Multiple sclerosis (MS) is one of the most frequent causes of neurological disability in young adults in western countries. Despite extensive efforts, little is known about events that trigger the disease or factors that control its highly variable course and severity. Given its unpredictable nature, alongside the accumulation of significant disability in a large proportion of patients, MS is a feared disease, often leading to a severe impact on patients and their families as well as a large cost for society. The established immune modulation MS therapies are only indicated for the relapsing remitting forms of MS and are often only partly effective, some with serious side effects. The development of more successful treatments is limited by our poor understanding of pathogenesis and disease mechanisms. Through genetic and molecular studies of MS, guidance to ‘personalised medicine’ and establishment of new therapies can hopefully be achieved.

Familial clustering is a firmly established feature in MS, with 15-20% of affected individuals having a family history of the disease, epidemiological studies showing this is primarily a result of shared genes rather than a shared environment [1]. The importance of genetic factors in determining susceptibility to the disease prompted efforts towards identifying responsible genes in the expectation that this knowledge will provide invaluable information about pathogenesis and inform future research into effective treatments.

Candidate gene studies identified the importance of HLA genes in MS

Early genetic research efforts quickly established association with the human leukocyte antigen (HLA) region in the major histocompatibility complex (MHC) on chromosome 6p21 [2]. Subsequent research efforts have refined this association and confirmed that in virtually every population tested, risk is primarily determined by the class II allele HLA-DRB1*15:01 [3]. Carriers of this risk allele typically have a three-fold increased risk of developing MS, making this the largest genetic factor predisposing an individual to MS yet identified. Considerable progress in fine mapping and dissecting this important signal has provided growing evidence supporting the involvement of genes within the class I region with MS, independent of the 15:01 association [4]. Much work still needs to be undertaken to completely understand the role of this complex region in the development of MS.

In the years following the HLA discovery, despite the heritable nature of susceptibility to MS, candidate gene studies made remarkably little progress in identifying the genes involved in MS. The invariable use of inadequate sample sizes coupled with the limited probability that a relevant gene might be selected for study have been prominent amongst the reasons for the limited success of this approach. Genome screening identified the first non-HLA gene associations in MS As such the momentum shifted towards screening the genome, an advantageous method as no prior knowledge of the pathogenesis of disease is required as genetic variants are screened throughout the genome in the hope that they will be correlated with the disease causing allele. The first genome screens were performed by linkage analysis genotyping microsatellite markers in affected sibpair families in the mid-1990s in the UK5, US6 and Canadian7 population and have since been completed in several other populations. Disappointingly, no region of genome wide significance was identified in any study and little overlap in the results between studies was found. In 2005, a definitive linkage screen was completed by the International Multiple Sclerosis Genetics Consortium (IMSGC), by whom 4506 single nucleotide polymorphisms (SNPs) were typed in 730 multiplex families.8 While the only region to reach genome wide significance was the already established HLA region, this linkage study did establish that outside the HLA region, common susceptibility alleles (frequency >10%) are unlikely to increase the risk of disease by a factor of more than two and therefore association screening is a more powerful method to establish these small genetic effects in MS.

It was only as the understanding of the nature and extent of human genetic variation increased and the technology to screen hundreds of thousands of single nucleotide polymorphisms (SNPs) in the human genome in a cost and time efficient manner become available, that the ability to complete genome-wide association screens (GWAS) was made possible. The first high-density genome wide association screen in MS was published in 2007.9 Close to 1000 trio families (an affected individual and both of their parents) were screened for over 300,000 SNPs and implicated the IL7RA and IL2RA genes in MS susceptibility, which was successfully replicated and confirmed in other populations.10 Since then more than 10 GWAS and meta-analysis studies have been completed and alongside replication studies have confirmed a growing list of genes involved in MS susceptibility (see Figure 1) [9,20]. These are the first genuine associations to be identified in multiple sclerosis since the long established association within the HLA region. As indicated by the MS linkage studies [9], no other MS loci have been identified with a higher risk than the HLA region, reflected in odds ratios typically around 1.2 for the now established non-HLA MS risk loci (Figure 1).

Figure 1 shows the MS associated risk loci as identified from published GWAS and replication studies in MS (references 9-20) and the odds ratios for the risk variants identified at each loci. A large proportion of the associated genes in MS are identified as being involved in immune system processes (as identified from the Gene Ontology database) and are shown in green in the figure, while those not involved in immune system processes are shown in blue.

Interestingly these associations have uncovered a growing overlap in susceptibility loci between MS and other autoimmune diseases, including for example the IL7R, IL2RA, CLEC16A and CD226 genes.11, 21 This result is not surprising as epidemiological studies have identified an increased frequency of autoimmune disease in the family members of MS patients, suggesting shared disease mechanisms based on a common genetic background.

Acknowledging the crucial importance of the sample size for well-powered genetic studies, the IMSGC decided to perform the largest and most well powered MS GWAS. In collaboration with the Wellcome Trust Case Control Consortium 2 (WTCCC2) close to 10,000 MS samples and 20,000 controls were analysed using a 660K SNP chip, providing one of the largest and statistically most complex GWAS studies performed both due to the number of samples included as well as the large number of populations represented in the screen. This screen will identify an additional list of MS associated loci.22 The results from this screen will be published in the near future.

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Moving into the post GWAS area of molecular characterisation in MS

Much work still remains to understand the full genetic architecture of susceptibly to MS. As the variants typed in a GWAS are only a small fraction of variants that co-segregate, causal variants for disease will only occasionally be directly typed in GWAS. Fine mapping studies, in which the regions that are found to be associated with disease in GWAS are followed up and extensively mapped to identify the causal variants, are essential and are currently being completed. These studies will further define the causative associations, and lead to molecular studies aimed at characterising the functional effects of the identified MS associated loci.

Analyses of cellular pathways as well as genegene and gene-environment interaction studies of the established MS loci are further needed to fully comprehend the mechanisms of disease. So far, there does not appear to be a genetic difference between the different clinical subgroups of MS. This may merely be a reflection of the lack of clearly defined subgroups. Careful genotype-phenotype studies, comparing the clinical and paraclinical expression of the disease (for example as evaluated by detailed MRI examinations), are needed in order to define if the mechanisms of disease development varies between different MS patient groups.

Future of genetic analysis in MS

Despite the success of the recent GWAS in MS, the variations associated with MS to date account for only a moderate proportion of the inheritable risk of MS. This “missing heritability” is a feature not only in MS but also other complex genetic diseases. Factors that can contribute to this missing heritability include missed or rare genetic variants, allelic heterogeneity (where more than one allele at a single locus is associated with disease) and epigenetic effects. Identification of the missing heritability is one of the next challenges in MS genetics.

In conclusion, genetic studies have the potential to identify molecules of importance to MS aetiology through systematic well powered scientific studies, most successfully applied by recent GWAS studies made possible by large international collaborative projects. Genetic research of MS susceptibility is therefore now quickly moving into another phase, characterising the full genomic architecture of disease susceptibility alleles as well as focusing on characterisation of the molecules involved in MS development.

References

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