Exploiting the potential of Selective serotonin receptor antagonists

Linking epigenetics and brain structure and function in depression
Supervisors: Dr Heather Whalley, Dr Kathy Evans, Prof Andrew McIntosh
Major Depressive Disorder (MDD) has a complex aetiology involving an intricate mix
of genetic and environmental factors. Whilst the associations identified by genomewide association studies (GWAS) have yet to translate into causative variants, such
studies have indicated that alterations within regulatory regions may be a frequent
mechanism underlying this, and related, conditions. This implication of regulatory
mechanisms fits with data from those investigating epigenetic modification, which
points to differential modification of genes involved in inflammation and brain
development3, 4. Structural and functional brain imaging studies have also indicated
differences in brain development in the disorder. Neuroimaging studies have
revealed abnormalities in cortico-striatal-limbic circuitry, consistent with altered
mood regulation, anhedonia, deficits in emotion processing, motivation and reward 5.
It is unclear however whether these deficits relate to underlying vulnerability to the
disorder, are a secondary consequence of illness or its treatment, or indeed how
they relate to epigenetic modification in the genome. So far directly the linking brain
DNA methylation and expression changes with structural and functional brain
imaging measures in MDD has yet to be fully exploited and is ripe for examination.
The current project will specifically address the effects of DNA methylation and gene
expression in MDD on brain structure and function.
The successful applicant will analyse fMRI data and integrate this with DNA
methylation and gene expression data providing new insights into the connections
between these currently relatively disparate areas. This proposal brings together two
complimentary groups from different disciplines, being conducted jointly between
the Division of Psychiatry and the Institute of Genetics and Molecular Medicine in
Edinburgh. Together the applicants have expertise in all areas of the proposal.
This project will be of particular interest to students with a neuroscience, and/or
genetics background.
Lopez-Leon, S. et al. Meta-analyses of genetic studies on major depressive disorder. Mol.
Psychiatry 13, 772-785 (2008).
Bosker, F.J. et al. Poor replication of candidate genes for major depressive disorder using
genome-wide association data. Mol. Psychiatry 16, 516-532 (2011).
Uddin, M. et al. Epigenetic and inflammatory marker profiles associated with depression in a
community-based epidemiologic sample. Psychol. Med. 41, 997-1007 (2011).
Sabunciyan, S. et al. Genome-wide DNA methylation scan in major depressive disorder. PLoS
One 7, e34451 (2012).
Phillips, M.L., Drevets, W.C., Rauch, S.L. & Lane, R. Neurobiology of emotion perception II:
Implications for major psychiatric disorders. Biol. Psychiatry 54, 515-528 (2003).
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