Objective:

In this work, we integrated summary level data from GWAS with orthogonal evidence of transcriptional regulation to perform a pathway analysis using sub-significant variants with a plausible biological effect.

Background:

The genetic risk of developing MS is determined by more than 200 common DNA variants. To address the genetics of disease progression, the IMSGC recently conducted a GWAS using ARMSS. A single variant was genome-wide significant and independently replicated. With only one variant identified, pathway analyses were not feasible.

Design/Methods:

We extracted more than 600 replicated and non-replicated non-MHC associated SNPs from the latest susceptibility GWAS. Similarly, 27 lead SNPs with a p-value < 1.10e-6 (n=27) were selected from the recent GWAS in MS progression. Using OpenTarget ML-powered algorithm, we identified possible gene targets for each SNP. We also obtained the chromatin state for every variant in cell types of interest (B, T, monocytes, and CNS cells. Keratinocytes as controls) from RegulomeDB, and grouped them into three activation states. We subsequently scored each target gene for each cell type from totally repressed (-1) to fully enhanced (+1). Finally, we used a protein interactome and transcriptomic information to create cellular-specific protein interaction networks.

Results:

GWAS associations for MS susceptibility were enriched for functional effects in immune cells but not for CNS. Furthermore, immune but not CNS cell-specific protein interaction networks showed significantly enhanced connectivity. Strikingly, the GWAS for MS progression revealed an absence of regulatory effects in immune related cells and a modest but significant effect in the CNS. Similarly, CNS, but not immune cell-specific protein interaction networks showed significant connectivity.

Conclusions:

Our study provides data-driven evidence for differences in the underlying molecular pathways and cellular specificity in the genetic architecture of MS susceptibility and progression. Involvement of CNS structural proteins supports the hypothesis that progression in MS is influenced by alterations in CNS resilience.