U01AG072573

Multi-Omic Functional Assessment of Novel AD Variants Using High-Throughput and Single-Cell Technologies - Project Summary / Abstract

Through decades of research, genome-wide association studies (GWAS) have identified heritable coding and noncoding single-nucleotide polymorphisms (SNPs) that lead to an increased risk of developing Alzheimer's disease (AD). However, the vast majority of these SNPs remain largely under-characterized, and their contribution to AD pathogenesis remains unclear, marking a critical roadblock to our understanding of AD genetics and pathogenesis.

While SNPs within the APOE and TREM2 genes have identified vital nodes in AD biology, most AD-related SNPs reside within the noncoding genome, making their functional roles in the disease less clear. Co-inheritance of nearby SNPs (linkage disequilibrium) and the cell type-specificity of noncoding regulatory elements further complicate functional annotation of noncoding SNPs in AD.

As part of the Alzheimer's Disease Sequencing Project Functional Genomics Consortium (ADSP FGC), this project will provide a robust and conclusive functional characterization of AD-related noncoding SNPs. To do this, we will first create a comprehensive single-cell atlas of gene expression and chromatin accessibility across a cohort of diverse clinico-pathologic states related to AD (Aim 1).

Using these cell type-specific gene regulatory landscapes, we will develop and implement innovative machine learning and statistical genomics methods to predict functional noncoding, splicing, and coding SNPs (Aim 2). We will then validate these predictions using massively parallel reporter assays (MPRAs) and large-scale, scarless, single-base CRISPR editing of iPSCs followed by cell type-specific differentiations (Aim 3).

Taken together (Aim 4), this project will pinpoint the functional SNPs and target cell types for dozens of AD-related risk loci and provide an unprecedented picture of the gene regulatory landscape of AD. This work will be performed as a joint collaboration between Stanford University and the Gladstone Institutes at UCSF. Our team, with many long-standing collaborations, has extensive experience in consortium science with long-term involvement in the Encyclopedia of DNA Elements, the Cancer Genome Atlas, and the Genotype-Tissue Expression Project.

The proposed project is thus well-positioned to integrate into the highly collaborative ADSP Functional Genomics Consortium.

The Leland Stanford Junior University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

Alzheimers Disease Sequencing Project Functional Genomics Consortium (U01 Clinical Trial Not Allowed) (RFA-AG-21-006)

Amendment Since initial award the total obligations have increased 389% from $1,698,183 to $8,305,058.