CEO, Neuroscience Research Australia (NeuRA)
Interim Joint CEO, The Mindgardens Alliance
Professor, School of Medicine, UNSW
+612 9399 1604
Appointed institute head in 2004, Peter graduated from the University of Sydney with the University Medal and was awarded a PhD in genetics from The Australian National University in 1985. He undertook postdoctoral positions in biotechnology in the US and the University of Heidelberg. Peter was appointed a NHMRC Senior Research Fellow at the Garvan Institute in 1993, becoming head of the Neurobiology Research Program in 1999. His research interests focus on identifying genes that lead to mental illness and to dementia.
Genetic research into bipolar disorder traditionally uses strict categorical criteria to define a clinical diagnosis. However, it is common for relatives of individuals with bipolar to exhibit some evidence of mood disturbance, but not sufficient to meet the strict clinical criteria for a positive diagnosis. These individuals are correctly considered clinically unaffected, although they likely share some of the susceptibility genes underlying the disorder. Dr Fullerton has been examining the use of subclinical traits to identify individuals who share susceptibility genes in order to follow the pattern of genetic transmission of bipolar disorder through families more accurately.
Mental health and wellbeing is not simply the absence of mental illness, yet we know very little about its underlying neural and genetic mechanisms in relative comparison. Similarly, we know very little about the underlying mechanisms that contribute towards resilience to stress and adversity. This project led by Dr Justine Gatt aims to identify the genetics and neuroscience of resilience and wellbeing in a prospective cohort of 1,600 healthy adult twins.
Team Members & Collaborators
Dr Justine Gatt is leading this project as NHMRC CDF Research Fellow. Additional investigators on this project include Prof Peter Schofield (NeuRA and UNSW, Australia) and Prof Leanne Williams (Stanford University, USA). The PhD and graduate students involved in this project include: Kylie Routledge (PhD, completed), Rebecca Alexander (PhD), Sandy Wong (ILP, 2018), Miranda Chilver (PhD), Javad Jamshidi (Scientia PhD), and Arthur Montalto (PhD). Research Assistants involved in this project include: Sicong Tu (2016), Emily Crocetti (volunteer RA from Dartmouth USA, 2018). The twin participants for this project were drawn from the Twins Research Australia (TRA) twin registry (https://www.twins.org.au/).
This project is supported by a NHMRC Career Development Fellowship awarded to Dr Justine Gatt (APP1062495, 2014-2017), a Commonwealth Health Minister’s Award for Excellence in Health and Medical Research awarded to Dr Justine Gatt ($50,000, 2014-2017), and PhD Scholarships awarded to each PhD student.
Key Outcomes & Publications
One key outcome from this project is the development of the 26-item COMPAS-W Wellbeing Scale (Gatt et al., 2014, Psychiatry Research). What differentiates this wellbeing scale from many others is that it provides a “composite” measure of wellbeing; that is, a measure of both subjective (hedonia) and psychological (eudaimonia) wellbeing. The COMPAS-W scale can be used to calculate total wellbeing, as well as subscale measures of composure, own-worth, mastery, positivity, achievement and satisfaction. Twin modelling was conducted on the scale and heritability (genetic variability) was confirmed to be 48%.
We have since conducted a number of studies examining the association between the COMPAS-W Wellbeing Scale and measures of depression and anxiety symptoms using the DASS-42 Scale (Routledge et al., 2016); measures of neurocognitive performance such as motor coordination, processing speed, sustained attention, cognitive control and flexibility, inhibition, working memory, recall memory and executive function (Routledge et al., 2017); and measures of emotion processing of positive and negative facial expressions (Routledge et al., 2018). Most recently, we have also demonstrated associations between COMPAS-W Wellbeing scores and grey matter volumetric differences in the brainstem pontine nuclei using MRI (Gatt et al., 2018). Across these studies, statistical analyses incorporated univariate and multivariate modelling of phenotypic, as well as genetic and environmental variance between twin pairs.
Gatt JM (In Press). The neuroscience of wellbeing: Part 1. In: Cohen L. Ed. The Encyclopedia of Health Psychology. Chichester, West Sussex: John Wiley & Sons Ltd.
Gatt JM (In Press). The neuroscience of wellbeing: Part 2. In: Cohen L. Ed. The Encyclopedia of Health Psychology. Chichester, West Sussex: John Wiley & Sons Ltd.
Alexander R and Gatt JM (2019). Resilience, Chapter 20. In: Miu AC, Homberg JR, Lesch K-P. Eds. Genes, Brain and Emotions: Interdisciplinary and Translational Perspectives. Oxford: Oxford University Press. ISBN: 9780198793014.
Gatt JM, Burton KLO, Routledge KM, Grasby KL, Korgaonkar MS, Grieve SM, Schofield PR, Harris AWF, Clark CR, Williams LM. (2018). A negative association between brainstem pontine gray matter volume, wellbeing and resilience in healthy twins. Journal of Psychiatry and Neuroscience, Jun 20; 43(5): 170125. doi: 10.1503/jpn.170125.
Routledge KM, Williams LM, Harris AWF, Schofield PR, Clark CR, Gatt JM. (2018). Genetic correlations between wellbeing, depression and anxiety symptoms and behavioral responses to the emotional faces task in healthy twins. Psychiatry Research, 264, 385-393.
Routledge KM, Burton KLO, Williams LM, Harris A, Schofield PR, Clark CR, Gatt JM. (2017). The shared and unique genetic relationship between mental wellbeing, depression and anxiety symptoms and cognitive function in healthy twins. Cognition and Emotion, 31(7), 1465-1479.
Routledge KM, Burton KLO, Williams LM, Harris A, Schofield PR, Clark CR, Gatt JM. (2016). Shared versus distinct genetic contributions of mental wellbeing with depression and anxiety symptoms in healthy twins. Psychiatry Research, 244, 65-70.
Gatt JM, Burton KLO, Schofield PR, Bryant RA, Williams LM. (2014). The heritability of mental health and wellbeing defined using COMPAS-W, a new composite measure of wellbeing. Psychiatry Research, 219 (1), 204-213.
Recent advances in technology have enabled sequencing at the level of the entire genome to become a reality. We have access to number of rare families with highly heritable forms of bipolar disorder, for which we will apply this powerful technology to identify specific genetic factors which increase disease risk. We will assess loss-of-function variation within genes, at both the level of single base mutations and variation in gene copy number, which track with illness in these families to identify new genes which contribute to illness.
Because of the complex pattern of genetic transmission, it is expected that multiple genes will contribute to susceptibility to bipolar disorder. It is possible that combinations of genes will be stronger risk factors for developing bipolar disorder than individual genes, so we are examining gene-gene interactions (genetic epistasis) throughout the genome to identify genes which, in concert, may increase susceptibility. This analysis has led to the identification of multiple such interacting regions, and the group is now seeking to identify the specific genes involved in these interactions.
In addition to genes identified in our own laboratory, we have also been involved in assessing the risk attributed by genes identified by other groups and in sharing data and samples in large international collaborative studies. We are contributors to the Psychiatric Genomics Consortium (PGC) and Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortia, which aim to identify risk genes which contribute to disease, and examine their effect on brain structure, function and disease.
Together with Professor Peter Schofield (NeuRA) and Professor Philip Mitchell (Black Dog Institute), our group is investigating the genetic contributors to bipolar disorder using Australian families with multiple individuals who have been diagnosed with the disorder.
The group previously identified a bipolar susceptibility locus located on chromosome 15 in a pooled analysis of 35 families. More detailed analysis of this region has identified a single gene, which confers an increased susceptibility to both bipolar disorder and schizophrenia, and has also been implicated as a risk factor for autism.
The group is now aiming to understand how alterations in ST8SIA2 translate into an increased genetic susceptibility by characterising alterations in the DNA, RNA and protein product of this gene and its interaction partners in patients with either bipolar disorder or schizophrenia.
The offspring of individuals with bipolar disorder are at increased risk of mental illness, but our tools to predict which of these genetically at-risk young people will eventually develop disorder are very imprecise. Longitudinal studies that ascertain at-risk participants and monitor them prospectively are an effective approach for identifying early clinical and biological markers of future illness. In collaboration with the Black Dog Institute plus groups from four independent US-based sites, including: Johns Hopkins University; University of Michigan; Washington University in St. Louis; Indiana University; we are following a cohort of young kids and siblings of bipolar disorder patients with annual clinical, neurocognitive and lifestyle assessments; plus bi-annual brain imaging of the Australian participants. We are assessing the genetic load of multiple risk variants across the genome in these at-risk individuals to determine if we can use genetic information to help predict which individuals will ultimately transition to illness, and whether genetic load will influence early structural brain changes which are seen prior to onset of symptoms which lead to a clinical diagnosis.
We are also examining whether epigenetic changes – which occur on-top-of the DNA sequence in response to environmental influences – are involved in transition from health to illness. Early identification of those most likely to develop illness will provide a firm basis on which to develop preventive and early intervention strategies to reduce the impact of this devastating disorder.
Both genetic and environmental factors are involved in the development of bipolar disorder, a severe mood disorder characterised by oscillations from normal mood to periods of elevated mood (mania) or low mood (depression). Dr Jan Fullerton and Professor Peter Schofield are investigating the genetic contributors to bipolar disorder using Australian families with multiple individuals who have been diagnosed with the disorder. Together with PhD student Erica McAuley, the group has recently identified a bipolar susceptibility locus located on chromosome 15 in a pooled analysis of 35 families. Further, more detailed analysis of this region using a newly acquired campus Illumina beadstation facility for the analysis of SNP markers has identified a single gene, which confers an increased susceptibility to bipolar disorder. They are now aiming to understand how these alterations translate into an increased genetic susceptibility by characterising the biological pathways involved.
Because of the complex pattern of genetic transmission, they expect that multiple genes will contribute to susceptibility to bipolar disorder. It is possible that combinations of genes will be stronger risk factors for developing bipolar disorder than individual genes, so they are examining gene-gene interactions (genetic epistasis) throughout the genome to identify genes which, in concert, may increase susceptibility. This analysis has led to the identification of multiple such interacting regions, and they are now seeking to identify the specific genes involved in these interactions.
In a collaborative study with Professors Kay Wilhelm and Phil Mitchell from the UNSW School of Psychiatry, Professor Peter Schofield and his team examined the genetic variation in the transporter protein that is involved in the reuptake of the neurotransmitter serotonin. There is an association between low serotonin transporter levels, stress and depression. The group has further shown that there is an association between the serotonin transporter genotypes and the way an individual copes with stress. This has led to further clinical studies correlating how individuals can use different methods to handle stress. Their research has significant implications for reducing the likelihood of developing depression and a planned future study will be to evaluate whether specific training in stress management, matched to an individual’s genotype, may lead to a reduction in the incidence of depression.
KERRIE PIERCE Senior Research Assistant
MIRELLE D’MELLO Research Assistant
These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.