Neurodegenerative diseases associated with aging are clinically and pathologically defined syndromes with heterogeneous genetic endophenotypes, some of which are unique to one disease while others are shared across diseases. Despite the economic and healthcare burden, treatments targeted to endophenotypes are not available for neurodegenerative tauopathies such as Alzheimer?s disease (AD) and Progressive Supranuclear Palsy (PSP). AD and PSP are pathologically related by abnormal tau protein inclusions and the tau gene is a shared genetic risk factor. Unique genetic risk in common variants have been identified for AD (ABCA7, BIN1) and PSP (STX6, EIF2AK3). However, a significant part of genetic heritability remains unexplained; a proportion of which is likely due to rare variants. Identification of rare genetic risk factors may delineate the endophenotypes of AD and PSP, unlocking future therapeutic targets. The objectives of this proposal are to identify and validate rare genetic risk factors that are unique to or shared by AD and PSP. The long-term goal is to realize precision medicine for neurodegenerative dementias by leveraging genomics and biomedical informatics. Traditional rare variant analyses have limited power due to the large number of variants and small variant effect size. Although one solution is to group variants into genes, genes do not act in isolation, but rather interact with one another in networks. Grouping variants in a network can improve power. Additionally, since most genetic risk lies in large noncoding regions of the genome, focusing analyses on noncoding regulatory regions should further increase power. We hypothesize that incorporating network connectivity in rare variant statistical tests and prioritizing functional noncoding variants followed by validation will identify rare genetic risk factors in AD and PSP by overcoming deficiencies in traditional methods. To test this hypothesis, we propose the following aims.
Aim 1 is to develop and apply rare variant statistical tests that incorporate network connectivity to identify dementia risk genes.
Aim 2 is to identify noncoding rare genetic risk variants by developing a noncoding prioritization and gene assignment strategy.
Aim 3 is to validate rare variants that are unique to or shared by AD and PSP. The advances from these studies will expand our understanding of dementia risk and provide new targets for therapeutic development in neurodegenerative disease. The K08 training will build on my previous strengths in clinical informatics to gain expertise in genetics, genome informatics and functional genomics. My mentorship team will consist of faculty with expertise in these domains and clinical care. We will have regular meetings and monitor progress. The environment at UCLA includes interdepartmental collaborations, powerful computing resources, and genetic laboratory resources to complete the aims. The career development plan forges a pathway to become a clinician-scientist.
Neurodegenerative diseases including Alzheimer?s disease and Progressive Supranuclear Palsy are characterized by abnormal tau protein accumulation and do not currently have disease modifying treatments. Analyzing whole genome sequencing with novel genomic and genome informatic methods may identify rare genetic risk factors that lead to these diseases. The shared or unique rare genetic risk factors of Alzheimer?s disease and Progressive Supranuclear Palsy may become future therapeutic targets.
