ABSTRACT
Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.
Subject(s)
Cell Adhesion Molecules/genetics , Multiple Sclerosis/genetics , Antigens, CD/genetics , Blood-Brain Barrier/cytology , Blood-Brain Barrier/immunology , Cell Adhesion Molecules/immunology , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Integrin alpha Chains/genetics , Intercellular Adhesion Molecule-1/genetics , Multiple Sclerosis/immunology , Polymorphism, Single Nucleotide , Signal Transduction/genetics , T-Lymphocytes/immunologyABSTRACT
A previous study using cumulative genetic risk estimations in multiple sclerosis (MS) successfully tracked the aggregation of susceptibility variants in multi-case and single-case families. It used a limited description of susceptibility loci available at the time (17 loci). Even though the full roster of MS risk genes remains unavailable, we estimated the genetic burden in MS families and assess its disease predictive power using up to 64 single-nucleotide polymorphism (SNP) markers according to the most recent literature. A total of 708 controls, 3251 MS patients and their relatives, as well as 117 twin pairs were genotyped. We validated the increased aggregation of genetic burden in multi-case compared with single-case families (P=4.14e-03) and confirm that these data offer little opportunity to accurately predict MS, even within sibships (area under receiver operating characteristic (AUROC)=0.59 (0.55, 0.53)). Our results also suggest that the primary progressive and relapsing-type forms of MS share a common genetic architecture (P=0.368; difference being limited to that corresponding to ± 2 typical MS-associated SNPs). We have confirmed the properties of individual genetic risk score in MS. Comparing with previous reference point for MS genetics (17 SNPs), we underlined the corrective consequences of the integration of the new findings from GWAS and meta-analysis.
