Moving the Cure Alzheimer’s Fund Genome Project Beyond Simple Associations: Integrating Functional Information, Fine-Mapping and Causal Inference Approaches into the Family-Based Analysis of the Cure Alzheimer’s Fund Whole-Genome Sequencing (WGS) Family Study

We will develop and implement a set of analysis approaches that will enable us to move our whole-genome sequencing analysis approaches of the family data in the Cure Alzheimer’s Fund Alzheimer’s Genome ProjectÔ beyond “simple association analysis,” fostering a deeper understanding of the underlying genetic architecture of Alzheimer’s disease (AD). We will develop a testing methodology that will allow conditional, regional testing that incorporates annotation information. We will modify the existing equivalence testing approaches to allow testing for the absence of direct, causal genetic effects, enabling valid Mendelian randomization analysis in the family data of the genome project. Furthermore, we will implement SUSIE approaches (SUm of SIngle Effects) for the fine mapping of AD phenotypes that identify minimal, plausible sets of causal variants. In summary, the proposed methodologies will enable a faster and more efficient follow-up of genetic loci for Alzheimer’s disease, fostering a more rapid understanding of the underlying genetic architecture of AD.