Improved characterization of Alzheimer's disease genetic risk through fine-mapping and long-read sequencing of DNA and single-nuclei RNA.
Description: Alzheimer's disease (AD) is the most common form of dementia and a complex neurodegenerative disease with strong genetic component. We performed a genome-wide association study (GWAS) of AD and identified an unpreceded number of 42 new risk loci, in which I prioritized risk genes and AD-associated molecular alterations in majority of risk loci mainly by integrating molecular quantitative trait loci (QTL) with GWAS. In this project I propose to expand these analyses with a set of new approaches, focusing on genetically unresolved loci and understudied brain molecular phenotypes. These approaches include (i) fine-mapping associations to identify likely causal variants and optimizing GWAS-QTL colocalization, (ii) long-read targeted DNA sequencing of 9 unresolved loci to reveal GWAS-linked structural variants, DNA methylation and chromatin accessibility alterations, and (iii) characterizing brain cell-type and allele-specific transcript structure and abundance through long-read single-nuclei RNA sequencing. With these, I hypothesize that the majority of association signals will be explained and mapped to a set of prioritized variants, genes, mechanisms, and cell types. This will greatly contribute to our understanding of AD genetic risk, which consequently may lead to development of better diagnosis, risk stratification, and therapeutic opportunities.
Funder: Vlaamse regering
Funding type: fellowship
Funder scheme: BOF - postdoctoral mandates
Start date: 2023-10-01
End date: 2024-09-30
Investigator: Kristel Sleegers
Institution: UAntwerpen
Funded outputs count: 0
Funder award ID: vlaamse-4c72aca6-be40-4b17-b42b-977410924007
OpenAlex ID: G3417474151