Illuminating the dark road from schizophrenia genetic associations to disease mechanisms

• 来源期刊: 国家科学评论（英文版）
• 关键词: schizophrenia GWAS,functional genomics molecular mechanism disease biology
• 年，卷（期）: 2017,（2）
• 页码范围: 240-251
• 页数: 12页
• 语种: 英文
• DOI: 10.1093/nsr/nww065

摘要

Recent large-scale genome-wide association studies (GWAS) have enabled the discovery of common genetic variations contributing to risk architectures of schizophrenia in human populations;however,the majority of GWAS-identified variants are located in large genomic regions spanning multiple genes,and recognizing the precise targets and mechanisms of these clinical associations is now the major challenge.Here,we review recent progress in schizophrenia genetics,functional genomics and related neuroscience research,and propose a functional pipeline to translate schizophrenia GWAS risk loci into disease biology and information for drug discovery.The pipeline includes identification of underlying molecular mechanisms using transcriptomic data in human brain,prioritization of putative functional causative variants by the integration of genetic epidemiological and bioinformatics methods as well as molecular approaches,and in vitro and in vivo experimental characterizations of the identified targeted species and causative variants to dissect the relevant disease biology.These approaches will accelerate progress from schizophrenia genetic studies to biological mechanisms and ultimately guide the development of prognostic,preventive and therapeutic measures.