Novel Statistical Methods For Genetic Epidemiology
Funder
National Health and Medical Research Council
Funding Amount
$481,505.00
Summary
We are in the midst of a genomics revolution that is transforming epidemiology, medicine and drug discovery. However, the scarcity of sophisticated statistical techniques to deal with the complicated problems inherent in genetic investigations of complex diseases is currently the critical factor limiting the success of human gene discovery programs. Statistical genetic methodology is currently one of the fastest developing areas of epidemiology. In information-intensive' areas such as genetic ep ....We are in the midst of a genomics revolution that is transforming epidemiology, medicine and drug discovery. However, the scarcity of sophisticated statistical techniques to deal with the complicated problems inherent in genetic investigations of complex diseases is currently the critical factor limiting the success of human gene discovery programs. Statistical genetic methodology is currently one of the fastest developing areas of epidemiology. In information-intensive' areas such as genetic epidemiology, genomics, and proteomics, there is a high demand for data analysis and statistical skills. WA has some world class expertise in statistical science, both in academia and in industry. However, this expertise has not yet been applied in a system way to genetic data analysis. We propose to undertake advanced methodological research in statistical genetics and bioinformatics, to produce easy-to-use and accessible software tools and resources that allow methodological advances to be accessed by the Australian research community, and to apply our new methods and tools both to specific disease research and to the developing human genome epidemiology (HuGE) enterprise in WA. These new initiatives in methodological research will draw together a number of currently separate research strands and will provide new tools and resources that will allow applied Australian programs to improve the efficiency of their research into the causes of important. Methodological development in both bioinformatics and statistical genetics are recognized international areas of need.Read moreRead less
Variation And Inheritance Of Retrotransposon Epigenotype In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$355,500.00
Summary
It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way gene ....It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way genes are used. Epigenetic factors can be passed from one generation to the next like the DNA itself, and this can make it difficult to know if a trait is encoded in the DNA itself or is epigenetic. We have found that some epigenetic traits in mice are caused by retrotransposons, which are parasitic elements that reside in and among genes, and can reproduce themselves, but do not have any known function (nearly half the human genome is made up of retrotransposons). Retrotransposons are generally kept silent by epigenetic factors, but may sometimes become active; when they do they may disturb normal patterns of gene activity and cause changes in traits and even disease. Much variation in humans may thus be due to variation in the epigenetic state (epigenotype) of retrotransposons. We propose to investigate variation and inheritance of epigenotype in mice, focussing on retrotransposons. We will use simple methods to compare epigenotype of a number of retrotransposons in genetically identical mice, and we will ask if any differences we find are heritable. We will also investigate the resetting of epigenotype the point in development when epigenetic factors are cleared and reset. We suspect that this occurs in early development. These studies may reveal a system of variation and inheritance with rules completely different from those found by Mendel, which may have a pervasive influence on traits, including sporadic diseases in humans.Read moreRead less
Development And Evaluation Of Statistical Methods And Software For Analysis Of Complex Genetic Disease Data
Funder
National Health and Medical Research Council
Funding Amount
$1,250,371.00
Summary
What are the major factors underpinning complex genetic diseases like diabetes, bipolar disorder or cancer? To answer this question new tools are needed, including software for mining the human genome with interactions between the genome and environment being incorporated. This is our focus. It will form the basis of a superior understanding of the overall process leading to disease and hence better predictions with important ramifications for new treatments and health care planning.
PIPK2A, A Candidate Gene For Schizophrenia: Impact Of DNA Polymorphisms On Gene- And Protein Expression And -function
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the ....Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the disorder. Evidence for genetic factors has been obtained and consistently confirmed by family-, twin-, and adoption studies. After many years of research, evidence for several genes, conferring susceptibility to schizophrenia, has been obtained by gene finding approaches applied to large family samples with multiple affected members. However, these genes have to be considered as candidates until more is known about their impact on brain function resulting in schizophrenic disorders. We have dissected a gene locus on chromosome 10p detected by linkage analysis by several groups including ourselves. We obtained statistical evidence for association of DNA sequence variants in the gene encoding the enzyme phosphatidyl-4-phosphate 5-kinase with schizophrenia. This enzyme is a critical component of the phosphoinositide pathways, which are involved in cell signalling. Our aim is to identify a possible dysfunction in the pathways. We will search for mutations involved in function or dysfunction of the enzyme. We will investigate gene- and protein expression and enzyme function in lymphoblast cell cultures and in post mortem brain tissue. Our ultimate goal is to characterise the possible impairment of intracellular cell signalling and thus identify molecular targets for development of novel and specific pharmacological treatments that have the potential to replace the currently available medication which is symptom-oriented and usually accompanied by severe adverse effects.Read moreRead less
Identification Of Schizophrenia Susceptibility Genes: A Collaborative Project With The University Of Indonesia
Funder
National Health and Medical Research Council
Funding Amount
$546,825.00
Summary
Schizophrenia is present in all populations at a similar incidence. The project aims to identify genetic risk factors in three genomic regions previously detected by us in a genome-scan for genetic linkage in 152 Indonesian families. Colleagues at the University of Indonesia will collect an additional sample of 2000 individuals for replication. This sample will be available for research in Australia. Knowledge of risk factors will aid in diagnosis, prevention, and development of novel therapies.
From Linkage To Genes Conferring Susceptibility To Schizophrenia: Investigation Of Candidate Genes On Chromosome 6p
Funder
National Health and Medical Research Council
Funding Amount
$462,250.00
Summary
Schizophrenia is a potentially disabling disorder with severe impact on the individual, the family and the community. The risk that a child born today will develop schizophrenia is about 1%. Genetic factors play a major predisposing role in schizophrenia, but environmental factors contribute as well. The molecular causes of schizophrenia are yet to be discovered, as knowledge about complex brain functions and their disorders is rapidly increasing. The identification and characterisation of genet ....Schizophrenia is a potentially disabling disorder with severe impact on the individual, the family and the community. The risk that a child born today will develop schizophrenia is about 1%. Genetic factors play a major predisposing role in schizophrenia, but environmental factors contribute as well. The molecular causes of schizophrenia are yet to be discovered, as knowledge about complex brain functions and their disorders is rapidly increasing. The identification and characterisation of genetic factors involved in brain function and dysfunction is likely to bring about novel insights into the neural and molecular mechanisms underlying schizophrenia. There is evidence, reported by several groups including our own, that genes, co-segregating with schizophrenia in families are located in a region on chromosome 6p. By fine-grain genetic dissection of this region, we and others have found that the gene coding for the protein dysbindin is associated with schizophrenia. Our aim is to identify the DNA variant(s) in the dysbindin gene, as well as variants in other candidate genes that may be located in chromosome 6p. We will use state-of-the art methods and information on genes and DNA variants, made available through the Human Genome Project. Once genetic variants are identified, we will analyse gene expression in post mortem brain tissue of persons with schizophrenia and study the distribution and function of the proteins coded by the identified genes. Our ultimate goal is to identify specific genetic factors involved in the brain dysfunction characterising schizophrenia. If successful, this should lead to clues about the causes of the disorder. In addition, the study will contribute to the development of methods for early diagnosis and prevention. Possibly, the most important outcome will be the identification of molecular targets for novel and more specific pharmacological treatments that may eventually replace current symptom-oriented antipsychotic medications.Read moreRead less
Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the ....Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the identification of the genetic basis of the disease has proved exceedingly difficult, with numerous studies producing no definitive data. The lack of convincing results has been interpreted as an indication of complex genetic mechanisms and underlying differences between affected families and ethnic groups. Genetically isolated populations, where most individuals descend from a small number of founders, are believed to hold great potential for understanding the genetic basis of complex diseases, such as bipolar disorder. Affected subjects in such populations are likely to share the same predisposing genes, making these genes easier to identify. During the last 10 years, we have been involved in the study of bipolar disorder in one such population, with very promising results. In this project, we propose to take the research further by collecting more affected families, confirming the current positive findings and narrowing down the search to a small region, possibly a single gene. If successful, the study will be a major breakthrough which, by identifying a molecular pathway and disease mechanism, will contribute valuable and generally valid information on the biological basis of mood disorders.Read moreRead less
The Identification Of A Novel NIDDM Susceptibility Gene Localised To Human Chromosome 12q
Funder
National Health and Medical Research Council
Funding Amount
$438,055.00
Summary
Non-insulin dependent diabetes mellitus (adult-onset diabetes) is very common in Australia and is a major public health problem. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 3% of the Australian population have adult-onset diabetes, and very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that an inherited tende ....Non-insulin dependent diabetes mellitus (adult-onset diabetes) is very common in Australia and is a major public health problem. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 3% of the Australian population have adult-onset diabetes, and very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that an inherited tendency is important. By finding genes which cause diabetes we have the opportunity to unravel much of the mystery of this condition. This research program will find genes which cause diabetes by searching for them in large pedigrees in which many family members are affected by diabetes. Finding the genes which cause diabetes will have a significant impact in at least three major ways. Firstly, it will increase our understanding of the disease process. Secondly, it will be possible to develop tests to identify people at risk of diabetes at a very early stage so that therapy can be introduced and complications averted. Thirdly, it will be possible to develop new and more effective approaches for the prevention and treatment of diabetes.Read moreRead less
Chronic or extreme reactions to stress can lead to pathological conditions such as long term anxiety states, depression and panic disorders. Stress related disease also contributes to other major health problems such as heart disease and disorders of the immune system. These disease states include some of the major medical problems of our times. This proposal is to define genes which may be involved in stress responsiveness, to further understand and treat stress related disease.
Heroin Dependence In WA: Identification Of Candidate Genes Involved In Susceptibility And Treatment Outcome
Funder
National Health and Medical Research Council
Funding Amount
$560,797.00
Summary
We will address identification of genetic factors which are important for the development of heroin addiction. In addition, we will correlate variation in genes involved in metabolism of heroin as well as the drugs used to treat heroin addiction with treatment outcome. Once these genetic factors are identified it will allow earlier intervention for treatment. In addition, it will allow identifying which treatment option might be most successful for the single individual.