Liharska Lora E, Park You Jeong, Ziafat Kimia, Wilkins Lillian, Silk Hannah, Linares Lisa M, Thompson Ryan C, Vornholt Eric, Sullivan Brendan, Cohen Vanessa, Kota Prashant, Feng Claudia, Cheng Esther, Johnson Jessica S, Rieder Marysia-Kolbe, Huang Jia, Scarpa Joseph, Polanco Jairo, Moya Emily, Hashemi Alice, Levin Matthew A, Nadkarni Girish N, Sebra Robert, Crary John F, Schadt Eric E, Beckmann Noam D, Kopell Brian H, Charney Alexander W
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mol Psychiatry. 2025 Aug 23. doi: 10.1038/s41380-025-03163-1.
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?").
精神病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研究。由于无法从活人身上获取脑组织，大多数此类研究都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大脑中基因表达的准确反映。这个迄今为止尚未得到充分验证的假设，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来进行检验。近80%的基因表达水平存在显著差异，对这一观察结果的替代解释进行系统检查后确定，这些差异无法用细胞类型组成、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来解释。利用来自两个独立队列的基因表达数据，活体样本和死后样本之间的差异得到了重复验证，并表明在所有脑细胞类型中都存在。将本研究生成的数据与早期使用死后脑捐赠者组织的研究数据进行整合分析表明，精神疾病和神经疾病以及衰老等正常特征的死后脑基因表达特征，可能并不总是活脑这些基因表达特征的准确反映。通过使用从大量活人队列中安全获取的组织，未来对人类大脑的研究有可能：（1）确定哪些生物医学研究问题可以用死后组织替代活体组织来解决；（2）扩大医学研究的范围，将关于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得到解决（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？”）。
