Over the past two decades, the field of neuroimaging genetics, through its systematic integration of human molecular genetics and in vivo neuroimaging, has considerably advanced our understanding of how DNA sequence-based genetic variations (i.e., polymorphisms) influence individual differences in brain activity, behaviour and associated risk for psychopathology 1. For example, these association studies have shown that, in comparison to individuals homozygous for the high activity allele of the Monoamine Oxidase A (MAOA) gene, which degrades serotonin pre‐and postsynaptically 2, individuals homozygous for the low activity allele show heightened amygdala response to threating stimuli, which in turn increases their risk of displaying reactive aggression. These basic mechanistic findings are also in line with epidemiological data indicating that the low activity allele of the MAOA gene is associated with an increased risk for conduct disorder and antisocial personality disorder following maltreatment 3.
However, the neuroimaging genetics approach suffers from several problems 4,5. First, it can only explain a very small amount of variance in inter-individual variability in these types of neural phenotypes. Second, this line of research assumes that the genetic influence on brain and behaviour is unidirectional (i.e., genes code for RNA, are translated into proteins, determine brain development, which in turn influences behaviour) and static. However, there is now good evidence that environmental influences (e.g., childhood maltreatment) can get ‘under the skin’ by altering genetic expression during the lifespan through epigenetic modifications. DNA methylation is the best understood epigenetic modification and thus will be the focus of this proposal. The neuroimaging epigenetic approach described below circumvents the problems discussed above.
The overarching question of this PhD project is: How do early life experience, genes, brain activity, and behaviour relate to one another? To address this question, the proposed PhD project will use a neuroimaging epigenetic approach to go beyond the genome and examine the role of epigenetic modifications in the association between genetic markers and variability in brain activity that are associated with individual differences in behaviour and risk for psychopathology. This follows the recent proposal that ‘considering the impact of epigenetics is the logical next step in imaging genetics’ 4. This PhD project will use data collected from a large F7 multisite European study focussing on male and female youths aged 9-18 years (www.femnat-cd.eu). Specifically, for the first time the association between childhood maltreatment, DNA methylation, fMRI BOLD response/connectivity (task 1: emotional facial expressions; task 2: reward stimuli), and measures of externalising and internalising disorders will be examined in youths. Patterns of DNA methylation are currently being obtained from blood for a number of genes implicated in the brain’s threat and reward circuitries (e.g., MAOA, COMT, SLC6A4, OXTR, DRD2, and DRD4). The fMRI data analyses will focus on a network of cortical (e.g., anterior cingulate and orbitofrontal cortices) and subcortical (e.g., amygdala and basal ganglia) brain regions central to threat and reward processing and with dense serotonin, dopamine or oxytocin receptors and transporters. By systematically examining the association between childhood maltreatment, DNA methylation, and brain function/connectivity, it is hoped that this project will further our understanding of the molecular mechanisms of risk for psychopathology6.
This studentship is competition funded by the BBSRC MIBTP scheme: http://www.birmingham.ac.uk/research/activity/mibtp/index.aspx
Deadline: January 10, 2016
Number of Studentships available at UOB: 18
Stipend: £ 13,726 per annum (plus £600 travel allowance, and a MacBook Pro)
***IMPORTANT*** Prior to submitting a PhD application to the University of Birmingham, all interested candidates should first contact Dr De Brito at [email protected] Following this, only applicants with the most competitive CV will be requested to submit a PhD application using the University of Birmingham on-line application system. Candidates should submit a personal statement, CV, 2 references, and transcript of grades.
1. Bogdan R, Hyde LW, Hariri AR. A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology. Mol Psychiatry. Mar 2013;18(3):288-299.
2. Buckholtz JW, Meyer-Lindenberg A. MAOA and the neurogenetic architecture of human aggression. Trends Neurosci. 2008;31(3):120-129.
3. Caspi A, McClay J, Moffitt T, et al. Role of genotype in the cycle of violence in maltreated children. Science. Aug 2002;297(5582):851-854.
4. Nikolova YS, Hariri AR. Can we observe epigenetic effects on human brain function? Trends Cogn Sci. Jul 2015;19(7):366-373.
5. Wiers CE. Methylation and the human brain: towards a new discipline of imaging epigenetics. Eur Arch Psychiatry Clin Neurosci. Apr 2012;262(3):271-273.
6. Insel TR, Cuthbert BN. Brain disorders? Precisely. Science. May 1, 2015 2015;348(6234):499-500.
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