Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA): Antisocial Behaviour working group

Secondary Supervisor(s): Professor Peter Tino (Computer Science, University of Birmingham)

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Neuroscience and Behaviour)

Project Outline

ENIGMA is an international collaborative effort that brings together over 1400 researchers across 43 countries to better understand brain structure, function, health and disease, based on meta-/mega-analyses of brain imaging and genetic data (http://enigma.ini.usc.edu). There are currently over 50 active ENIGMA working groups covering various fields within psychiatry and neuroscience (see our recent review here). We have recently set-up the ENIGMA Antisocial Behaviour working group on which the student will work (https://enigma.ini.usc.edu/ongoing/enigma-antisocial-behavior/). Despite notable advances in recent years, the overall impact and replicability of work in this field has been limited by small sample sizes and heterogeneous participant characteristics, imaging acquisition methods, and data analysis techniques. The harmonized meta-analytical approach of ENIGMA allows one to address these challenges more adequately, gain deeper insights into underlying pathophysiology, and generate more reproducible and generalizable findings.

The ENIGMA Antisocial Behavior initiative will focus on data covering the entire lifespan; this includes structural and functional MRI data on Conduct Problems/Disorder in youths, as well as Antisocial Personality Disorder/Psychopathy in adults. Analyses will not only be focused on disorders and categorical approaches, but also dimensional approaches where neuroimaging/genetics data that can be linked to dimensional measures indexing externalizing behaviors and environmental risk factors (e.g., childhood maltreatment) in both clinical/forensic and community samples. The student working on this project will have the opportunity to liaise and network with researchers across the globe. There will be opportunities for training at the ENIGMA headquarter at the University of Southern California as well as with our ENIGMA collaborators in the Netherlands. The project will combine and train the student in methods from psychology, neuroimaging, and computer/data science, which together will put this project at the forefront of research on antisocial behaviour.

Neuroimaging genetics and epigenetics of threat and reward circuitry in humans and Drosophila to understand risk for psychopathology

Secondary Supervisor(s): Dr Carolina Rezaval

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Neuroscience and Behaviour)

Project Outline

Over the past two decades, neuroimaging genetics has advanced our understanding of how DNA sequence-based variations influence brain activity, behaviour, and the risk for psychopathology. For example, studies show that individuals homozygous for the long allele of the serotonin transporter gene (5-HTTLPR) exhibit heightened amygdala responses to threatening stimuli, increasing their risk of mood and anxiety disorders. This is consistent with epidemiological data indicating that the short allele of 5-HTTLPR is associated with a higher risk of depression following childhood adversity.

However, neuroimaging genetics faces several challenges. First, it explains only a small proportion of variance in neural phenotypes. Second, it assumes genetic influence on the brain and behaviour is unidirectional and static, while evidence shows environmental influences (e.g., early adversity) can alter gene expression through epigenetic modifications, such as DNA methylation. Third, the complexity of the human brain makes it difficult to understand how genetic changes and life experiences result in neuropsychiatric disorders.

Drosophila has become a powerful model for behavioural neuroscience, offering a simple nervous system that supports complex behaviours while maintaining molecular principles conserved across species. Drosophila's tools enable precise single-neuron mapping and gene manipulation, which are not yet feasible in mammalian models. Physiological and neurological similarities between Drosophila and humans make it a relevant model for neuropsychiatric research, with strong translational potential. The overarching question of this PhD project is: How do early life experiences, genes, brain activity, and behaviour relate in humans and Drosophila? By integrating neuroimaging genetics and epigenetics research in humans with mechanistic studies in Drosophila, the project aims to uncover the molecular and neural circuit mechanisms underlying the risk for mental health disorders.

The research programme will first use neuroimaging genetics and neuroimaging epigenetics in humans to examine how genetic variations and epigenetic modifications influence brain activity, behaviour, and the risk of psychopathology. Human data will come from a large (N=11800) study of male and female youths aged 9-10 years (https://abcdstudy.org/). The project will then explore the role of key genes (e.g., serotonin and dopamine pathways) identified in human studies in modulating neural circuits and behavioural responses to threats using advanced assays in Drosophila. Genetic tools will knock down components of these pathways in targeted neurons to explore their functional roles. Additionally, optogenetics will selectively activate or inhibit neurons in the brain's threat circuitry. By integrating connectomic data with live imaging techniques, such as calcium reporters, we will visualise real-time neuronal activity at single-cell resolution during threat responses. Combined with behavioural assays, this approach will reveal how disruptions in serotonin and dopamine systems affect the brain's ability to process and respond to threats, enhancing our understanding of the molecular and neural mechanisms underlying vulnerability to psychopathology.

Together, this research programme leverages cutting-edge approaches in both human and animal models to provide a comprehensive mechanistic understanding of how genes, neural circuits, and early life experiences shape brain function and contribute to the risk of psychopathology.

References

Fairchild, G., Hawes, D. J.,... Freitag, C. M., & De Brito, S. A. (2019). Conduct disorder. Nature Review Disease Primers. DOI: 10.1038/s41572-019-0095-y.

Cazalé-Debat, L., Scheunemann, L., Day, M., Fernandez-d.V. Alquicira, T., Dimtsi, A., Zhang, Y., Blackburn, L. A., Ballardini, C., Greenin-Whitehead, K., Reynolds, E., Lin, A. C., Owald, D., & Rezaval, C. (2024). Mating proximity blinds threat perception. Nature. doi:10.1038/s41586-024-07890-3.