From genes to function: the next challenge to understanding multiple sclerosis

Key Points

  • The availability of genetic determinants of multiple sclerosis that have emerged from recent genome-wide association studies creates opportunities to explain for the first time the biological factors that are responsible for the pathophysiology of this disease. These associations implicate genes that fall into two broad categories, immunological genes and neurological genes.

  • Much more work is needed to confirm the disease-associated genetic variants that are responsible for these associations and to attribute this risk to individual loci. In addition, other sorts of genetic variation that have not yet been systematically evaluated in multiple sclerosis, such as rare variants, private mutations and copy number variations, could contribute further to our understanding of heritability.

  • The ultimate proof of causality for a genetic variant will require functional data. This may be partly provided by expression analysis or simple cellular assays but may also require new approaches and animal models that allow exploration of pathway variations using multiple variants or that alter the activity of pathways implicated in disease in humans.

  • Environmental factors will remain crucial to our understanding of disease risk and pathogenesis. These may be easier to identify if genetics analysis provides clues as to what they may be or if epigenetic modification can be detected that indicates how environmental factors and genes may interact.

  • Other tools, such as experimental medicine in genotyped individuals to detect the biological effects of these polymorphisms as well as modelling and simulation, will also be crucial approaches to dissecting functional roles of these new variants.

Abstract

Susceptibility to multiple sclerosis is jointly determined by genetic and environmental factors, and progress has been made in defining some of these genetic associations, as well as their possible interactions with the environment. However, definitive proof for the involvement of specific genetic determinants in the disease will only come from studies that examine their functional roles in disease pathogenesis. New and combined approaches are needed to analyse the complexity of gene regulation and the functional contribution of each genetic determinant to disease susceptibility or pathophysiology. These studies should proceed in parallel with the use of genetically defined human populations to explore how both genetic and environmental factors affect the function of the pathways in individuals with and without disease, and how these determine the inherited risk of multiple sclerosis.

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Figure 1: The HLA-DR2a molecule modifies multiple sclerosis-like disease mediated by the HLA-DR2b molecule by functional epistasis.
Figure 2: Opposing effects of HLA class I molecules on autoreactive CD8+ T cells in a mouse model of multiple sclerosis.

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Acknowledgements

We thank N. Willcox and A. Vincent for critical reading of the manuscript. Work in the authors' laboratories is supported by the Danish and UK Medical Research Councils, the Karen Elise Jensen Foundation, the Lundbeck Foundation, the Danish Multiple Sclerosis Society, the European Union (European Commission Descartes Prize, FP6 (Neuropromise, Mugen and ARDIS) and FP7 (SYBILLA)). M.A.F. is supported by the DFG Emmy Noether Programme (grant number FR1720/3-1).

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Correspondence to Lars Fugger or John I. Bell.

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OMIM

amyotrophic lateral sclerosis

spinal muscular atrophy

Parkinson's disease

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1000 genomes website

Glossary

Demyelination

Damage to the myelin sheath surrounding nerves in the brain and spinal cord, which affects the function of the nerves involved.

Axonal degeneration

Loss of nerve fibres in response to local damage.

Genome-wide association study

A study designed to look for association between disease and a dense set of markers covering the entire genome.

Linkage disequilibrium

A situation in which alleles in a chromosomal region occur together more often than can be accounted for by chance, indicating that the alleles are in close proximity on the DNA strand and are most likely to be passed on together within a population.

Candidate gene association study

A study that compares the allele frequency of a gene for which there is evidence, usually functional, for a possible role in a disease or trait of interest in cases and controls to assess the contribution of genetic variants to phenotypes in specific populations.

HLA-DR2 haplotype

A combination of alleles at many linked loci that are inherited together; in this case the MHC class II alleles HLA-DRB1*1501 and HLA-DRB5*0101.

Single nucleotide polymorphism

(SNP). Genomic variant in which a single base in the DNA differs from the usual base at that position. SNPs are the most common type of variation in the human genome.

Private variant

The specific genetic variant that only occurs in one individual or family that functionally gives rise to an increased risk conferred by the causal gene or genomic region.

Next generation sequencing technology

Technology that allows for parallel sequencing of massive amounts of DNA. This technology can be used for deep sequencing to sequence whole genomes, transcriptome analysis and for the identification of rare mutants.

eQTL mapping

Combination of quantitative trait loci (regions of DNA that are closely linked to a phenotypic outcome) mapping and gene-expression analysis to study the genetic basis of gene expression and, by extension, biological regulation.

Regulatory T cell

(TReg cell). A type of CD4+ T cell that is characterized by its expression of forkhead box P3 and high levels of CD25. TReg cells can downmodulate many types of immune response.

Induced pluripotent stem cell

A type of pluripotent stem cell that is artificially derived from a non-pluripotent cell, typically an adult somatic cell, by retroviral transfer of a panel of developmentally regulated genes. They can differentiate into multiple cell lineages.

Epigenome

The chromatin states that are found along the whole genome, defined for a given time point and cell type.

Epistatic interaction

Any non-additive interaction between two or more variants at different loci, such that their combined effect on a phenotype differs from the one that would be produced if the two genes were acting independently.

T helper 17

A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves transforming growth factor-β, IL-6, IL-23 or IL-21, IL-1 and the transcription factors RORγt and STAT3.

Tissue acidosis

Lowered pH (acidosis) that is caused by increased glycolysis, production of lactic acid and decreased extracellular and intracellular pH. Tissue acidosis is associated with imbalance between energy supply and demand.

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Fugger, L., Friese, M. & Bell, J. From genes to function: the next challenge to understanding multiple sclerosis. Nat Rev Immunol 9, 408–417 (2009) doi:10.1038/nri2554

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