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

Abstract 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. Competing Interest Statement EM, AN, JQ and AK are current or former employees of Eli Lilly and Company and may own stock in this company Funding Statement This study was funded by Eli Lilly and Company. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UK Biobank database received ethical approval from the North-West Haydock Research Ethics Committee (REC reference 21/NW/0157) and participants gave informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability This research has been conducted using data from UK Biobank, a major biomedical database under project ID 85173.