NEW YORK – With sequences from tens of thousands of Icelanders, a team led by investigators at Amgen subsidiary Decode Genetics has demonstrated that clinically actionable pathogenic or likely pathogenic variants are relatively common in the population and associated with a shorter life.
"We have found evidence of an association between actionable genotypes in the Icelandic population and a shortened life span," co-senior and co-corresponding authors Patrick Sulem, a medical doctor, epidemiology and public health researcher, and head of clinical sequencing at Decode Genetics, and Kári Stefánsson, Decode founder and CEO, and their colleagues wrote in the New England Journal of Medicine on Thursday.
Based on their findings, they argued that "identification and disclosure of actionable genotypes to participants holds considerable potential to mitigate the disease burden on individual persons as well as on society in general."
With genome sequences for 57,933 individuals from Iceland, the researchers used manual curation and pathogenicity scores to search for actionable coding and splice variants in dozens of genes on version 3.0 of the American College of Medical Genetics and Genomics (ACMG) secondary findings (SF) list. Across a set of more than 4,400 variants found in the sequences, they uncovered 235 actionable genotypes affecting 53 ACMG v3.0 genes in 2,306 study participants, or almost 4 percent of study participants.
The available "genotypic and phenotypic information on a large fraction of Icelanders, combined with nationwide death registry [data], enabled us to systematically assess the effect of actionable genotypes on disease risk and their impact on lifespan," Sulem and Stefánsson said in an email.
The team found that Icelanders who carried at least one actionable genotype appeared to have shorter average lives than non-carriers, particularly when the actionable alterations affected cancer-related genes or certain genes linked to cardiovascular disease such as the familial hypercholesterolemia-related gene LDLR.
While individuals who did not carry actionable genotypes had a median survival of 87 years, Icelanders with actionable variants had a median survival of 86 years. The survival distinction "is even more evident for early deaths," they explained, noting that 10 percent of actionable genotype carriers died before the age of 69 years, while the same proportion of non-carriers died before reaching their 73rd birthday.
One actionable genotype was uncovered most frequently in the study participants, the researchers reported: an Icelandic founder variant falling in the hereditary breast and ovarian cancer-related gene BRCA2. In individuals carrying that BRCA2 founder mutation, they found that female carriers lived an average of 9.3 years shorter than non-mutation carriers. But male carriers had shorter survival times as well, living 4.6 years less than non-carriers.
Shorter survival was also documented in Icelanders carrying pathogenic or likely pathogenic changes in eight other cancer group genes, the team reported, noting that individuals carrying cancer-related actionable genotypes lived an average of three years less than non-carriers.
The investigators cautioned that effective disease treatment may dial down early death risk for individuals carrying certain actionable genotypes and noted that the study likely did not include individuals dealing with severe disease or those affected by genetic conditions that lead to especially early death.
Given their results in the Icelandic population, Sulem and Stefánsson suggested that "[d]ata on the molecular diversity of a population, such as those described in the paper, are going to be the foundation of the implementation of precision medicine that is destined to revolutionize healthcare."
In an effort to return results to individuals from Iceland, the team came up with a web platform for participants to check whether they carry the BRCA2 founder mutation described in the study. More broadly, the group called on other investigators to shore up a strategy for addressing actionable genotypes when they arise in other population sequencing studies.
"Ongoing large-scale sequencing efforts, such as the All of Us and Our Future Health projects, highlight the need for reaching a consensus on the return of genomic results to participants in research studies, biobanks, and clinical trials, as has been done for patients seeking a diagnosis through clinical exome and genome sequencing," the authors suggested.
"The ACMG has highlighted the fact that the ACMG SF were not designed to be implemented for population screening outside of research," Baylor College of Medicine researchers Sharon Plon and University of Washington Medical Center's Gail Jarvik wrote in a related editorial in NEJM.
Even so, they explained, many of the life span-affecting genes in the new study "are also considered to be 'tier 1' by the Centers for Disease Control and Prevention; knowledge of their status could have a positive effect on population health."
The duo, who were not involved in the study, noted that the proportion of Icelandic participants carrying pathogenic or likely pathogenic variants in genes from the ACMG v3.0 list (4 percent) was "somewhat higher" than reported in other populations in the past, potentially owing to the large set of genes analyzed or founder mutations in the population.
"Patient-centered research on the return of ACMG secondary findings in specific health systems and through the participants in the All of Us cohort, as well as a recent cost-effectiveness evaluation of tier 1 population screening, may spur an informed consideration of population screening for variants in genes that are associated with a shortened lifespan," Plon and Jarvik concluded.