Strategies and issues in the detection of pathway enrichment in genome-wide association studies.
Strategies and issues in the detection of pathway enrichment in genome-wide association studies.
复制标题
DOI：
10.1007/s00439-009-0676-z
复制
发表时间：
2009-08
期刊：
影响因子：
5.3
通讯作者：
Prince JA
中科院分区：
文献类型：
--
作者：
Hong MG;Pawitan Y;Magnusson PK;Prince JA
A fundamental question in human genetics is the degree to which the polygenic character of complex traits derives from polymorphism in genes with similar or with dissimilar functions. The many genome-wide association studies now being performed offer an opportunity to investigate this, and although early attempts are emerging, new tools and modeling strategies still need to be developed and deployed. Towards this goal we implemented a new algorithm to facilitate the transition from genetic marker lists (principally those generated by PLINK) to pathway analyses of representational gene sets in either threshold or threshold-free downstream applications (e.g. DAVID, GSEA-P, and Ingenuity Pathway Analysis). This was applied to several large genome-wide association studies covering diverse human traits that included type 2 diabetes, Crohn’s disease, and plasma lipid levels. Validation of this approach was obtained for plasma HDL levels, where functional categories related to lipid metabolism emerged as the most significant in two independent studies. From analyses of these samples we highlight and address numerous issues related to this strategy, including appropriate gene based correction statistics, the utility of imputed vs. non imputed marker sets, and the apparent enrichment of pathways due solely to the positional clustering of functionally related genes. The latter in particular emphasizes the importance of studies that directly tie genetic variation to functional characteristics of specific genes. The software freely provided that we have called ProxyGeneLD may resolve an important bottleneck in pathway-based analyses of genome-wide association data. This has allowed us to identify at least one replicable case of pathway enrichment but also to highlight functional gene clustering as a potentially serious problem that may lead to spurious pathway findings if not corrected for.
登录
查看更多内容
影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
14.9
作者：
Chen, Yan-Hau;Liu, Chuan-Kun;Yao, Adam
通讯作者：
Yao, Adam
影响因子：
5.8
作者：
Gaulton, Kyle J.;Mohlke, Karen L.;Vision, Todd J.
通讯作者：
Vision, Todd J.
影响因子：
7.7
作者：
Buchanan, Anne V.;Weiss, Kenneth M.;Fullerton, Stephanie M.
通讯作者：
Fullerton, Stephanie M.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y