The role of SEX in the genetics of brain gene regulation and neurodegenerative disease risk

Active Project Grant Awarded Last action

Award ID
F32AG104442
Recipient
Awarding agency
Obligated
$80,297

Award facts

Assistance listing
93.866 Aging Research
Completion date 0% complete
Place of performance
Aurora, CO 80045, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Alzheimer's (ad) and parkinson's (PD) diseases are the two most common neurodegenerative diseases in the united states, affecting ~7.2 and 1.1 million americans respectively, with prevalence rising as the population ages. Together, ad and PD pose major individual, familial, societal, and economic burdens, exceeding $400 billion annually. Both diseases exhibit SEX differences in prevalence (two-thirds of ad cases are women while men are 1.5 times more likely to develop PD), clinical course, and treatment response. Identifying the genetic mechanisms driving these SEX differences may inform individualized prevention and treatment. Genome-wide association studies (gwas) detect genetic variants associated with complex diseases, such as ad and PD; however, most LIE in non-coding regions of the genome. Integrating gwas with expression quantitative trait loci (eqtl) that identify genetic variants associated with gene expression levels, provide biological insight to how genetic regulation shapes SEX differences in biological mechanisms. Additionally, some variants exert SEX differentiated regulatory effects (SEX-biased eqtls), which can reveal genes whose expression contributes differently to disease in men and women. Ad and PD are highly heterogeneous, with SEX-specific comorbidities that complicate diagnosis and treatment. Identifying SEX-specific CO-occurring conditions that shape how neurodegenerative diseases present and progress will provide insight into biological and clinical pathways that differ between men and women and may improve intervention strategies. The goal of my project is two-fold: (1) discover SEX-biased gene regulation in brain tissue that influences SEX differences in ad and PD; (2) reveal SEX differences in trait associations with the genetic risk for ad and PD. First, i will combine existing brain eqtl datasets in a large meta-analysis to increase statistical power in three ways: (1) SEX-combined, (2) SEX-stratified (males and females separated), and (3) SEX-interaction to evaluate SEX-differentiated effects. I will integrate SEX- biased eqtls with gwas data from ad and PD to identify genetic variants that influence both gene expression and phenotype. Together, this will allow me to detect genetic effects on gene regulation in the brain that contribute to ad and PD in a SEX-differentiated manner. Second, i will quantify associations between ad and PD genetic risk and all other measured phenotypes in the electronic health record to assess SEX differences in disease comorbidities. The results will allow me to determine if ad and PD disease risk is linked to specific health traits in men and women, revealing SEX-differentiated biological disease mechanisms. Together, this work will advance understanding of how SEX influences ad and PD genetic risk and disease manifestation, informing future SEX- aware precision medicine.

Quick answers

Who received award F32AG104442?

F32AG104442 was awarded to The Regents Of The University Of Colorado by National Institute on Aging (National Institutes of Health) on March 2, 2027.

How much is award F32AG104442 worth?

$80,297 has been obligated on F32AG104442.

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