Academic journal article Environmental Health Perspectives

Announcements: Fellowships, Grants, & Awards

Academic journal article Environmental Health Perspectives

Announcements: Fellowships, Grants, & Awards

Article excerpt

Gene Discovery for Complex Neurological and Neurobehavioral Disorders

The goal of this program announcement (PA) is to promote the identification of susceptibility genes for complex neurological and neurobehavioral disorders. For this PA, complex disorders are defined as those caused by the interaction of multiple genes or by a combination of genetic and environmental risk factors. Many of these disorders are relatively common and clinically heterogeneous. Projects focusing on any phase of the gene discovery process, from initial patient ascertainment to positional cloning, are appropriate. Novel approaches, including the use of intermediate phenotypes that potentially underlie complex disorders, are also encouraged.

Genetic factors contribute to a broad spectrum of neurological and neurobehavioral diseases. During the last decade, genes that cause many single-gene neurological disorders have been identified (e.g., Huntington disease, neurofibromatosis, Rett syndrome). For these disorders, familial inheritance patterns follow the rules of Mendelian segregation. For many common disorders (e.g., stroke, Parkinson disease, epilepsy, Alzheimer disease, attention deficit/hyperactivity disorder), inheritance patterns are more complex, and progress in identifying genes that affect susceptibility and disease outcome has been slow. Such disorders appear to be caused by multiple genes or by a combination of genetic and environmental factors.

The wealth of genomic information becoming available through the Human Genome Project is providing a powerful tool for gene discovery. Once disease susceptibility genes are identified, it will be possible to study gene function, investigate disease pathophysiology, and explore strategies for therapeutic intervention. Gene identification will also provide a basis for improved diagnostic classification, genetic counseling, and understanding of pharmacogenetic interactions.

Applications submitted in response to this PA should focus on the identification of susceptibility genes that contribute to genetically complex disorders affecting the nervous system or to the phenotypes that underlie these disorders. Proposed studies can involve the initial collection of biomaterials and clinical information from a patient population or the subsequent application of genetic or molecular strategies for gene localization. Possible methodologies include, but are not limited to, traditional linkage analysis, sibling pair and affected-pedigree-member methods, case-control or family-based association studies, linkage disequilibrium mapping in genetically isolated populations, candidate gene analysis, cytogenetic studies to identify chromosomal abnormalities associated with a disorder, and positional cloning. This PA focuses on human studies; projects using invertebrate or vertebrate animal models are not appropriate. As gene discovery requires collaborations among epidemiologists, geneticists, clinicians, molecular biologists, and other researchers, multidisciplinary projects are encouraged.

Because complex disorders are clinically and genetically heterogeneous, the identification of susceptibility genes by standard genetic methodologies has been difficult. Therefore, the development of novel approaches and the use of state-of-the-art technologies are essential. An example of such an emerging strategy is the use of intermediate phenotypes (endophenotypes) to facilitate gene discovery. Endophenotypes are characteristics that may represent more proximal readouts of gene function. Examples include enzyme activities, plasma levels of particular neurotransmitters, changes in gene expression, structural or functional phenotypes detected by brain imaging, and behavioral or cognitive deficits. Classifying patients based on such parameters has, in certain cases, accelerated the process of gene discovery. The use of this strategy is appropriate if the applicant 1) demonstrates that the phenotype in question can be reliably and accurately measured, 2) provides evidence suggesting that the phenotype underlies a particular neurological or neurobehavioral disorder or group of disorders, and 3) makes a strong case that use of this phenotype will facilitate the discovery of susceptibility genes. …

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