Final Report Summary - MTLE-HS (Genomic sequence variants that correlate with gene expression and different epigenetic patterns modify risk for mTLE+HS)
Some changes in gene expression, however, are not attributable to alterations in DNA sequence, but to epigenetic mechanisms. Methylation, the most commonly studied epigenetic modification of DNA, occurs naturally on cytosine bases at CpG sequences. No studies currently exist addressing epigenetic mechanisms in the development of epilepsy, although increasing evidence points to its contribution in the presentation of seizures and their control.
Therefore, the research project tries to identify those genomic sequence variants that correlate with gene expression and different epigenetic patterns that could modify risk for mTLE.
The main aims of the proposed research project are:
(1) identify genetic loci, which alter risk for mTLE+HS;
(2) understand the effects of these loci implicated in mTLE+HS on gene expression in tissue relevant to mTLE+HS;
(3) identify epigenetic patterns that modify mTLE+HS pathogenesis and response to therapy; and
(4) provide new information regarding pathways that are potentially affected in mTLE+HS.
During the Marie Curie period we aimed the following:
-To show that the combination of genome wide assays of gene expression and genetic variation can provide information about the biological control of gene expression and aid in interpreting the results of GWA studies. This approach has helped to identify two risk alleles for mTLE+HS (manuscript in preparation), and several genetic variants associated with human hippocampal and intracranial volume in mTLE+HS and subjects free of neurological disorders (Nature Genetics).
-Perform a genome-wide profiling of methylation in our sample and identify epigenetic mechanisms that may contribute to mTLE+HS susceptibility (manuscript in preparation).
-Identify a potential marker (BDNF Val66Met polymorphism) of verbal and visual memory decline in patients with mTLE (manuscript in preparation).
This is the first study that has found common genetic variants associated with risk for mTLE+HS in sporadic cases. It will be also the first study to report epigenetic changes associated with mTLE+HS. This work has not only improved our knowledge about epileptogenesis and pharmacoresistence, but we have also found different biological mechanisms underlying the susceptibility of this complex disease.
Future replication and confirmation of these findings would support the possibility of identifying populations at risk of mTLE+HS and better targeting of therapies. In the long term it is anticipated that these findings will have clinical implications that will improve the quality of life of these patients.
-E. E. Schadt, Current Opinion in Biotechnology 16 (6), 647 (2005).
-W. Cookson, L. Liang, G. Abecasis et al., Nature Reviews Genetics 10 (3), 184 (2009).
-S. Jessberger, K. Nakashima, G. D. Clemenson, Jr. et al., Journal of Neuroscience 27 (22), 5967 (2007).
- J. Hauke, M. Riessland, S. Lunke et al., Human Molecular Genetics 18 (2), 304 (2009).
-K. L. Gilby, S. Sydserff, A. M. Patey et al., Behavioural Neuroscience 123 (2), 337 (2009).
-Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. Common genetic polymorphisms contribute to the variation in human hippocampal and intracranial volumen. Nature Genetics 2012 Apr 15;44 (5):552-561.