捐赠者的组织）的数据相结合进行分析表明，神经和精神疾病以及衰老等正常特征的死后脑基因表达特征，可能无法准确反映活体大脑中的这些基因表达特征。通过使用大量活人群体的组织，未来对人类大脑生物学的观察性研究有可能：（1）确定哪些医学研究问题可以使用死后组织替代活体组织来解决；（2）扩大医学研究的范围，将有关人类大脑健康与疾病分子基础的问题纳入其中，而这些问题只能在活人身上进行研究（例如，“当一个人经历某种情绪时，大脑在分子水平上会发生什么？”）。
