一种综合功能基因组学方法,用于发现精神分裂症中的生物标志物。

An integrative functional genomics approach for discovering biomarkers in schizophrenia.

机构信息

Functional Genomics Laboratory, Department of Psychiatry, University of California, Irvine, USA.

出版信息

Brief Funct Genomics. 2011 Nov;10(6):387-99. doi: 10.1093/bfgp/elr036. Epub 2011 Dec 8.

Abstract

Schizophrenia (SZ) is a complex disorder resulting from both genetic and environmental causes with a lifetime prevalence world-wide of 1%; however, there are no specific, sensitive and validated biomarkers for SZ. A general unifying hypothesis has been put forward that disease-associated single nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) are more likely to be associated with gene expression quantitative trait loci (eQTL). We will describe this hypothesis and review primary methodology with refinements for testing this paradigmatic approach in SZ. We will describe biomarker studies of SZ and testing enrichment of SNPs that are associated both with eQTLs and existing GWAS of SZ. SZ-associated SNPs that overlap with eQTLs can be placed into gene-gene expression, protein-protein and protein-DNA interaction networks. Further, those networks can be tested by reducing/silencing the gene expression levels of critical nodes. We present pilot data to support these methods of investigation such as the use of eQTLs to annotate GWASs of SZ, which could be applied to the field of biomarker discovery. Those networks that have association with SNP markers, especially cis-regulated expression, might lead to a more clear understanding of important candidate genes that predispose to disease and alter expression. This method has general application to many complex disorders.

摘要

精神分裂症(SZ)是一种复杂的疾病,由遗传和环境因素共同引起,全球终身患病率为 1%;然而,目前尚无针对 SZ 的特异性、敏感和经过验证的生物标志物。人们提出了一个普遍的统一假设,即全基因组关联研究(GWAS)中的疾病相关单核苷酸多态性(SNP)更有可能与基因表达数量性状基因座(eQTL)相关。我们将描述这一假设,并回顾主要的方法学,包括针对 SZ 中这一典范方法的改进。我们将描述 SZ 的生物标志物研究,并检验与 eQTL 和现有的 SZ GWAS 均相关的 SNPs 的富集情况。与 eQTL 重叠的 SZ 相关 SNP 可被纳入基因-基因表达、蛋白质-蛋白质和蛋白质-DNA 相互作用网络。此外,还可以通过降低/沉默关键节点的基因表达水平来测试这些网络。我们提供了支持这些研究方法的初步数据,例如使用 eQTL 注释 SZ 的 GWAS,这可应用于生物标志物发现领域。与 SNP 标记,尤其是顺式调控表达相关的网络,可能有助于更清楚地了解导致疾病和改变表达的重要候选基因。这种方法具有广泛的适用性,可用于许多复杂疾病。

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