Another issue is that gene set annotation is still incomplete. So far, only about 5000 human genes have been annotated to the KEGG pathways, which are most frequently used in the literature. Thus, in gene set analysis of GWAS, all non-annotated genes will be automatically filtered out. A potential improvement is to use protein-protein interaction (PPI) data. As of March 4, 2010, there were approximately 11,000 proteins included in an integrated PPI network analysis platform, Protein Interaction Network Analysis (PINA), which collected and annotated six other public PPI databases (MINT, IntAct, DIP, BioGRID, HPRD, and MIPS/MPact) [25]. This provides much more annotation information about human proteins than does KEGG, and has been used for dense-module searching (DMS) of enriched association signals from one or multiple GWAS datasets [26]. Another advantage in the DMS approach is its flexibility in defining gene set size, which overcomes a potential limitation of the fixed size in KEGG or other biological pathways. However, DMS utilizes the information only from PPIs, rather than from gene regulation as in typical biological pathways. Even so, it highlights the degree of incompleteness of our current knowledge about the human genes and their regulation.
