Quantifying risk modifiers of hereditary hemochromatosis using genomic and electronic health record data from FinnGen and UK Biobank

Abstract Hereditary hemochromatosis is an autosomal recessive disorder characterized by excessive iron accumulation in the body. Early diagnosis of hemochromatosis allows starting treatment before severe organ damage has occurred. The C282Y variant in the HFE gene is the most common cause of hemochromatosis. However, its penetrance of only 20% limits its utility for population-wide screening. We aimed to identify and quantify the predictive value of novel genetic variants and non-genetic factors from electronic health care records that could modify the effect of the C282Y variant on hemochromatosis, thereby partly explaining its incomplete penetrance. We carried out a cohort study on data from 420,543 individuals in the FinnGen project, for whom genotype information and health care records were available. We performed a regular and an interaction GWAS of hemochromatosis and fitted statistical models of hemochromatosis with multiple genetic and non-genetic predictors. We validated our results using data from the UKBB. Our analyses identified one novel statistically significant variant (rs181949568) in CASC15 gene, within 4 Mb from the HFE gene, and we were able to quantify the strong protective role of blood donation. We found that donating at least twice a year is likely to be sufficient to drop the risk of C282Y homozygote to that of a C282Y-H63D compound heterozygote. To facilitate clinical application, we present the results as individual-level risk tables. Also, we found that in Finland hemochromatosis related diagnosis predicted later hemochromatosis diagnosis suggesting that in Finland hemochromatosis is not well recognized. Competing Interest Statement The authors have declared no competing interest. Funding Statement Jarkko Toivonen was funded by Valtion tutkimusrahoitus (VTR). 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 Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa gave ethical approval for this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 statement Data will be made available on request.