High Frequency of Repeat Expansions in UK Biobank Suggests Protective Rare Variants Modulate C9ORF72 Penetrance in Neurodegeneration

Short tandem repeat expansions are significant contributors to human disease and several repeat-carrying loci have been identified as responsible for severe neurological disorders. Recent population-based studies showed that the frequency of repeat expansion variants is considerably higher than the prevalence of the disease they cause, suggesting that additional genetic, epigenetic, or environmental factors may influence penetrance and clinical manifestation. This is expected in the case of severe, adult-onset disorders where penetrance is age-dependent, and the incidence is lower than the prevalence. Nonetheless, it remains uncertain whether these variants also exhibit incomplete penetrance in later stages of life. The availability of genetic data linked to longitudinal health records in the UK Biobank allows for direct tracking of disease risk for repeat expansion carriers by age. In our work show that the penetrance of C9ORF72 repeat expansions, but not that of HTT or CACNA1A, remains low even late in life and we leverage this feature to identify potential protective variants in ALS.