Follow-up and fine-scale mapping of multiple sclerosis loci identified in genome wide association studies

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). During my PhD program, I identified and functionally characterized sequence variations associated to the risk to develop MS in the Italian continental population. To this end we performed two different parallel analyses on already known MS associated loci and genes: a fine mapping analysis in order to find the primarily associated variant or gene and a burden test analysis on rare and low frequency variants. We identified the strongest non-HLA signal in the Italian population maps in the Tumor Necrosis Factor (ligand) superfamily member 14 (TNFSFI-4) gene encoding for LIGHT, å transmembrane glycoprotein expressed on various immune cells and Involved in dendritic cells (DC) maturation. We demonstrated through a fine-mapping approach that an intronic variant is the primarily associated one and we were able to define its functional role in the regulation of gene transcription and protein production. Subsequently, we focused our attention on LIGHT receptor (TNFRSFT) but we were not able to identify the primary associated variant due to high linkage disequilibrium (LD). Despite this, we observed a cis-eQTL effect for different variants in this region on TNFRSFI4 gene expression. So, based on these evidences, we proposed for these variants a possible role in gene regulation. Gene-gene interaction analysis. burden test and weight genetic risk score on INFSF14-INFRSF14 pathway seemed to confirm our hypothesis that also genes which interact with TNFSF/4, can also play a role in MS pathogenesis. Parallel to these analysis, we conducted a research of rare functional variants in MS associated loci in order to assess if the genes in these regions showed an imbalance of rare variant frequencies (burden) between MS patients and healthy controls. EFC4B/3 was the gene that seemed to show the most promising result especially for disruptive variants.