三维基因组学在神经精神疾病领域的研究进展

Progress of 3D Genomics in Neuropsychiatric Disorders

神经精神疾病影响着全球数千万人的生活,成为日益严重的社会问题。遗传是介导神经精神疾病发生的重要因素之一。但是,人群全基因组关联研究(genome-wide association studies, GWAS)检测出的疾病风险位点大多位于基因组的非编码区域,是目前进一步鉴定疾病风险基因及推动发病机制研究的瓶颈所在。三维基因组学(three-dimensional genomics)关注染色质空间构象及基因组序列的远程相互作用,相关技术的开发和应用为建立疾病风险位点与靶向基因间的关联提供直接证据,拓展了疾病风险基因的鉴定。与此同时,疾病风险位点与基因相互作用的细胞特异性为理解疾病的发生机制提供了全新思路。最后,染色质空间构象重塑可调控集群基因的转录表达,可能参与介导疾病的表型复杂性及异质性。本文在简单介绍三维基因组学的基础概念和应用的基础上,重点总结及分析其在神经精神疾病领域的研究进展,主要包括精神分裂症(schizophrenia, SCZ)、阿尔茨海默病(Alzheimer's disease, AD)和孤独症谱系障碍(autism spectrum disorder, ASD),为相关疾病的发病机制研究提供新思路。

Neuropsychiatric disorders impact the lives of tens of millions of people globally and have become an increasingly severe social problem.Genetics is one of the critical factors contributing to the etiology of neuropsychiatric disorders.However,disease-associated risk loci,identified by genome-wide association studies(GWAS),are primarily located in non-coding regions of the human genome,presenting one of the most significant challenges in identifying disease-associated risk genes and elucidating the pathogenesis.Three-dimensional(3D)genomics focuses on spatial chromatin architecture and long-distance chromatin interactions.The development and application of 3D genomic technologies contribute to the identification of disease-associated risk genes,providing direct evidence of the chromatin interactions between disease-associated risk loci and their target genes.Meanwhile,cell-type-specific interactions bring new insights into the comprehension of pathogenesis.Lastly,the reorganization of spatial chromatin architectures regulates the transcription of multiple genes collectively,which may explain the complexity and heterogeneity of neuropsychiatric disorders.Based on a brief introduction to the basic concepts and applications of 3D genomics,this review primarily discusses the research progress of 3D genomics in the field of neuropsychiatric disorders,including schizophrenia(SCZ),Alzheimer's disease(AD),autism spectrum disorder(ASD),and others,aiming to offer new perspectives on associated diseases pathogenesis.