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，影响约1%的人口。最近的大规模基因组研究已经确定了数百个精神分裂症遗传风险位点，为急需的生物学见解铺平了道路。我们自己和其他人的研究表明，许多这些遗传风险变异在子宫内运作，证实了长期以来的神经发育理论。然而，这些遗传风险变异所通过的产前大脑区域和细胞类型仍不清楚。这个博士项目将建立在目前的MRC项目资助的基础上，该项目将使用单细胞测序来评估基因表达及其在人类胎儿大脑组成细胞类型中的调控。学生将结合联合收割机使用这种尖端的湿实验室技术与精神分裂症的最新遗传数据（可通过主机MRC中心神经精神遗传学和基因组学），以确定产前大脑的细胞类型介导的遗传风险的疾病。通过这两个东道中心，他们将接受关于细胞基因表达谱分析的最新实验室技术和分析细胞基因表达并将其与大规模遗传数据结合的复杂生物统计方法的培训。学生还将受益于使用由卡迪夫和埃克塞特主管小组（从胎儿和成人大脑）产生的相关表观基因组学和转录组学数据，以及建立国际合作（例如与精神病基因组学联盟，PsychENCODE）。学生研究的影响将通过定期参加国际会议（例如世界精神病学遗传学大会，神经科学学会），在领先期刊上发表和通过数据共享存储库传播来最大化。

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.