The Genetics of MS

Summary

The single strongest genetic risk factor for Multiple Sclerosis (MS) is located within the major histocompatibility complex (MHC). Dr Morahan is using the scientific equivalent of a ‘fine-tooth comb’ to identify the genetic differences in a particular MHC region.

Certain versions of genes within this region have been known to increase susceptibility to MS for some time. However, the genetic story in this region is more complex than originally thought and recent evidence has shown it is likely that other factors are also at play.

One such factor may be the mechanism that switches genes on and off within tissues. Changes to these biological switches, controlled by the presence or absence of methylation on the DNA strand, may also increase susceptibility to MS by changing when the underlying genes are switched on or off.

Progress to Date

In 2009 Dr Julia Morahan was awarded the prestigious Macquarie Group Foundation Australian–UK MS Society Exchange Fellowship to enable her to conduct research at the University of Oxford under the supervision of Professor George Ebers, one of the world’s foremost MS experts.

Dr Morahan has now completed her Fellowship and has chosen to return to Australia. She returns with a wealth of expertise and having made a significant contribution to our understanding of the role that genes play in a person's susceptibility to MS.

Dr Morahan has been researching the genetic basis of MS at Oxford’s renowned Wellcome Trust Centre for Excellence. She focussed on the genetic region which confers the highest risk of MS: the major histocompatibility complex or MHC class II.

“The work has focused on epigenetic changes, which refer to molecular differences that alter regulation of gene activity rather than altering the genes themselves,” explains Dr Morahan.

Epigenetic changes may result in the inappropriate silencing or activation of specific genes. They are often caused by differences in the number and position of chemical tags, known as methyl groups, on the DNA .

An ideal population for the examination of epigenetic differences is identical (monozygotic) twins, since they have identical DNA sequences but can differ in the amount and location of methylation.

Dr Morahan examined DNA methylation in pairs of identical twins ‘discordant’ for MS - where one individual in the twin pair has MS and the other twin does not. The twin pairs were identified via the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS).

The twin analysis identified different DNA methylation levels in discordant twins, particularly at two sites within the MHC class II region.

“While these DNA methylation differences support a potential role for epigenetic changes across the MHC region in the pathogenesis of MS, functional work now needs to be carried out to establish how they might impact gene regulation,” concludes Dr Morahan.

To date, this is the only study of methylation in MS that has covered the entire MHC region. The methods developed by Dr Morahan and her colleagues to conduct this analysis will enable further detailed investigation of larger samples of twins and wider groups of people with MS studied of longer time periods. This will lead to further insights into the molecular nature of epigenetic susceptibility to MS.

Dr Morahan has shared her findings with the MS research community through three publications directly resulting from her Fellowship project (see below). She also contributed to a further 13 publications in collaboration with her colleagues during her time in the UK.

Publications

Morahan JM, Michael J. Chao MJ, Sahgal N, Disanto G, Berlanga-Taylor AJ, Ramagopalan SV, Ebers GC. Methylation profile of the MHC in monozygotic twins discordant for MS. (underway)
Disanto G, Morahan JM, Ebers GC, Giovannoni G,Ramagopalan SV. Infectious mononucleosis in the development of MS and SLE in Scotland. (underway)
Disanto G, Morahan JM, De Luca GC,Giovannoni G, Ebers GC, Ramagopalan SV. Seasonal trend of psychiatric births in England. (underway)
Disanto G, Chaplin G, Morahan JM, Giovannoni G, Hyppönen E, Ebers GC, Ramagopalan SV. Month of birth and risk of autoimmune disease. (underway)
Disanto G, Sandve GK, Berlanga-Taylor AJ, Morahan JM, Dobson R, Giovannoni G, Ramagopalan SV. Genomic regions associated with MS are active in B cells. (underway)
Dyment DA, Cader MZ, Chao MJ, Lincoln MR, Morrison KM, Disanto G, Morahan JM, DeLuca GC, Sadovnick AD, Lepage P, Monpetit A, Ebers GC, Ramagopalan SV. Exome sequencing identifies a rare, MS susceptibility variant in the TYK2 gene. Neurology.
Disanto G, Morahan JM, Barnett MH, Giovannoni G, Ramagopalan SV. The evidence for a role of B cells in MS.Neurology.
Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC. Rare variants in the CYP27B1 gene are associated with MS. Annals of Neurology.
Orton SM, Ramagopalan SV, Para AE, Lincoln MR, Handunnetthi L, Chao MJ, Morahan JM, Morrison KM, Sadovnick AD, Ebers GC. Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians. J Neurol Sci. 2011 Jun 15;305(1-2):116-20.
Disanto G, Handel AE, Morahan JM, De Luca GC, Kimball SM, Hyppönen E, Giovannoni G, Ebers GC, Ramagopalan SV. Vitamin D and multiple sclerosis hospital admissions in Scotland. QJM. 2011 Nov;104(11):1001-3.
Burrell AM, Handel AE, Ramagopalan SV, Ebers GC, Morahan JM. Epigenetic mechanisms in multiple sclerosis and the major histocompatibility complex (MHC). Discov Med. 2011 Mar;11(58):187-96.
Watson CT, Para AE, Lincoln MR, Ramagopalan SV, Orton SM, Morrison KM, Handunnetthi L, Handel AE, Chao MJ,Morahan JM, Sadovnick AD, Breden F, Ebers GC. Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis. Genes Immun. 2011 Mar;12(2):59-66.
Disanto G, Berlanga AJ, Handel AE, Para AE, Burrell AM, Fries A, Handunnetthi L, De Luca GC, Morahan JM. Heterogeneity in multiple sclerosis: scratching the surface of a complex disease. Autoimmune Dis. 2011:932351.
Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton SM, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010 Oct;20(10):1352-60.
Handel AE, De Luca GC, Morahan JM, Handunnetthi L, Sadovnick AD, Ebers GC, Ramagopalan SV. No evidence for an effect of DNA methylation on multiple sclerosis severity at HLA-DRB1*15 or HLA-DRB5. J Neuroimmunol. 2010 Jun;223(1-2):120-3.
Handel AE, Handunnetthi L, Berlanga AJ, Watson CT, Morahan JM, Ramagopalan SV. The effect of single nucleotide polymorphisms from genome wide association studies in multiple sclerosis on gene expression. PLoS One. 2010 Apr 13;5(4):e10142.