Penetrance and the Healthy Elderly

Area of Science:

• Human Genetics
• Genomic Medicine
• Aging Research

Background:

• Variable penetrance of pathogenic variants (PVs) complicates genetic risk assessment and clinical decisions.
• Nonpenetrance, where PVs are present without disease, is common but poorly understood.
• Identifying protective factors against disease in individuals with genetic risk is a key challenge.

Purpose of the Study:

• To investigate the factors influencing the variable penetrance of pathogenic variants.
• To leverage the study of healthy elderly individuals harboring PVs to understand nonpenetrance.
• To enhance the understanding of genetic variant penetrance for improved clinical care.

Main Methods:

• Utilizing the ASPREE Biobank of Healthy Ageing, a cohort of over 14,000 healthy individuals aged 70+.
• Analyzing DNA from elderly participants in an aspirin clinical trial, ascertained without typical genetic study biases.
• Identifying individuals within the cohort who carry known pathogenic variants in clinically actionable genes.

Main Results:

• The ASPREE cohort provides a unique resource of healthy elderly individuals with PVs.
• This population offers an unprecedented opportunity to study nonpenetrance in actionable genes.
• Findings will contribute critical knowledge regarding the penetrance of genetic variants.

Conclusions:

• Studying the genomic profile of healthy centenarians is pivotal for understanding disease resilience.
• Insights from healthy elderly individuals with PVs can illuminate mechanisms of nonpenetrance.
• This research will form a foundation for better clinical management of genetic risks.