NEW YORK – Investigators have identified actionable genetic variants present in founder populations on the Orkney and Shetland islands of Scotland, leading to personalized health insights for dozens of individuals descended from these populations.
"By tailoring our approach to fit specific genetic backgrounds, we can offer more precise, predictive, and preventative healthcare, thereby protecting communities, preserving health and saving lives," senior author James Wilson, human genetics chair at the University of Edinburgh, said in a statement. "The results of this study provide a foundation for creating bespoke genetic screening programs for the Scottish Islanders and other unique genetic populations."
As they reported in the American Journal of Human Genetics on Friday, Wilson and his colleagues analyzed array-based genotyping data and exome sequences generated by the Regeneron Genetics Center for 4,198 deeply phenotyped participants with ancestry from the Orkney or Shetland islands, who were part of the Viking Genes research cohort — an effort that has enrolled thousands of individuals with three or four grandparents from Scotland's northern and western isles since it began two decades ago.
"The genetic structure in the Northern Isles of Scotland with multiple founder effects provides a unique opportunity for a tailored approach to disease prevention through genetic screening," the authors explained, noting that the Viking Genes effort "comprises a set of Northern and Western Isles population cohort studies aiming to explore the genetic causes of disease."
Building on past findings from the Viking Genes study, including work that uncovered BRCA1/2 alterations behind clusters of rare breast and ovarian cancer cases in Shetland and Orkney, the latest study focused more broadly on clinically actionable variants found across protein-coding sequences for 81 genes on version 3.2 of the American College of Medical Genetics and Genomics (ACMG) actionable gene list.
In the process, the team identified 104 individuals who carried such actionable variants, as based on ACMG guidelines. In particular, they uncovered 108 actionable genotypes based on 39 pathogenic or likely pathogenic variants in 23 genes implicated in cancer, metabolic conditions, or cardiovascular disease.
"Our data highlight the clinical relevance of local genetic sub-populations, as most of the founder variants are also associated with one or another parish or isle, with deep genealogies linking most participants with the variants to ancestors from there," the authors wrote, adding that additional actionable genotypes "are likely to be uncovered in the future, as genetic analyses move from limited gene panels toward [whole-exome sequencing and whole-genome sequencing]."
After a return-of-results step was added to the study in 2023, the investigators reached out to individuals with returnable genetic results that were confirmed through the National Health Service's Grampian clinical genetics service, which also provided genetic counseling, and ultimately shared results with 64 participants.
Ten individuals had apparently actionable genotypes that were not considered "returnable" after NHS review, they reported, while two participants did not consent to receive results and 41 individuals or their next of kin did not reply or were deceased. 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 authors said.
Along with insights into individual participants' disease risk, the study pointed to actionable genotypes found at higher- or lower-than-usual rates in those descended from founder populations on the Orkney or Shetland islands.
"Ten founder variants showed strong enrichment, having risen [more than 50-fold] in frequency in Orkney or Shetland," the authors reported, "while otherwise commonly seen variants, notably those causing [familial hypercholesterolemia], were at least 10-fold lower in frequency."