Stratification of candidate genes for Parkinson's disease using weighted protein-protein interaction network analysis.
Stratification of candidate genes for Parkinson's disease using weighted protein-protein interaction network analysis.
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使用加权蛋白质-蛋白质相互作用网络分析对帕金森病候选基因进行分层。
DOI：
10.1186/s12864-018-4804-9
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发表时间：
2018-06-13
期刊：
影响因子：
4.4
通讯作者：
Manzoni C
中科院分区：
文献类型：
--
作者：
Ferrari R;Kia DA;Tomkins JE;Hardy J;Wood NW;Lovering RC;Lewis PA;Manzoni C
全基因组关联研究（GWAS）已经帮助确定了大量与疾病风险增加显著相关的遗传位点。然而，迄今为止，将遗传知识转化为对疾病基础分子机制（即疾病特异性影响的生物过程）的理解已被证明是一项重大挑战。这主要是由于在GWAS风险位点确定候选基因的困难。本研究的目的是使用基于蛋白质相互作用组的方法和帕金森病（PD）数据作为测试案例，更好地表征GWAS基因座内的候选基因。我们应用了最近开发的加权蛋白质-蛋白质相互作用网络分析（WPPINA）管道作为定义受影响的生物过程，风险途径及其关键功能参与者的手段。我们使用先前建立的孟德尔形式的PD来识别种子蛋白，并构建遗传帕金森氏症的蛋白质网络，并进行功能富集分析。我们分离出PD特异性过程，表明“线粒体应激因子介导的细胞死亡”，“免疫反应和信号传导”，以及通过“自噬”介导的“废物处理”。将所得到的蛋白质网络与帕金森病GWAS的数据合并，我们确认了先前通过纯邻近选择的10个候选基因，并能够提名17个新的散发性PD候选基因。通过这项研究，我们能够更好地表征特发性PD的潜在遗传和功能结构，从而验证WPPINA作为复杂疾病的计算机遗传和功能解剖的强大管道。本文的在线版本（10.1186/s12864-018-4804-9）包含补充材料，可供授权用户使用。
Genome wide association studies (GWAS) have helped identify large numbers of genetic loci that significantly associate with increased risk of developing diseases. However, translating genetic knowledge into understanding of the molecular mechanisms underpinning disease (i.e. disease-specific impacted biological processes) has to date proved to be a major challenge. This is primarily due to difficulties in confidently defining candidate genes at GWAS-risk loci. The goal of this study was to better characterize candidate genes within GWAS loci using a protein interactome based approach and with Parkinson’s disease (PD) data as a test case. We applied a recently developed Weighted Protein-Protein Interaction Network Analysis (WPPINA) pipeline as a means to define impacted biological processes, risk pathways and therein key functional players. We used previously established Mendelian forms of PD to identify seed proteins, and to construct a protein network for genetic Parkinson’s and carried out functional enrichment analyses. We isolated PD-specific processes indicating ‘mitochondria stressors mediated cell death’, ‘immune response and signaling’, and ‘waste disposal’ mediated through ‘autophagy’. Merging the resulting protein network with data from Parkinson’s GWAS we confirmed 10 candidate genes previously selected by pure proximity and were able to nominate 17 novel candidate genes for sporadic PD. With this study, we were able to better characterize the underlying genetic and functional architecture of idiopathic PD, thus validating WPPINA as a robust pipeline for the in silico genetic and functional dissection of complex disorders. The online version of this article (10.1186/s12864-018-4804-9) contains supplementary material, which is available to authorized users.
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影响因子：
14.9
作者：
Reimand J;Arak T;Adler P;Kolberg L;Reisberg S;Peterson H;Vilo J
通讯作者：
Vilo J
影响因子：
4.3
作者：
Lamparter D;Marbach D;Rueedi R;Kutalik Z;Bergmann S
通讯作者：
Bergmann S
帕金森氏病：从人类遗传学到临床试验。
影响因子：
17.1
作者：
van der Brug MP;Singleton A;Gasser T;Lewis PA
通讯作者：
Lewis PA
DOI：
10.1073/pnas.1318306111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Beilina, Alexandria;Rudenko, Iakov N.;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
30.8
作者：
Marigorta UM;Denson LA;Hyams JS;Mondal K;Prince J;Walters TD;Griffiths A;Noe JD;Crandall WV;Rosh JR;Mack DR;Kellermayer R;Heyman MB;Baker SS;Stephens MC;Baldassano RN;Markowitz JF;Kim MO;Dubinsky MC;Cho J;Aronow BJ;Kugathasan S;Gibson G
通讯作者：
Gibson G