It is now well established that there are genetic factors contributing to risk of depression but it is far from clear what these are and how they interact with environmental risk factors such as stressful life events (SLE) and poor social support (SS). A recent, highly cited paper has claimed that those carrying a particular genotype at the sertonin transporter gene are much more badly affected by stressful life events than other genotypes, and that this puts these people at much higher risk of ....It is now well established that there are genetic factors contributing to risk of depression but it is far from clear what these are and how they interact with environmental risk factors such as stressful life events (SLE) and poor social support (SS). A recent, highly cited paper has claimed that those carrying a particular genotype at the sertonin transporter gene are much more badly affected by stressful life events than other genotypes, and that this puts these people at much higher risk of depression. If true, this could have important practical implications for preventative mental health, in identifying those at greatest risk if depression and counselling them to avoid stressful situations. However, success in replicating this finding has been mixed, and this is possibly because another important risk factor, social support, has not been taken into account. We have DNA samples from over 5000 twins who have been assessed for depression and risk factors including SLE and SS. This will give us unprecedented power to estimate the importance of the genotype x environment interaction. We shall also type other genes that have been implicated in depression and check for interactions with life events and social support. Our results will inform preventative strategies in mental health practice.Read moreRead less
Melanoma is one of Australia?s major cancer problems, but we still do not completely understand why certain people are at higher risk than others. This study is focussed on people who have developed melanoma at an early age (under 40yrs) and will compare their family history of cancer, skin features, genetic characteristics and various aspects of their previous sun exposure with people who don?t have melanoma. The large number of people involved and the fact that they will be selected at random ....Melanoma is one of Australia?s major cancer problems, but we still do not completely understand why certain people are at higher risk than others. This study is focussed on people who have developed melanoma at an early age (under 40yrs) and will compare their family history of cancer, skin features, genetic characteristics and various aspects of their previous sun exposure with people who don?t have melanoma. The large number of people involved and the fact that they will be selected at random from the population of Melbourne, Sydney and Brisbane which have very different melanoma rates, means that the study will be able to clarify what roles genes and environment play in the disease. It is intended to be an international benchmark in this regard, and Australia is the only country in which a study of this scope could be mounted. Potential benefits from this research will be a better understanding of the way sun exposure affects people differently, depending on their genetic makeup, the place of genetic testing in assessing people?s risk of melanoma, particularly if they have relatives with the disease, and way in which skin features like moles should be taken into account in that assessment. Finally, it is likely that better information about the types of genetic susceptibility to melanoma in the population will translate to more effective programs for the prevention of melanoma and for detection of melanomas efficiently at the earliest possible stage.Read moreRead less
Life Course Trajectories And Neuropsychiatric Outcomes In An E-cohort Of High Risk Children Of Mothers With Psychosis
Funder
National Health and Medical Research Council
Funding Amount
$796,484.00
Summary
This study investigates how genetic and environment factors operate over the life course to increase risk of adverse outcomes for children of women with severe mental illness. We examine the clustering of neuropsychiatric outcomes in families and individuals, the role of developmental adverse life events in the risk for these outcomes, and the children's physical morbidity and offending profiles. This is an electronic cohort (e-cohort), constructed by record linkage across many databases.
Gene-environment Interactions And Experience-dependent Plasticity In The Healthy And Diseased Cerebral Cortex
Funder
National Health and Medical Research Council
Funding Amount
$249,250.00
Summary
Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for envi ....Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for environmental factors in disease onset and progression. Following on from our work showing that environmental enrichment delays disease and progression in this mouse model of HD, we are using experimental manipulations of the environment to examine effects on brain degeneration and behaviour. This project aims to investigate gene-environment interactions in HD, focusing on dysfunction of neurons in the cerebral cortex. The combination of behavioural, physiological, anatomical and molecular analysis of HD mice will bring us closer to a comprehensive understanding of HD. This will have implications for the development of new therapies for HD. Our environmental enrichment paradigm may also lead to development of occupational therapy strategies for HD and other neurological disorders. There are at least ten other fatal brain disorders which are caused by the same DNA repeat expansion in other genes. New insights into HD will therefore have implications for the understanding and development of therapeutics for these other DNA repeat expansion brain diseases. Furthermore, another devastating brain disorder which, like HD, involves abnormal protein interactions and dysfunction of the cortex, is Alzheimer's disease. Understanding HD may therefore also have implications for our understanding of Alzheimer's disease. Additionally, analysing control mice in this project will provide new information on mechanisms of plasticity in the normal cortex, which may underlie learning and memory.Read moreRead less
The Predictors Of Prostate Cancer In The Melbourne Collaborative Cohort Study
Funder
National Health and Medical Research Council
Funding Amount
$358,457.00
Summary
In 1990 we set up a long-term study of diet and health. The aim was to measure diet and other risk factors in healthy people in order to see how they might affect future development of cancer. To do this we recruited 41,500 people aged 40 to 69, measured what they ate and drank, and collected information on other aspects of lifestyle, medical history, and family history of common diseases. All had height and weight and blood pressure measured and gave a blood sample. People were selected so that ....In 1990 we set up a long-term study of diet and health. The aim was to measure diet and other risk factors in healthy people in order to see how they might affect future development of cancer. To do this we recruited 41,500 people aged 40 to 69, measured what they ate and drank, and collected information on other aspects of lifestyle, medical history, and family history of common diseases. All had height and weight and blood pressure measured and gave a blood sample. People were selected so that men and women and migrants from Italy and Greece would be included. In this way we could widen the range of dietary habits, other lifestyle factors and genetic variation (measured in DNA from blood). Since then participants have completed another questionnaire and instances of disease have been noted from self reports and from examining medical records. We want to analyse data from 700 men in the study who have developed prostate cancer (PC). First we will analyse data collected on all 17,000 men (collected when joining the study, and at follow up). Next we will use data from only the 700 men with PC and 1400 men who have not developed PC. This study will focus on measuring substances in the blood. We want to measure a range of fats, vitamins, antioxidants and phytoestrogens, as well as male sex hormones and related substances. In the DNA from the blood we plan to measure variations in genes that influence how male sex hormones and other growth factors important in the prostate are produced and used. We will then be able to estimate what affect these factors have on the risk of getting PC. We will also be able to see if any of them act together to make the risk of PC much higher in certain men. This work should identify what lifestyle factors could reduce the risk of PC. It should also identify what genetic variations are associated with increased risk of PC and thus identify a sub group of men who might benefit from early medical attention or from changes in lifestyle.Read moreRead less
LMO2-containing Complexes In Leukemia And Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$803,652.00
Summary
Childhood T-cell leukemias have a poor prognosis for recovery. We are determining, with atomic level precision, how the proteins Lmo2 (also linked to prostate and other cancers) and Tal1, and their binding partners contribute to both normal blood cell development and T-cell leukemia. With this information we are developing reagents that can be used to disrupt disease-causing complexes, and which will lead towards the development of new, specific, therapeutics for leukemias and other cancers.
Role Of FHA Domains As Protein-protein Interaction Modules In Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$191,973.00
Summary
The proper processing of information in cells involves the association of different proteins to signalling complexes. We will decipher the role the so-called FHA module plays in the formation of protein complexes. FHA modules are present in several proteins that are important for the repair of damaged DNA and the stability of chromosomes. Understanding the structure and function of this module will be relevant for various forms of cancer where DNA is damaged.
Genes Controlling The Development Of Lung Disease In Normal And Cystic Fibrosis Mice.
Funder
National Health and Medical Research Council
Funding Amount
$362,582.00
Summary
Patients with cystic fibrosis have a lethal predisposition to bacterial infection which causes irreversible lung disease. It is clear that even when patients carry the same mutation in the defective gene (CFTR), genetic background influences the course of the disease. Very little is known of the nature of these other genes and this proposal will identify those genes which influence the response of the CF lung to pathogens and in doing so may indicate novel therapeutic strategies.