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Highlights of our recently published results

Pathway and network-based analysis of genome-wide association studies in multiple sclerosis

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association. Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance.. In addition to the expected immunological pathways, we report here for the first time the potential involvement of neural pathways in MS susceptibility, specifically namely axon-guidance and synaptic potentiation (Baranzini et al. Hum. Mol. Genet. 15:767, 2009).

Copy number gene variation in African Americans

Copy number variants (CNVs) have been identified in several studies to be associated with complex diseases. It is important, therefore, to understand the distribution of CNVs within and among populations. This study is the first report of a CNV map in African Americans. The duplication identified in high frequency in Whites and low frequency in African Americans on chromosome 17q21 reflects haplotype specific frequency differences between ancestral groups. The generation of the CNV map will be a valuable tool for identifying disease associated CNVs in African Americans (McElroy et al. BMC Genet. 10:226, 2009).

Meta-analysis of genome scans and replication identify CD6, ICSBP1, and TNFRSF1A as novel multiple sclerosis susceptibility loci

We pooled genome-wide data from three independent GWAS studies for a meta-analysis, totaling 2,264 cases and 7,220 controls. Since each of the studies used a different genotyping platform, we imputed missing autosomal SNPs in each of the three original datasets using MACH. This effort produced a dataset containing a common set of 2.56 million SNPs that met quality control criteria in all datasets. Replication of top resulst in an independent set of 2,215 subjects with MS and 2,189 controls validates new MS susceptibility loci at TNFRSF1A, ICSBP1/IRF8, and CD6. A secondary analysis that includes a term for gender was performed and was successful in highlighting the role of the CXCR4 locus (De Jager et al. Nat. Genet. 41:776, 2009).

Longitudinal system-based analysis of transcriptional responses to type I interferons

To identify mechanisms underlying differential type I interferon signaling, we used whole genome microarrays to measure longitudinal transcriptional events within human CD4+ T cells, treated IFN-beta2b or IFN-alpha1a. We identified differentially regulated genes, analyzed them for the enrichment of known promoter elements and pathways, and constructed a network modules based on the weighted gene co-expression network analysis (WGCNA). Overall, differential responses to IFN in CD4+ T cells related to three dominant themes: migration, antigen presentation, and cytotoxic response. For migration, WGCNA identified subtype specific regulation of PRPF4B and EIF4A2, which work at various levels within the cell to affect the expression of the chemokine CCL5. WGCNA also identified SAMD9L as critical in subtype independent effects of IFN treatment. RNA interference of SAMD9L expression enhanced the migratory phenotype of activated T cells treated with IFN-beta, as compared to controls. Through the analysis the dynamic transcriptional events following differential IFN treatment, we were able to identify specific signatures and to uncover novel genes that may underpin the type I interferon response (Pappas et al. Physiol. Genomics 2009).