The benefits of returning clinically actionable genetic results to participants in research cohorts are accruing, yet such a genome-first approach is challenging. Here, we describe the return of such results in two founder populations from Scotland. Between 2005 and 2015, we recruited >4,000 adults with grandparents from Orkney and Shetland into the Viking Genes research cohort. Return of genetic data was not offered at baseline, but in 2023 we sent invitations for consent to return of actionable genetic findings to participants. We generated exome sequence data from 4,198 participants, and used the ACMG v3.2 list of 81 genes, ClinVar review and pathogenicity status, plus manual curation, to develop a pipeline to identify potentially actionable variants. We identified 104 individuals (2.5%) carrying 108 actionable genotypes at 39 variants in 23 genes, and validated these. Working with the NHS clinical genetics service, which provided genetic counselling and clinical verification of the research results, and after expert clinical review, we notified 64 consenting participants (or their next of kin) of their actionable genotypes. Ten actionable variants across seven genes (BRCA1, BRCA2, ATP7B, TTN, KCNH2, MUTYH, GAA) have risen 50 to >3,000-fold in frequency through genetic drift in ancestral island localities. Viking Genes is one of the first UK research cohorts to return actionable findings, providing an ethical and logistical exemplar of return of results. The genetic structure in the Northern Isles of Scotland, with multiple founder effects, provides a unique opportunity for a tailored approach to primary and secondary prevention through genetic screening.

AS and GT are employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. LK is an employee of BioAge Labs and holds share options. JSW has received research support from Bristol Myers Squibb, and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics.

This work was funded by the Medical Research Council University Unit award to the MRC Human Genetics Unit, University of Edinburgh, MC_UU_00007/10 and a Wellcome Trust Institutional Translational Partnership Award (University of Edinburgh 222060/Z/20/Z -PIII031). LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276 and CZB/4/710), a Royal Society URF to JFW, and Arthritis Research UK. JSW was supported by the Medical Research Council (UK), Sir Jules Thorn Charitable Trust (21JTA), British Heart Foundation (RE/18/4/34215), and the NIHR Imperial College Biomedical Research Centre.

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 South East Scotland Research Ethics Committee of NHS Lothian gave ethical approval for this work, reference 19/SS/0104.

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

The datasets generated and analysed during the current study are available from accessQTL@ed.ac.uk on reasonable request, following approval by the Data Access Committee and in line with the consent given by participants. The ClinVar-exome pipeline code is available on GitHub (https://github.com/viking-genes/clinvar_pipeline).

https://github.com/viking-genes/clinvar_pipeline