Rare Genetic Risk and Gene Networks in Tauopathy

The objectives of this proposal are to identify rare genetic risk factors that are unique to or shared by Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP).

We hypothesize we will identify a set of rare genetic risk factors associated with AD and another set of rare genetic risk factors associated with PSP, some of which may be shared between AD and PSP. To determine shared or unique genetic risk, we will compare AD to controls and PSP to controls. Both analyses will use the same controls and have similar number of cases. AD subjects will be included from Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Neuroimaging Initiative, and Accelerating Medicines Partnership – Alzheimer’s disease. From these studies, we will include adult controls. We will use roughly 1900 whole genomes from PSP subjects. Given the availability of AD sequencing, we will replicate the association of rare genetic risk with an independent holdout AD dataset, which will include AD and controls from the ADSP Follow Up Phase. We will also validate our finding in multi-ethnic cohorts from the ADSP.

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 will incorporate network connectivity in rare variant statistical tests and prioritize functional noncoding variants will identify rare genetic risk factors in AD and PSP by overcoming deficiencies in traditional methods. Analyzing rare variants in protein coding, promoter and distal noncoding regions, we will compare the proposed network and non-coding prioritization methods to traditional gene-based, unprioritized non-coding methods.

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.