Network-assisted causal gene detection in genome-wide association studies: an improved module search algorithm

The recent success of genome-wide association (GWA) studies has greatly expanded our understanding of many complex diseases by delivering previously unknown loci and genes. A large number of GWAS datasets have already been made available, with more being generated. To explore the underlying moderate and weak signals, we recently developed a network-based dense module search (DMS) method for identification of disease candidate genes from GWAS datasets, leveraging on the joint effect of multiple genes. DMS is designed to dynamically search for the best nodes in a step-wise fashion and, thus, could overcome the limitation of pre-defined gene sets. Here, we propose an improved version of DMS, the topologically-adjusted DMS, to facilitate the analysis of complex diseases. Building on the previous version of DMS, we improved the randomization process by taking into account the topological character, aiming to adjust the bias potentially caused by high-degree nodes in the whole network. We demonstrated the topologically-adjusted DMS algorithm in a GWAS dataset for schizophrenia. We found the improved DMS strategy could effectively identify candidate genes while reducing the burden of high-degree nodes. In our evaluation, we found more candidate genes identified by the topologically-adjusted DMS algorithm have been reported in the previous association studies, suggesting this new algorithm has better performance than the unweighted DMS algorithm. Finally, our functional analysis of the top module genes revealed that they are enriched in immune-related pathways.