Use Of Expression Profiling To Identify Genes Influencing Cardiovascular Risk In The Norfolk Island Population Isolate
Funder
National Health and Medical Research Council
Funding Amount
$697,409.00
Summary
This study will use a unique population isolate from Norfolk Island. We aim to identify genes that play a role in cardiovascular disease risk. Norfolk has a population of ~1200 permanent residents, most of whom are direct descendents of 18th century English Bounty mutineers and Polynesian women. We will undertake gene expression mapping to identify genomic loci that influence cardiovascular disease using samples from this population isolate.
Functional Variants Of RUNX2 Related To Bone Density
Funder
National Health and Medical Research Council
Funding Amount
$451,938.00
Summary
Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ....Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ancestral form of this gene. We now need to know how this change in this promoter alters bone density and we are following up on observations that other important transcription factors bind to the variable site in the promoter. Furthermore, we have assembled a large collection of samples from people who have had extensive measures of bone density and arthritis in order to accurately measure the impact of this gene on bone density, osteoarthritis and bone fracture. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. Such mutations in a region called the Q-repeat are rather common, 1-200 people are carriers. Our data show that these mutant proteins are not as efficient at their task of regulating other genes. We now want to know how this occurs in a molecular sense, since it is known that the Runx2 protein resides in the nucleus of the cell and interacts with many other regulators. This part of the project is being done with one of the world experts on gene regulation in bone cells. Since RUNX2 is a master regulator of the cells that make bone, this gives hope that it may be possible to alter bone formation through this master regulator.Read moreRead less
High scorers on the personality trait neuroticism are at greatly increased risk of major depression and other neurotic disorders. Neuroticism is a personality trait that shows considerable stability over adulthood. It has a strong genetic basis and it seems that the same genes also determine risk of depression, anxiety and other neuroses. By selecting twins and sibs extremely discordant and concordant (EDAC) for neuroticism we can greatly reduce the cost and increase the power to find genes infl ....High scorers on the personality trait neuroticism are at greatly increased risk of major depression and other neurotic disorders. Neuroticism is a personality trait that shows considerable stability over adulthood. It has a strong genetic basis and it seems that the same genes also determine risk of depression, anxiety and other neuroses. By selecting twins and sibs extremely discordant and concordant (EDAC) for neuroticism we can greatly reduce the cost and increase the power to find genes influencing depression. Questionnaire responses and interviews from 15,027 Australian twins and 11,389 of their family members were reviewed to identify individuals with neuroticism scores in the top and bottom 10%. These individuals were invited to participate in a structured psychiatric interview by telephone, and to give a blood sample. Participation and DNA sampling rates were high and there was minimal evident participation bias. DNA was collected from 2,926 individuals from 884 families including 1,333 EDAC sibling pairs and over 795 parents. A preliminary genome scan on one third of this sample yields several linkage peaks suggesting genes of major effect that appear to replicate findings in similar studies conducted in Holland and England. Given these results it is highly desirable that we obtain a genome scan on the remainder of selected extreme sample. Another one third of this sample is currently being genotyped in America and here we request funds to genotype the remaining third. .If we are successful in identifying genes underlying neuroticism, we will also be able to analyse their contribution to depression and anxiety. This could lead to better drug treatments.Read moreRead less
Twin and family studies show schizophrenia has a genetic basis. Attempts to find and characterise the underlying genes have not been successful so far. A main reason for this is that insufficient attention has been paid to the complexity of the underlying genetic architecture of the disorder. The pathway from genes to symptoms of schizophrenia is likely to involve elementary processes at neuronal and neural circuitry levels that vary between individuals and this variation is reflected in a grade ....Twin and family studies show schizophrenia has a genetic basis. Attempts to find and characterise the underlying genes have not been successful so far. A main reason for this is that insufficient attention has been paid to the complexity of the underlying genetic architecture of the disorder. The pathway from genes to symptoms of schizophrenia is likely to involve elementary processes at neuronal and neural circuitry levels that vary between individuals and this variation is reflected in a graded susceptibility to schizophrenia. During the last three years we have recruited a large number of families with at least one family member diagnosed with schizophrenia. The proband and all participating first-degree relatives have been assessed with a neurocognitive test battery including measures of sustained attention, working memory, speed of information processing, auditory verbal learning and executive function. Analysis of the neurocognitive data on this sample produced strong evidence that several measures are altered in patients with schizophrenia and a proportion of their asymptomatic first-degree relatives compared to unrelated normal controls. In the study we will systematically search the human genome for DNA markers linked to these measures. This will set the stage for the systematic search and characterisation of the underlying genes. This will allow us to better understand the predisposition to develop schizophrenia. In the individual case it is likely that this vulnerability results from a high-risk combination of a number of relatively common alleles which contribute to basic neural processes.Read moreRead less
Fine Mapping Of The ADH Region For Alcohol Metabolism, Use And Dependence
Funder
National Health and Medical Research Council
Funding Amount
$215,690.00
Summary
It is widely known that alcohol use and alcohol dependence can cause many social problems and morbidity. We know that social and and cultural factors can affect the possibility of becoming alcohol dependent. We also know that inheritance plays a major role in the risk of becoming dependent upon alcohol. Two inherited causes or genes have already been identified as causing some people to avoid alcohol and so have less chance of becoming dependent upon it. Clues as to why this happens come from wh ....It is widely known that alcohol use and alcohol dependence can cause many social problems and morbidity. We know that social and and cultural factors can affect the possibility of becoming alcohol dependent. We also know that inheritance plays a major role in the risk of becoming dependent upon alcohol. Two inherited causes or genes have already been identified as causing some people to avoid alcohol and so have less chance of becoming dependent upon it. Clues as to why this happens come from what happens to alcohol following a drink. The body detoxifies itself of alcohol in the liver. There it is converted to very highly toxic acetaldehyde and this is normally rapidly removed by a protein called aldehyde dehydrogenase. Some people do not have a normally functioning form of this protein and cannot remove the acetaldehyde from their bodies. They suffer unpleasant side effects such as nausea, facial flushing and sickness. Consequently they learn by experience to avoid alcohol use and are less likely to develop dependence. We now know that even people with a normally inherited form of aldehyde dehydrogenase can have a lowered risk of dependence. The rate at which our livers convert alcohol to actetaldehyde is also a key factor. Those who are inherently quick at this process again learn to avoid alcohol, others are more at risk. The hypothesis will be tested with a unique set of twins who have provided us with detailed information on how quickly they detoxify alcohol and of their drinking habits for over 20 years. Collectively they will enable us to determine if there is a major genetic influence on alcohol use and dependence that is caused by inter-individual differences in a gene for alcohol metabolism. The DNA of these twins will be used to locate mutations that we predict have a common effect upon our measures of alcohol detoxification, drinking habits and risk of alcoholism.Read moreRead less
Morphological Determinants Of Neurotransmission In Autonomic Ganglia.
Funder
National Health and Medical Research Council
Funding Amount
$450,111.00
Summary
The nervous system consists of billions of nerve cells that are connected together in special ways to process information about the outside world and our internal state and then generate the appropriate responses of our body to this information. To understand the complex working of the brain and its nerves, we have to understand how all these nerves are connected to each other. We are interested in the nerves that control the functions of the internal organs, such as arteries, glands and the gut ....The nervous system consists of billions of nerve cells that are connected together in special ways to process information about the outside world and our internal state and then generate the appropriate responses of our body to this information. To understand the complex working of the brain and its nerves, we have to understand how all these nerves are connected to each other. We are interested in the nerves that control the functions of the internal organs, such as arteries, glands and the gut. The brain controls these functions automatically, so we usually are not directly aware of their activity. The instructions to change the activity of the internal organs are sent from the brain down the spinal cord. The information is then sent from the spinal cord to the organs via a special set of nerves. However, instead of going directly to their targets, these nerves make connections with yet another set of nerves, which then go on to make the final connections with the appropriate target organs. We know a lot about these final nerve cells, including how big they are, how complicated they look, and what kinds of chemicals they use to send messages to the organs that they control. However, we still do not very much about how all these nerves are connected to each other. In this project we will use different types of modern microscopes that use either lasers or electron beams to look directly at the nerves and their connections. We then will use computerised models to construct a detailed map of the pathways taken by the nerves on their way to their target organs. By knowing how the nerves are connected to each other in these pathways, we will be able to understand how the instructions of the brain are modified depending on what other things are going on in the body at the same time. This information will be vital to help us appreciate how the nerves work when we get sick or injured.Read moreRead less
MALE OSTEOPOROSIS: A POPULATION-BASED STUDY IN GEELONG
Funder
National Health and Medical Research Council
Funding Amount
$432,645.00
Summary
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is i ....Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is increasingly being recognised in men. In Australia, 39% of all fractures occur in men and prognosis for fracture in men is worse than in women. A consequence of increasing male longevity is that osteoporosis will affect a growing number of Australian men. It is anticipated that between 1996 and 2051, the number of men with fracture will double, with a 4-fold increase in the number of male hip fractures. Unless the problem of osteoporosis in men is addressed and effective interventions are implemented, the substantial health burden imposed by age-related fractures will continue to escalate. In this case-control study of fracture risk in men, men with fractures (cases) will be identified prospectively for 3 years from radiological reports. Controls will be selected concurrently, at random from electoral rolls. Anticipated number of cases and controls are 800 and 1400, respectively. Cases and controls will be characterised for risk factors for fracture: bone density and bone geometry will be measured, serum samples collected, and diet, lifestyle and medical history documented by questionnaire. The advantage of this type of data is that information from patients with fracture will be used to tell us about the risk of fracture in healthy, unaffected men and about the characteristics of the Australian male population at risk for fracture. The information can be used in decision making for the individual and in policy making for the whole population.Read moreRead less
Australian Genomewide Association Study In Osteoporosis
Funder
National Health and Medical Research Council
Funding Amount
$882,722.00
Summary
Osteoporosis is a common condition in which bone strength is reduced due to reduced amount and quality of bone. Reduced bone strength means an increased risk of fracture. Osteoporotic fractures occur in 1 in 2 women and 1 in 3 men in their lifetime, and the likelihood of suffering osteoporotic fracture increases with age. Most of the risk of developing osteoporosis is genetic, but few of the genes involved have been identified. Our goal is to identify those genes.
Structural And Diffusion Tensor Neuroimaging In Twins Concordant And Discordant For Psychosis.
Funder
National Health and Medical Research Council
Funding Amount
$477,375.00
Summary
Measures from specialised brain scans i.e. MRI's (Magnetic Resonance Imaging) have suggested that several areas in the brain are different in those individuals who suffer from psychosis compared to those who don't. Evaluations of these brain differences have helped us better understand the nature of these illnesses. For example, frontal lobe dysfunction has been linked with the loss of ability to plan and organize information, seen in those who have schizophrenia. These measures may also help cl ....Measures from specialised brain scans i.e. MRI's (Magnetic Resonance Imaging) have suggested that several areas in the brain are different in those individuals who suffer from psychosis compared to those who don't. Evaluations of these brain differences have helped us better understand the nature of these illnesses. For example, frontal lobe dysfunction has been linked with the loss of ability to plan and organize information, seen in those who have schizophrenia. These measures may also help clarify the relationship between the genetic and environmental factors contributing to the development of these disorders. One of the best ways to investigate this relationship is the use of a twin study design. The Australian study of twins with psychosis will recruit dizygotic (DZ) and monozygotic (MZ) twin pairs in which at least one twin is affected by a psychotic disorder, plus control twin pairs matched for age, sex and zygosity. Measures derived from MRI scans will be collected in an attempt to further define specific brain regions reported to be different in psychosis. In addition Diffusion Tensor Imaging (DTI) will be used to visualize white matter tracts in the brain. The twin study design will allow us to differentiate genetic and environmental factors associated with these brain measures and help evaluate the potential for these measures to genetically define sub-groups of individuals with psychotic disorders. The identification of these subgroups would facilitate the search for susceptibility genes. Additionally, this study will help clarify the possible clinical overlap between affective (i.e. bipolar affective disorder) and non-affective (i.e. schizophrenia) psychotic disorders. The information obtained from this study has the potential to greatly improve our understanding of caustive factors in psychosis, which may also lead to earlier diagnosis and treatment, thereby improving prognosis.Read moreRead less