Development And Application Of Novel Bioinformatics Approaches To Identify Pathogenetic Mechanisms Underlying Migraine
Funder
National Health and Medical Research Council
Funding Amount
$320,891.00
Summary
Migraine is a public health problem. Although GWAS lead to robust findings, the mechanisms and therapeutic strategies are unknown. This is caused by limited sample size hampering obtaining large number of SNPs by GWAS. Integrating priori knowledge with bioinformatics studies is promising to discover hidden SNPs. Here, I will develop a novel approach to find novel genetic risk loci and genes by integrating comprehensive knowledge on SNPs and genes with GWAS instead of increasing sample.
Genetic And Phenotype Studies Of Partial Epilepsy In Gypsies
Funder
National Health and Medical Research Council
Funding Amount
$646,136.00
Summary
Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies ....Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies have proved particularly difficult to understand and the numerous genetic studies conducted so far have failed to produce important and replicable results. It is becoming increasingly clear that enormous genetic heterogeneity, with many rare mutations occurring in different affected subjects, will be a major obstacle to understanding the molecular basis of complex epilepsies. In this context, genetically isolated populations, which stem from a small number of ancestors, can be particularly helpful and revealing, since their limited genetic diversity means that the number of genes involved in causing complex epilepsies may be smaller and shared between individuals and families. In this study, we will analyze affected families, as well as non-familial cases of epilepsy, from a genetically isolated population - the European Roma-Gypsies. We will determine the number of potential susceptibility genes involved in familial forms, the overlap and differences between families, as well as the contribution of the genes identified in families to the development of sporadic epilepsy.Read moreRead less
High Resolution Mapping Of Genomic Regions Implicated In Migraine
Funder
National Health and Medical Research Council
Funding Amount
$392,545.00
Summary
Migraine is a frequent, debilitating and painful disorder that affects a significant proportion of the population. Using the diagnostic criteria of the international Headache Society, the prevalence of migraine has been estimated to be approximately 12%, with a recent study in the United States showing that migraine affects 4% of children, 6% of men and 18% of women. The aetiology of migraine is unknown and there are no laboratory based diagnostic tests to identify those who suffer from the diso ....Migraine is a frequent, debilitating and painful disorder that affects a significant proportion of the population. Using the diagnostic criteria of the international Headache Society, the prevalence of migraine has been estimated to be approximately 12%, with a recent study in the United States showing that migraine affects 4% of children, 6% of men and 18% of women. The aetiology of migraine is unknown and there are no laboratory based diagnostic tests to identify those who suffer from the disorder. Clinical diagnosis is currently based on patient symptom descriptions, with individual symptoms being shown to vary with age. Migraine is believed to have a genetic basis with specific environmental factors, such as particular foods, hormonal levels and fatigue, being capable of inducing attacks in predisposed individuals. Migraine shows strong familial aggregation with about 50% of those affected, having another close relative also affected with the disorder. At present the number of genes involved in the disorder is unknown and have not been identified. Recent studies in our laboratory have localised two migraine genes, one to chromosome 19 and the other to the X chromosome. More recently we have also found evidence for a third gene on chromosome 1. This study is aimed at fine scale mapping analysis of these three chromosomal regions in order to pinpoint the location of migraine genes. Our ultimate aim is to identify the molecular causes of this disorder. This would have important implications to both the diagnosis and treatment of migraine.Read moreRead less
Genome-wide Association Study Of Migraine In Women With Endometriosis
Funder
National Health and Medical Research Council
Funding Amount
$320,036.00
Summary
Typical migraine, is a frequent, debilitating and painful disorder that affects people during their most productive years (25% of females and 7.5% of males). Women suffering endometriosis (a painful gynecologic disorder affecting up to 10% of women) are at an increased risk of suffering migraine headaches. Our proposed collection of migraine phenotype data on our endometriosis cohort will facilitate identification of genes underlying both disorders.
Identifying Rare Genetic Variants Conferring Susceptibility To Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$293,898.00
Summary
Recently there has been success in identifying common genetic variants that confer susceptibility to multiple sclerosis. The variants that have been discovered so far have modest effects on risk of disease, and only explain a small proportion of familial aggregation of disease. In this study we aim to identify rarer genetic variants that have stronger effects on risk of disease, using new statistical methods and new methods to sequence very large amounts of DNA.
Molecular Genetics Of Hereditary Motor And Sensory Neuropathy With Pyramidal Signs
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
This project aims to determine the molecular cause of hereditary motor neuropathies with pyramidal signs by chromosomal linkage studies and to screen suitable families to locate genes with disease causing mutations. We propose to use the resources of the human genome project to locate the defective gene. In previous studies we have used these methods to identify genes of two other hereditary diseases of nerve. Our data suggests that this disorder forms part of the largest group of hereditary neu ....This project aims to determine the molecular cause of hereditary motor neuropathies with pyramidal signs by chromosomal linkage studies and to screen suitable families to locate genes with disease causing mutations. We propose to use the resources of the human genome project to locate the defective gene. In previous studies we have used these methods to identify genes of two other hereditary diseases of nerve. Our data suggests that this disorder forms part of the largest group of hereditary neuropathies yet to be defined. Because this disorder affects long spinal cord neurones, identifying the mutated gene and studying its function may shed light on possible mechanisms involved in other spinal cord diseases. This research is a systematic search and should lead to identifying the abnormal gene causing disease. Once the gene involved is known then an effective diagnostic test will be developed. When a test for the disease is available, it is likely that we will find that the disorder is more common than previously recognised. Knowledge of the function of the gene will lead to an understanding of how the disease develops and will eventually enable development of effective treatments.Read moreRead less
Genetic Analysis Of Migraine And Comorbid Psychiatric Disorders Using Twin Families
Funder
National Health and Medical Research Council
Funding Amount
$554,450.00
Summary
Typical migraine, is a frequent, debilitating and painful disorder that normally affects people during their most productive years (up to 25% of females and 7.5% of males in Western populations). Additionally, several studies have demonstrated a cross-sectional relation between psychiatric disorders (namely anxiety and depression) and migraine in community samples. The World Health Organization (WHO) recently identified migraine and major depression among the world's top 20 leading causes of dis ....Typical migraine, is a frequent, debilitating and painful disorder that normally affects people during their most productive years (up to 25% of females and 7.5% of males in Western populations). Additionally, several studies have demonstrated a cross-sectional relation between psychiatric disorders (namely anxiety and depression) and migraine in community samples. The World Health Organization (WHO) recently identified migraine and major depression among the world's top 20 leading causes of disability, with an impact that extends far past the suffering individual, to the family and community. In both sexes of all ages, depression and migraine are the 1st and 19th leading causes of disability affected life years. Although both migraine and depression are highly prevalent in our society, their aetiologies remain relatively obscure and there are no laboratory based diagnostic tests that identify those who suffer from the disorders. Because so little is known about them, a positional cloning approach is the only feasible way to identify the molecular mechanisms underlying these disorders. This project will collect a sample with sufficient power to perform a genome wide linkage screen to i) identify novel susceptibility genes, and ii) confirm previously reported susceptibility genes for migraine and co-occurring psychiatric disorders. The susceptibility genes identified (and confirmed) in this sample will provide clues to the further elucidation of the complex molecular pathways of migraine (and co-occurring psychiatric disorders) and, finally, will help in the development of diagnostic tests and rational treatment strategies.Read moreRead less
Developing methods for the analysis of massively parallel sequencing data in family studies. This project will develop analytical methods to use the latest, high-throughput method of generating sequencing data, i.e. the letters of the human genome alphabet. These tools will be used to identify the causal mutations in families with inherited disorders, leading to diagnostic tests for these families.
Genetic Bases For Charcot-Marie-Tooth And Hereditary Sensory Type 1 Neuropathies
Funder
National Health and Medical Research Council
Funding Amount
$618,055.00
Summary
This project aims to identify the defective gene in a hereditary disease of peripheral nerve. The hereditary disorders of peripheral nerve form the commonest group of human genetic diseases, collectively called Charcot-Marie-Tooth neuropathy. Although few hereditary nerve diseases are fatal most cause lifelong disability. All cause weakness of the lower legs and later weakness and wasting of the muscles of the arm and hand. Affected individuals have difficulty running, frequent falls with gradua ....This project aims to identify the defective gene in a hereditary disease of peripheral nerve. The hereditary disorders of peripheral nerve form the commonest group of human genetic diseases, collectively called Charcot-Marie-Tooth neuropathy. Although few hereditary nerve diseases are fatal most cause lifelong disability. All cause weakness of the lower legs and later weakness and wasting of the muscles of the arm and hand. Affected individuals have difficulty running, frequent falls with gradually increasing disability eventually requiring splints and other walking aids. We propose to use the newly developed resources of the human genome project to locate the defective gene. In previous studies we have used these methods to locate the defective genes of 2 other hereditary diseases of nerve. In this study we propose to investigate a newly recognised form of CMT called intermediate CMT. Intermediate CMT has characteristics intermediate between the better known forms of CMT affecting the nerve itself (the axon) or the nerve insulation (the surrounding myelin sheath). The disorder may therefore affect both components of nerve. The affected gene may mediate communication between the nerve and its sheath. This research should give valuable insight into the mechanisms responsible for the maintenance of normal nerve. Finding the gene may therefore have relevance to many other diseases of nerve. This research is a systematic search and should lead to the abnormal gene causing the disease. Once the gene involved is known then an effective test will be developed. When we can test for the disease, we probably will find that the disorder is much more common than previously recognised. Knowledge of the function of this gene will lead to an understanding of how the disease develops and will eventually lead to effective treatments.Read moreRead less
Understanding the molecular mechanisms of intellectual disability. Intellectual disability is frequent in the population, with one in every fifty people in the world directly affected. This project will improve our understanding of the correct development and function of the brain required for cognition by investigating specific roles and regulation of key molecules involved.