Abstract Details

Title Regulatory Potential of Sub-significant GWAS Signals for MS Progression

Topic Multiple Sclerosis

Presentation(s) S17 - Multiple Sclerosis: Immunology/Basic Sciences (1:48 PM-2:00 PM)

Poster/Presentation
Number 005

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.

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.

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.

Authors/Disclosures
Gabriel A. Cerono (UCSF) PRESENTER	No disclosure on file
Sergio Baranzini (UCSF)	Sergio Baranzini has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Sergio Baranzini has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono . Sergio Baranzini has stock in MATE Bioservices. The institution of Sergio Baranzini has received research support from Valhalla Charitable Fund. The institution of Sergio Baranzini has received research support from Salah Foundation. The institution of Sergio Baranzini has received research support from NIH. The institution of Sergio Baranzini has received research support from NSF. Sergio Baranzini has received intellectual property interests from a discovery or technology relating to health care. Sergio Baranzini has a non-compensated relationship as a co-funder with Mate Bioservices that is relevant to AAN interests or activities.