A genomewide association study of neurodegeneration in a characterized and genetically defined population

• Ireland

Health Research Board

1693469

01-12-2007

60

• Motor neurone diseases

neurodegeneration; amyotrophic lateral sclerosis; clinical phenotype; frontotemporal dementia; genetic susceptibility

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder of unknown etiology. Sporadic ALS is a complex genetic disease, in which ethnic/genetic background and environmental risks interact leading to the process of neurodegeneration. My group has identified a novel series of loss of function mutations in ANG, a gene not hitherto associated with neurodegeneration. Although originally considered as a pure motor degeneration, it is now recognized that considerable overlap exists between ALS and other neurodegenerative diseases, particularly frontotemporal dementia(FTD). Despite recent advances, common pathways shared between ALS and other neurodegenerative disease remain to be fully elucidated. The principal research hypothesis underling this project is that novel genes for neurodegeneration can be identified by phenotype/genotype characterization of a genetically homogenous population. This unique project will collect clinical phenotypes of ALS in the Irish population that will be stratified according to strict clinical and neuropsychological criteria. This clinical dataset will be complemented by an associated genetic resource that will permit detailed genetic characterization by whole genome association. This process will allow detailed phenotype genotype correlation, the later generation of endophenotypes within ALS kindreds and thus dissection of common pathways involved in the process of neurodegeneration. This work is likely to lead to the discovery of novel genes associated with neurdegeneration, and new pathways that can be targeted for therapeutic intervention.

• Basic research