Exploring the early genetic origins of schizophrenia at the cellular level

精神分裂症是一种严重的精神疾病，约占人口的1%。最近的大规模基因组研究已经确定了数百个精神分裂症的遗传风险位点，为深入了解这种疾病铺平了道路。我们自己的研究和其他人的研究表明，许多这些遗传风险变异在子宫内起作用，证实了长期以来关于这种疾病的神经发育理论。然而，产前大脑区域和细胞类型通过这些遗传风险变异的运作仍不清楚。该博士项目将建立在当前MRC项目资助的基础上，该项目由首席导师Bray负责，他正在使用单细胞测序来评估人类胎儿大脑组成细胞类型中的基因表达及其调控。该学生将结合使用这种尖端的湿实验室技术和最新的精神分裂症基因数据（可通过宿主MRC神经精神遗传学和基因组学中心获得），以确定产前大脑中介导该疾病遗传风险的细胞类型。通过这两个主办中心，他们将接受培训，掌握最先进的实验室技术，分析细胞基因表达，以及复杂的生物统计方法，分析细胞基因表达并将其与大规模遗传数据结合起来。该学生还将受益于使用由卡迪夫和埃克塞特监督小组（来自胎儿和成人大脑）以及已建立的国际合作（例如与精神病学基因组学联盟，PsychENCODE）产生的相关表观基因组学和转录组学数据。通过定期参加国际会议（如世界精神病学遗传学大会、神经科学学会）、在主要期刊上发表论文和通过数据共享库传播，学生研究的影响将最大化。

Schizophrenia is a severe psychiatric disorder affecting ~1% of the population. Recent large-scale genomic studies have identified hundreds of schizophrenia genetic risk loci, paving the way for much-needed biological insights into the condition. Our own research and that of others has indicated that many of these genetic risk variants operate in utero, substantiating long-held neurodevelopmental theories of the disorder. However, the prenatal brain regions and cell types through which these genetic risk variants operate remain unclear. This PhD project will build upon a current MRC project grant to lead supervisor Bray which is using single-cell sequencing to assess gene expression and its regulation in the constituent cell types of the human foetal brain. The student will combine use of this cutting-edge wet-lab technology with the latest genetic data for schizophrenia (available through the host MRC Centre for Neuropsychiatric Genetics & Genomics) to identify cell types of the prenatal brain mediating genetic risk for the disorder. Through the two host centres, they will be trained in both state-of-the-art laboratory techniques for profiling cellular gene expression and sophisticated biostatistical methods for its analysis and integration with large-scale genetic data. The student will additionally benefit from use of related epigenomic and transcriptomic data generated by the Cardiff and Exeter supervisors' groups (from both foetal and adult human brain) as well as from established international collaborations (e.g. with the Psychiatric Genomics Consortium, PsychENCODE). The impact of the student's research will be maximised through their regular attendance at international conferences (e.g. World Congress on Psychiatric Genetics, Society for Neuroscience), publication in leading journals and dissemination through data-sharing repositories.