A systematic method for mapping multiple loci: an application to construct a genetic network for rheumatoid arthritis.

The advent of high-throughput single nucleotide polymorphisms (SNPs) omics technologies has brought tremendous genetic data. Systematic evaluation of the genome-wide SNPs is expected to provide breakthroughs in the understanding of complex diseases. In this study, we developed a new systematic method for mapping multiple loci and applied the proposed method to construct a genetic network for rheumatoid arthritis (RA) via analysis of 746 multiplex families genotyped with more than five thousands of genome-wide SNPs. We successfully identified 41 significant SNPs relevant to RA, 25 associated genes and a number of important SNP–SNP interactions (SNP patterns). Many findings (loci, genes and interactions) have experimental support from previous studies while novel findings may define unknown genetic pathways for this complex disease. Finally, we constructed a genetic network by integrating the results from this analysis with the rapidly accumulated knowledge in biomedical domains, which gave us a more detailed insight onto the RA etiology. The results suggest that the proposed systematic method is powerful when applied to genome-wide association studies. Integrating the analysis of high-throughput SNP data with knowledge-based SNP functional annotation offers a promising way to reversely engineer the underlying genetic networks for complex human diseases.