R01AG075827

Integrative Genomic, Transcriptomic, and Proteomic Analyses to Investigate Sex-Specific Differences in Alzheimer's Disease

Alzheimer's Disease (AD) affects 35 million people worldwide. However, there are no effective treatments to slow or halt the underlying neurodegeneration of AD. Strikingly, women are affected by AD about twice as much as men. Why women are disproportionately affected by AD is not well understood.

Here, we hypothesize that there is an interaction between biological sex and brain gene expression that predisposes women to have a higher risk for AD. This hypothesis builds on our work investigating the genetic control of gene expression in the human brain. In those studies, we have identified genetic sites that are associated with variation in gene expression at the transcript and protein level in the human brain.

Identifying genetic sites associated with natural variation in brain gene expression is incredibly useful to resolve genetic signals identified by genome-wide association study (GWAS) to specific causal transcripts and proteins. We have successfully used brain gene transcript and protein expression results with GWAS results to identify novel proteins for AD (Wingo et al, Nat Genet, 2021) and depression (Wingo et al, Nat Neurosci, 2021). These analyses implicate the causes of inherited genetic risk, which are presumably among the most important early contributors to disease, making them highly relevant to resolving sex-specific disease risk.

To test our hypothesis, we will first perform a sex-specific brain expression analysis for transcripts and proteins (Aim 1). To do this, we will leverage existing brain transcripts and protein expression data generated by national resources, and we propose a novel approach to cost-effectively increase the depth of proteomes to improve power. We expect to generate sex-specific quantitative trait loci (QTL) for brain transcripts (N=1655, 61% women) and proteins (N=1584, 66% women), and each gene will then be tested for evidence of interaction with sex. These results are likely to be of general interest to the neuroscience and genetics communities, and the data and results will be made widely available to the science community.

In Aim 2, we will perform a sex-specific GWAS of AD, and we will identify genetic variants that interact with sex. To do this, we will perform sex-stratified GWAS using 1) case-control status for AD in participants from US studies (N=27,580), 2) AD-proxy case-control in participants from the UK Biobank (N=431,000), and III) a meta-analysis of 1 and 2.

In Aim 3, we will identify brain transcripts and proteins contributing to AD pathogenesis that are specific to men or women, respectively. To do this, we will integrate the sex-specific brain QTLs with the sex-specific GWAS results to resolve GWAS signals to proteins for women and men, separately. For AD genetic signals with evidence for sex interaction, we will test whether sex-specific gene expression accounts for the differences in AD risk between the sexes using causal inference approaches (e.g., Mendelian randomization).

Findings from this project are highly likely to provide novel mechanistic insights into sex differences in AD and promising new targets for further sex-specific mechanistic and therapeutic studies of AD.

Davis University Of California

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]

Sacramento, California 958172201 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 296% from $763,880 to $3,022,095.