Saturday, 28 February 2015

Genetics of thin brains give ideas to control progression

Matsushita T, Madireddy L, Sprenger T, Khankhanian P, Magon S, Naegelin Y, Caverzasi E, Lindberg RL, Kappos L, Hauser SL, Oksenberg JR, Henry R, Pelletier D, Baranzini SE. Genetic associations with brain cortical thickness in multiple sclerosis.
Genes Brain Behav. 2015. doi: 10.1111/gbb.12190. [Epub ahead of print]

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of grey matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by MRI. The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified 9 areas showing different thickness between cases and controls (regions of interest, ROI) (8 of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for sub networks enriched with nominally associated genes and searched for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signalling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS.

We are a product of our genes and Genome Wide Association Studies (GWAS) have so far found about 150 MS Susceptibility  genes or gene products. In this study they looked for pathology and notably MRI-detected Grey matter thickness as a marker of cognitive disability and found no associate with any single gene. It has been said that unless you examine thousands of samples you get nothing that is reproducible. This what was found.

However if you look at networks of gene  they found associates that influenced calcium levels (we know if you have too much calcium it triggers cell suicide). Excessive glutamate levels trigger calcium excessive calcium concentrations within the cell that can lead to cell death. These will all need to verified in additional studies, but already we have been thinking about blocking glutamate signalling. 

In animals, blocking excessive glutamate signalling can slow progressive nerve loss however this is associated with significant side-effects and also the system is rapidly de-sensitized, so drugs don't work. So far in MS this approach has not worked..I won't say I told you so, but I could have told you so.

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