Actionable genetic variants in 4,198 Scottish participants from the Orkney and Shetland founder populations and implementation of return of results

Pioneering genetics study outlines practical and ethical pathway to return actionable results to volunteers and identifies ten genetic variants which have become common enough to warrant population screening.

The benefits of returning clinically ‘actionable’ genetic results to participants in research studies are many, but it is a challenging process and has rarely been attempted, particularly in the UK. From the outset of recruitment to VIKING II/II in 2019, the opportunity was taken to implement this process, working closely with NHS geneticists. This option of consent to return of selected clinically actionable results was chosen by an overwhelming majority (98%), of the participants who consented and completed the study questionnaire online.

Between 2005 and 2015, Viking Genes recruited >4,000 adults with grandparents from Orkney and Shetland into the ORCADES study and Viking Health Study – Shetland (VIKING I), respectively. In 2023, invitations were sent out for consent to return of actionable genetic findings to these participants. This meant that UK-based participants in all four studies within the Viking Genes project had the same opportunity to receive actionable genetic findings, if discovered.

Viking Genes is led by Dr Jim Flett Wilson, Professor of Human Genetics, University of Edinburgh. Back in 2023, Jim explained why consent was being sought:

It’s the most important thing we, as researchers, can do for the volunteers, and is a foretaste of the future of medicine, as more and more people get the chance to take part in screening like this. 

Through the partnership of Viking Genes with the Regeneron Genetics Centre in the USA, DNA “exome” sequence data from 4,198 participants in ORCADES and VIKING I was generated. Viking Genes then created an analysis pipeline using a list of 81 genes containing actionable variants that is compiled by the American College of Medical Genetics and Genomics. This is a list of genes that are related to serious conditions, which can be prevented or improved by treatment. Early knowledge could enhance how well the preventative measure or cure works – these are beneficial to know about. 

Following review of the disease-causing status of the genetic variants, 104 individuals were identified in the two studies, carrying actionable findings in 23 genes from the list. Data quality checks were done and each result was validated using a second method of DNA sequence analysis, at the University of Edinburgh. 

Working closely with the NHS Clinical Genetics Service in Aberdeen, and after expert clinical review, Viking Genes notified 64 consenting participants (or their next of kin) of their actionable results. The letter from Viking Genes included contact details for the NHS clinical genetics team who supported and advised participants and their families, allowing them to take up the pathway of care appropriate to their genetic findings (e.g. mammogram, heart echo, blood tests).

10 genetic variants which have become common enough to warrant population screening found in Orkney and Shetland

Orkney and Shetland parish map
Isles and parishes of Orkney and Shetland

The most extraordinary finding was a number of variants that were between 50 and over 3000 times more common in Orkney or Shetland than elsewhere. For example, a deletion in the titin (TTN) gene, that increases the risk of a heart condition called cardiomyopathy, which can lead to heart failure, was 3700 times more common in Shetland than in the general UK population. A variety of medical and surgical treatments are available for this condition. In total, ten actionable variants across seven genes (BRCA1, BRCA2, ATP7B, TTN, KCNH2, MUTYH, GAA) had become significantly more common in Orkney or Shetland. 

When someone carries actionable variants in both their copies of the ATP7B gene (one from their mother and one from their father), this causes the normally rare condition Wilson disease. Copper levels build up in the organs of people with this condition, particularly the liver, brain and eyes, leading to liver problems and neurological or psychiatric symptoms. The disease is very treatable, if caught in time. In Shetland, two different variants in the ATP7B gene have become much more common, such that 1/45 Shetlanders is a carrier and thus at risk of having a child with Wilson disease.

The distinct genetic identity of the Northern Isles of Scotland, with multiple founder variants at much higher frequency than elsewhere, provides a unique opportunity for a tailored approach to disease prevention through cost-effective genetic screening of the population. 

Professor Wilson said: 

The discovery that a relatively large number of disease-causing genetic variants are hundreds of times more common in Orkney and Shetland than in the rest of the UK presents an opportunity for low-cost genetic screening of the population. This would capture a significant portion of the inherited risk for a number of diseases, as we move away from treating people who are already ill to a preventative approach, that should deliver better outcomes. 

This work was funded by a number of research grants over the last 20 years, including the Medical Research Council award to the MRC Human Genetics Unit, University of Edinburgh and a Wellcome Trust Institutional Translational Partnership Award. ORCADES was supported by the Chief Scientist Office of the Scottish Government. 

This article was published on