Linking common variation in age-dependent genes to clinically and cognitively relevant brain structure and function
Aging in the human brain is characterized by specific cellular and molecular changes. Additionally, the brains of individuals with mental illness often show signs of premature aging. Previous work from our group has identified common genetic variants that change the expression (i.e., activity) of genes involved in brain aging. By measuring how many of these genetic variants an individual has, we are able to estimate how at risk they are for premature brain aging. This type of method is called calculating a polygenic risk score (PRS) and our measure of brain aging risk is called PRS-AGE. Our prior work has also singled out the FREM3 gene as especially likely to impact brain structure and cognition as part of brain aging. We previously found that lower levels of FREM3 expression in the brain result in less activity in brain areas sensitive to aging, reduced scores on cognitive tests, and less folding of the brain's surface. To learn more about brain aging, we plan to calculate PRS-AGE and FREM3 gene expression for participants in the UK Biobank and investigate how both relate to differences in brain structure and function, cognition, and risk for mental illness. The proposed work can help better understand mechanisms involved in premature brain aging, and their involvement in brain disorders. It may also contribute to future development of a clinical tool to screen individuals at increased risk for premature brain aging.