Identifying consensus disease pathways in Parkinson's disease using an integrative systems biology approach.
Identifying consensus disease pathways in Parkinson's disease using an integrative systems biology approach.
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DOI：
10.1371/journal.pone.0016917
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发表时间：
2011-02-22
期刊：
影响因子：
3.7
通讯作者：
Vance JM
中科院分区：
文献类型：
--
作者：
Edwards YJ;Beecham GW;Scott WK;Khuri S;Bademci G;Tekin D;Martin ER;Jiang Z;Mash DC;ffrench-Mullen J;Pericak-Vance MA;Tsinoremas N;Vance JM
帕金森病（PD）已经进行了六项全基因组关联研究（GWAS）以及几项基因表达研究。然而，只有MAPT和SNCA中的变体一直被复制。为了提高这些方法的实用性，我们应用了整合GWAS和基因表达的途径分析。鉴定了来自三个现有PD GWAS的联合分析的前5000个SNP（p<0.01），并将每个SNP分配给一个基因。对于基因表达，而不是一个解剖区域之间的患者和对照组的传统比较，我们确定了每个人的相邻Braak区域之间的差异表达基因，并使用平均控制表达谱进行调整。使用超几何统计比较计算过度代表的途径。一个综合的，系统的荟萃分析的过度代表的途径相结合的表达和GWAS的结果，使用Fisher的组合概率检验。每种方法的前七个途径中有四个是相同的。荟萃分析中的前三个途径及其校正p值为轴突引导（p = 2.8E-07）、粘着斑（p = 7.7E-06）和钙信号传导（p = 2.9E-05）。 这些结果支持系统生物学（途径）方法将提供更多的洞察PD的遗传病因，这些途径在PD中具有重要的生物学和统计学支持。
Parkinson's disease (PD) has had six genome-wide association studies (GWAS) conducted as well as several gene expression studies. However, only variants in MAPT and SNCA have been consistently replicated. To improve the utility of these approaches, we applied pathway analyses integrating both GWAS and gene expression. The top 5000 SNPs (p<0.01) from a joint analysis of three existing PD GWAS were identified and each assigned to a gene. For gene expression, rather than the traditional comparison of one anatomical region between sets of patients and controls, we identified differentially expressed genes between adjacent Braak regions in each individual and adjusted using average control expression profiles. Over-represented pathways were calculated using a hyper-geometric statistical comparison. An integrated, systems meta-analysis of the over-represented pathways combined the expression and GWAS results using a Fisher's combined probability test. Four of the top seven pathways from each approach were identical. The top three pathways in the meta-analysis, with their corrected p-values, were axonal guidance (p = 2.8E-07), focal adhesion (p = 7.7E-06) and calcium signaling (p = 2.9E-05). These results support that a systems biology (pathway) approach will provide additional insight into the genetic etiology of PD and that these pathways have both biological and statistical support to be important in PD.
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影响因子：
14.9
作者：
Kanehisa M;Araki M;Goto S;Hattori M;Hirakawa M;Itoh M;Katayama T;Kawashima S;Okuda S;Tokimatsu T;Yamanishi Y
通讯作者：
Yamanishi Y
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1073/pnas.0500346102
发表时间：
2005-07-19
影响因子：
11.1
作者：
Cha, GH;Kim, S;Cho, KS
通讯作者：
Cho, KS
DOI：
10.1016/j.cbd.2005.03.001
发表时间：
2006-03-01
影响因子：
3
作者：
Edwards, Yvonne J. K.;Walter, Klaudia;Elgar, Greg
通讯作者：
Elgar, Greg
帕金森氏病的线粒体激酶：神经毒素和遗传模型的融合见解。
影响因子：
4.4
作者：
Dagda, Ruben K.;Zhu, Jianhui;Chu, Charleen T.
通讯作者：
Chu, Charleen T.