Genetic studies are developing a comprehensive picture of the immune component of multiple sclerosis (MS) susceptibility, however we still know very little about the pathophysiology behind the cerebral demyelinating events which are the core pathological outcome. Individuals with MS do not present a good environment to study the biological processes surrounding demyelination and repair due to the extreme burden of disease. People from the general population show a degree of comparable white matter damage; however they generally have far fewer lesions thereby putting less strain on repair pathways. Our aim is to identify the genes involved in neurorepair processes in people with low levels of white matter damage, to gain insight into the pathways likely to be significantly disrupted by the higher degree of white matter insult in MS. These genes may be involved in disease susceptibility or differential disease progression in MS.
We are investigating the genes involved in remyelination and repair in unascertained pedigrees from the Genetics of Brain Structure study; utilising a combination of extensive neuroimaging with almost exhaustive genomic data.
While there are many MS-relevant measures of white matter damage; one example is MRI measured deep white matter lesion (DWML) volumes. When corrected for age and confounding aetiologies such as stroke, DWML volumes were highly heritably 60% (p=1x10-14) and correlated with neurocognitive processes such as working memory (p<0.01). Genome-wide association analyses using 830 individuals identified suggestive associations for DWMLs (p<1x10-6) at eight loci. Underlying sequence data were used to implicate several genes for further investigation, including three involved in the axonal guidance signalling pathway recently highlighted as a potential ‘handbrake’ for neurodegeneration in the mouse model of MS, and a gene involved in producing sphingomyelin - one of the core components of the myelin sheath that is the target of the immune-driven axonal damage in MS.