Linkage and association analysis in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, which is characterized by relapsing or progressive demyelinating plaques in the brain and spinal cord. It is well established that complex genetic factors influence susceptibility to MS. Much work concerning candidate genes and whole genome screens in MS has been done. Many genes or chromosomal regions have been reported to be linked or associated with MS, but the only consistent finding is with the human leukocyte antigen (HLA) region. Here, our aim was to study candidate genes and regions in the Nordic MS population.

We chose linkage and association analysis to investigate a number of non-HLA loci identified in published genome screens to determine whether they play a role for the risk of MS in the Swedish ethnic group and in MS families of similar ethnic origin. Three out of twelve promising chromosomal loci showed association and/or possible linkage in Swedish multiplex families. This suggests the possibility of locating susceptibility genes in 5p, 12q23 and 7ptr-15 (Paper I). The highest NPL score in Nordic affected sibpair families was found in 3p14-13. This region is not only formerly suggested by British and Canadian screens, but also contains the SCA7 gene which may cause spinocerebellar ataxia (SCA), a neurodegenerative disease sharing some clinical features with primary progressive MS. Although no SCA7 gene expansions were observed, we still believe support was obtained for the location of an MS susceptibility gene in this region (Paper II).

Recently, loci of importance for animal models of autoimmune diseases have been identified. We investigated eight chromosomal intervals syntenic to five quantitative trait loci (QTL) in rat collagen induced arthritis (CIA) or oil induced arthritis (OIA) models (Cia2-5, Oia2) in Swedish multiplex families for linkage. 7q34-36, 12p13-12, syntenic to Cia3 and Oia2, showed some indications of importance, in contrast to other regions (2p12, 3p25, 10q11.23, 17q21-25, 19q13, and 22q12-13) (Paper III).

Since MS is thought to be an autoimmune disease mediated by autoreactive T cells directed against myelin antigens, components of the immune system are attractive candidates as MS susceptibility genes. CD40 ligand is an immune regulatory molecule expressed on activated T cells and is found to be expressed in brain sections of MS patients, but not in controls or patients with other neurological diseases. In addition, high mRNA expression of CD40 and CD40 ligand in peripheral blood mononuclear cells (PBMC) of MS patients was recently observed by our group. A CD40 ligand gene (CD40LG) genetic association analysis did not indicate importance of allele variants of CD40LG with mRNA expression in PBMC and no association was found between polymorphisms of CD40LG and MS susceptibility or severity (Paper IV).

Interferon-γ (IFN-γ) is a proinflammatory cytokine thought to have a critical influence in MS pathogenesis. To investigate the possible genetic importance of the IFN-γ gene (IFNG) in MS, we performed a linkage and association study in 100 sib-pair families and 464 severity stratified patients and 266 controls. No linkage or association was found regardless of stratification for sex, severity or DR15. A mRNA expression analysis did not support a reported influence of the 12 CA repeat allele in the first intron of IFNG (Paper V).

In conclusion, six chromosomal regions have received supports for being of importance in MS. Adding more SNP and microsatellite markers for fine mapping these suggestive linkage regions is warranted. For the other studied chromosomal regions and genes, no evidence of linkage or association was found. The access to the entire human genome sequence will greatly facilitate a positional candidate gene analysis.

List of scientific papers

I. Xu C, Dai Y, Fredrikson S, Hillert J (1999). "Association and linkage analysis of candidate chromosomal regions in multiple sclerosis: indication of disease genes in 12q23 and 7ptr-15. " Eur J Hum Genet 7(2): 110-6
https://pubmed.ncbi.nlm.nih.gov/10196692

II. Dai Y, Xu C, Holmberg M, Oturi A, Fredrikson S, Sandverg-Wollheim M, Laaksonen M, Spurkland A, Vartdal F, Ryder LP, Svejgaard A, Hillert J (2001). "Linkage analysis suggests a gene with importance for MS in 3p14-13." Genes and immunity (Accepted)

III. Xu C, Dai Y, Lorentzen JC, Dahlman I, Olsson T, Hillert J (2001). "Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci. " Eur J Hum Genet 9(6): 458-63
https://pubmed.ncbi.nlm.nih.gov/11436128

IV. Dai Y, Masterman T, Huang WX, Hillert J (2001). "Analysis of a CD40 ligand dinucleotide microsatellite in MS." European Journal of Immunogenetics (In Print)

V. Dai Y, Masterman T, Huang WX, Sandberg-Wollheim M, Laaksonen M, Harbo HF, Oturai A, Ryder LP, Soelberg-Sorensen P, Svejgaard A, Hillert J (2001). "Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients. " Mult Scler 7(3): 157-63
https://pubmed.ncbi.nlm.nih.gov/11475438