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The genetics of multiple sclerosis: SNPs to pathways to pathogenesis

Key Points

  • Multiple sclerosis (MS) clusters with the so-called complex genetic diseases, a group of common disorders characterized by modest disease-risk heritability and multifaceted gene–environment interactions.

  • The genetic component of MS is reflected in the co-occurrence of cases within families and the high prevalence in some ethnic populations (particularly those of northern European origin) compared with others (African and Asian groups), irrespective of geographic location.

  • Concordance in families for early and late clinical features indicates that genes influence age of onset, disease course and other aspects of the clinical phenotype in addition to susceptibility.

  • The HLA-DRB1 gene on chromosome 6p21 is the strongest genetic factor identified as influencing MS susceptibility. However, recent studies suggest the possibility that complex trans-allelic interactions across the human leukocyte antigen (HLA) locus could determine the balance between susceptibility and resistance.

  • The power of genome-wide association (GWA) studies to isolate modest genetic variation associated with central nervous system autoimmunity was recently demonstrated with the confirmation of IL2R and IL7R as true MS disease genes.

  • Based on the allele-sharing date, common susceptibility alleles (that is, those with a frequency of >10%) are unlikely to increase the risk by more than a factor of 2.0. A 10,000–15,000 case GWA study would be a reasonable next step in the genetic analysis of MS.

  • Because of the redundancy and complexity inherent to the molecular, cellular and physiological pathways leading to disease, genetic studies in MS should move from the reductionist, single gene strategy to a multi-disciplinary, integrative and system-level research approach.

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disease and a common cause of neurological disability in young adults. The modest heritability of MS reflects complex genetic effects and multifaceted gene–environment interactions. The human leukocyte antigen (HLA) region is the strongest susceptibility locus for MS, but a genome-wide association study recently identified new susceptibility genes. Progress in high-throughput genotyping and sequencing technologies and a better understanding of the structural organization of the human genome, together with powerful brain-imaging techniques that refine the phenotype, suggest that the tools could finally exist to identify the full set of genes influencing the pathogenesis of MS.

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Figure 1: The 6p21–6p23 chromosomal region and multiple sclerosis.
Figure 2: Molecular modelling of HLA-DRB1 susceptibility alleles and resistance alleles in multiple sclerosis.

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Acknowledgements

The concepts and discussion presented in this paper reflect the interactions with our IMSGC colleagues. The authors are supported by the US and UK Multiple Sclerosis Societies, the National Institute of Health, the Wellcome Trust, and the Nancy Davis Foundation. We especially thank the many MS patients and their families who participated in our studies.

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Correspondence to Jorge R. Oksenberg or Stephen L. Hauser.

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DATABASES

OMIM

Multiple sclerosis

FURTHER INFORMATION

Chimera

Immunogenetics (IMGT) database

International Multiple Sclerosis Genetics Consortium

Swiss-PDB viewer

Glossary

Heritability

The proportion of the total phenotypic variation for a given characteristic in a population that can be attributed to genetic variance among individuals.

Heterogeneity

Allelic heterogeneity refers to the situation in which more than one allele from a gene is associated with a given disease, whereas genetic or locus heterogeneity refers to the situation in which variation in different genes might cause identical or similar forms of the disease in different subjects.

Viraemia

The presence of a virus in the bloodstream.

Oligoclonal

Oligoclonal bands are distinct immunoglobulin G bands detected by protein electrophoresis in the cerebrospinal fluid of most MS patients

Clonotype

Homogeneous group of cells of the immune system that share antigen receptors and antigen specificity.

Devic syndrome

Neuromyelitis optica (NMO; Devic syndrome) is characterized by separate attacks of acute optic neuritis and myelitis. Anti-aquaporin 4 antibodies in the serum are a biomarker for NMO. Whether NMO is a variant of MS or a distinct disease is uncertain.

Microsatellites

Short, polymorphic sequences of DNA repeated in tandem. Typically co-dominant, microsatellites are useful genetic markers with wide-ranging applications in disease, population and forensic studies.

LOD score

The logarithm (base 10) of the likelihood ratio (odds). The LOD score serves as a test of the null hypothesis of free recombination versus the alternative hypothesis of linkage.

Type I error

The probability of rejecting the null hypothesis when it is true. For association studies, type I errors are manifest as false-positive reports of phenotype–genotype correlation.

Linkage disequilibrium

(LD). The condition in which the frequency of a particular haplotype for two loci is significantly different from that expected if the loci were assorting independently.

Positive selection

The process by which new advantageous genetic variants become more common in a population.

Prior odds

Refers to the odds that a test hypothesis is true as compared with the null hypothesis before any experiment is undertaken. Prior odds can be derived from first principles, or based on general knowledge or previous experiments.

Posterior odds

Refers to the odds that a test hypothesis is true as compared with the null hypothesis after an experiment is completed; that is, in light of the new data provided by the experiment. If an experiment is well powered and the test hypothesis is true, then the expectation is that the posterior odds will be greater than the prior odds.

Bayesian approach

A statistical school of thought that, in contrast to the frequentist school, holds that inferences about any unknown parameter or hypothesis should be encapsulated in a probability distribution, given the observed data. Bayes' theorem is a celebrated result in probability theory that allows the computation of the posterior distribution for an unknown from the observed data and its assumed distribution before experiment.

Admixture mapping

Efficient approach to map disease-causing variants that differ in frequency (owing to either drift or selection) between two historically separated populations.

Negative selection

In immunology, the central tolerance that occurs during early T cell development in the thymus that causes cells with strong reactivity to self-antigens to undergo apoptosis and elimination. Cells with antigen-specific receptors that would enable them to respond efficiently to foreign peptides in association with self-MHC proteins survive, mature, and migrate to peripheral lymphoid organs.

Encephalitogenic cell

Lymphocyte of the T lineage that is capable of homing into the CNS from peripheral lymphoid compartments and mediating a damaging inflammatory process.

Tag-SNP

Representative SNP in a region of high LD used to identify short haplotypes.

Real-time quantitative PCR

Fluorescence-based enzymatic amplification method to quantify with high sensitivity gene expression levels, following reverse transcription (RT) of mRNA into complementary DNA (cDNA).

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Oksenberg, J., Baranzini, S., Sawcer, S. et al. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 9, 516–526 (2008). https://doi.org/10.1038/nrg2395

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