Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder.
Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder.
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DOI：
10.1038/tp.2012.80
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发表时间：
2012-08-14
影响因子：
6.8
通讯作者：
McKinney BA
中科院分区：
文献类型：
--
作者：
Pandey A;Davis NA;White BC;Pajewski NM;Savitz J;Drevets WC;McKinney BA
大多数途径和基因集富集方法通过基因的主要效应对基因进行优先级排序，并且不考虑由于途径中的相互作用而引起的变异。全基因组关联研究（GWAS）中假定缺失的遗传力的一部分可以通过基因-基因相互作用和加性遗传变异来解释。在这项研究中，我们通过机器学习（蒸发冷却）特征选择和上位性网络中心性分析，聚合基因-基因相互作用信息与主效应关联，优先考虑双相情感障碍（BD）GWAS中途径富集的基因。我们验证了这种方法在两个阶段（发现/复制）的途径分析GWAS的BD。发现队列来自BD的Wellcome Trust Case Control Consortium（WTCCC）GWAS，而复制队列来自BD的National Institute of Mental Health（NIMH）GWAS。上位网络中心性产生了钙粘蛋白信号通路的重复富集，其基因已被假设为在BD病理生理学中具有重要作用，但在先前的分析中未表现出富集。其他丰富的途径包括Wnt信号传导、昼夜节律途径、轴突导向和神经活性配体-受体相互作用。除了途径富集之外，集体网络方法提高了ANK 3、DGKH和ODZ 4在WTCCC GWAS中对BD易感性的重要性，尽管它们在数据中的单位点效应较弱。这些结果提供的证据表明，许多共同的等位基因之间的小的相互作用可能有助于BD的素质，并证明了包括从网络的基因-基因相互作用的信息，以及主要影响时，优先考虑基因的途径分析的重要性。
Most pathway and gene-set enrichment methods prioritize genes by their main effect and do not account for variation due to interactions in the pathway. A portion of the presumed missing heritability in genome-wide association studies (GWAS) may be accounted for through gene–gene interactions and additive genetic variability. In this study, we prioritize genes for pathway enrichment in GWAS of bipolar disorder (BD) by aggregating gene–gene interaction information with main effect associations through a machine learning (evaporative cooling) feature selection and epistasis network centrality analysis. We validate this approach in a two-stage (discovery/replication) pathway analysis of GWAS of BD. The discovery cohort comes from the Wellcome Trust Case Control Consortium (WTCCC) GWAS of BD, and the replication cohort comes from the National Institute of Mental Health (NIMH) GWAS of BD in European Ancestry individuals. Epistasis network centrality yields replicated enrichment of Cadherin signaling pathway, whose genes have been hypothesized to have an important role in BD pathophysiology but have not demonstrated enrichment in previous analysis. Other enriched pathways include Wnt signaling, circadian rhythm pathway, axon guidance and neuroactive ligand-receptor interaction. In addition to pathway enrichment, the collective network approach elevates the importance of ANK3, DGKH and ODZ4 for BD susceptibility in the WTCCC GWAS, despite their weak single-locus effect in the data. These results provide evidence that numerous small interactions among common alleles may contribute to the diathesis for BD and demonstrate the importance of including information from the network of gene–gene interactions as well as main effects when prioritizing genes for pathway analysis.
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影响因子：
3.7
作者：
McKinney BA;Pajewski NM
通讯作者：
Pajewski NM
DOI：
10.1176/appi.ajp.2010.10091340
发表时间：
2011-03
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Gershon ES;Alliey-Rodriguez N;Liu C
通讯作者：
Liu C
影响因子：
9.8
作者：
Liu, Jimmy Z.;Mcrae, Allan F.;Macgregor, Stuart
通讯作者：
Macgregor, Stuart
使用统计上居性网络在人类疾病关联研究中表征遗传相互作用。
影响因子：
3
作者：
Hu T;Sinnott-Armstrong NA;Kiralis JW;Andrew AS;Karagas MR;Moore JH
通讯作者：
Moore JH
影响因子：
10.6
作者：
Moskvina, Valentina;Craddock, Nick;Mueller-Myhsok, Bertram;Kam-Thong, Tony;Green, Elaine;Holmans, Peter;Owen, Michael J.;O'Donovan, Michael C.
通讯作者：
O'Donovan, Michael C.