Conquering complexity : successful strategies for finding disease genes in multiple sclerosis

Multiple sclerosis (MS) is a complex disease; at an intra-individual level several contributory factors cause the disease; at an inter-individual level different factors contribute to the disease. The aim of the thesis project was to reduce this complexity by focusing of subsets of patients that were likely to share to a higher extent contributory causes and to identify in these subsets genes conferring susceptibility.

In paper I we wanted to know the HLA-DRB1 allele associated to the small fraction of MS patients lacking signs of immunoglobulin synthesis within the central nervous system (OCB-negative MS). In papers III and IV we performed whole-genome singlenucleotide-polymorphism (SNP) scans to identify genetic susceptibility regions in distantly related patients from an MS cluster in a parish in Värmland (paper III) and in a consanguineous family with several affected family members (paper IV). We also asked the question if differences in etiology are reflected in clinical parameters such as the severity of the disease, which we looked at in both papers I and II in relation to OCB status (I and II) and HLA-DRB1 alleles (II).

Some of the main results in this thesis project and their congruence with previous reports of genetic susceptibility in MS are the following: the association between the OCB-negative entity and HLA-DRB1*04 seen both in our population and in Japan; the potential importance of the ACCN1 gene, identified in our distantly related MS patients and in an isolated population in Sardinia; the role of mutations in the PLP1 gene on the X chromosome reported in two MS case reports, thus indicating the plausibility of monogenic X-linked MS.

The results derived from this thesis project merit follow-up.

List of scientific papers

I. Imrell K, Landtblom AM, Hillert J, Masterman T (2006). "Multiple sclerosis with and without CSF bands: clinically indistinguishable but immunogenetically distinct." Neurology 67(6): 1062-4
https://pubmed.ncbi.nlm.nih.gov/17000979

II. Imrell K, Greiner E, Hillert J, Masterman T (2009). "HLA-DRB115 and cerebrospinal-fluid-specific oligoclonal immunoglobulin G bands lower age at attainment of important disease milestones in multiple sclerosis." J Neuroimmunol 210(1-2): 128-30. Epub 2009 Mar 26
https://pubmed.ncbi.nlm.nih.gov/19327846

III. Imrell K, Masterman T, Brynedal B, Bomfim IL, Wojcik J, Hillert J, Kockum I, Landtblom AM (2009). "Disease genes uncovered in 11 distantly related individuals affected with multiple sclerosis through SNP-based identical-by-descent heterozygosity mapping." (Manuscript)

IV. Imrell K, Bomfim IL, Roshanisefat H, Zucchelli M, Lamb B, Hillert J, Kockum I, Masterman T (2009). "SNP-based gene mapping in a consanguineous multiple sclerosis family." (Manuscript)