Effects of genetic variation in regulatory regions near ADRD-associated genes and replication of genetic findings in early-onset dementias

We seek access to ADSP data for two purposes. First, my lab is focused on understanding regulatory mechanisms of rare non-coding variation in neurodegeneration-associated loci. As a part of these efforts, we have generated data internally including 10X multiomics (matched single nucleus RNA-seq and ATAC-seq) and genome-wide restriction fragment resolution HiC data, which, along with publicly available data, we have used to nominate regulatory elements for neurodegeneration-associated genes. One question is if genetic variation in cases is enriched in these regulatory regions compared to controls, which we will use ADSP data to assess.

As a second independent effort, we are a part of collaborations with the Yokoyama lab at UCSF and the Kosik lab at UCSB as well as The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) to analyze genomes for early onset Alzheimer’s and frontotemporal dementia cohorts compared to unaffected controls. A critical part of these efforts is replication of any findings in independent cohorts. Access to Alzheimer's Disease Sequencing Project (ADSP) data is ideal for this purpose. We will analyze ADSP data for association signals identified in our independent cohorts using either single variant or burden analysis approaches. Phenotypic characteristics that will be evaluated in association with genetic variants will be either case/control status or age of symptom onset as available. Although we conduct these projects as collaborations, this application is for analysis of ADSP data at HudsonAlpha.

We seek access to all consent groups. Our research does not include the study of population origins or ancestry, and thus qualifies for HMB-designated studies. Our research is also applicable to each of the disease-specific (DS) categories: for example, we are interested in effects in Alzheimer's and related dementias as well as other phenotypes related to aging, brain and memory. We also note that this analysis involves methods development research (MDS) (new approaches to understand effects of non-coding variation). Finally, this is a genetics study only (GSO).

Our lab aims to understand function of the genome to gain confidence in the precise way in which genetic changes lead to risk for disease. We are working to identify stretches of DNA near genes associated with Alzheimer’s and related dementias and/or aging, brain and memory that may be involved in turning these genes on and off. A key test is if genetic changes in these regions are enriched in people with disease, which we will use these ADSP data to assess.

In a second project, we work with members of The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) to to analyze the DNA from patients with early onset Alzheimer’s and frontotemporal dementia. A critical part of this type of work is checking to see if findings from one set of patients are reproducible in different sets of patients. Access to ADSP data would allow for us to answer this question. The types of data that will be evaluated in association with genetics will be either if the individuals assessed have disease or not, or if their genetics affects when they develop disease.