Resilience to dominant genetic disease in the healthy elderly

Abstract

Here we describe genomic screening of the healthy elderly to identify those resilient to adult-onset genetic disease, despite being at exceptionally high genetic risk. We sequenced 13,131 individuals aged 70 or older (mean age 75 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no prior history of cardiovascular disease, life-threatening cancer, persistent physical disability or dementia. We compared the prevalence of pathogenic variants in medically actionable autosomal dominant disease genes with that from the UK Biobank population, and assessed their clinical impact using personal medical history and adjudicated study outcomes during 4.5 years of follow-up. The frequency of pathogenic variants was less than reported among the younger UK Biobank population, suggesting these variants confer a survival disadvantage during the middle years of life. Yet we identified 141 individuals with pathogenic variants free of any associated disease up to average age 79.5 years. Further study of these elderly resilient individuals might help uncover genetic mechanisms that protect against the development of disease.