Lots of People May Carry Life-Shortening Genetic Variants

Lots of People May Carry Life-Shortening Genetic Variants

Many people are carrying potentially harmful genes, research out this week has found. Scientists analyzed the genes of people living in Iceland and found that one in 25 people appear to have genetic variations linked to a shorter lifespan. The most dangerous variants were those tied to cancer.

In 2021, the American College of Medical Genetics and Genomics (ACMG) created a list of so-called actionable genes. Based on existing evidence, these genes—73 at the time—are believed to have variants tied to diseases that could be mitigated or even prevented with early knowledge of this genetic risk. One example would be certain variants of the BRCA2 gene that greatly raise the risk of breast and ovarian cancer; people who have these variants are often recommended to receive screenings at a much earlier age than the general public. The organization has continued to update this list, with the latest revision arriving in June 2023.

While these actionable genes and their variants are important to catalog, there’s still a lot that we don’t know about the practical implications of their existence, such as the overall impact that they have on population health. This new study, conducted by scientists from deCODE genetics, a pharmaceutical company under the larger umbrella of Amgen, tries to help answer that question.

Using the ACMG’s original 2021 list, the authors looked for harmful or potentially harmful variants in some 58,000 Icelanders who had their genomes completely sequenced as part of other studies conducted at deCODE. They also tracked the subjects’ longevity by analyzing data from the Icelandic Death Registry.

The researchers ultimately identified 235 actionable variants in 53 genes across the study population, with about 4% of people having at least one of these variants. The median lifespan of these carriers was 86 years, slightly lower than the 87 years median for non-carriers. But the differences were larger when only taking early deaths or certain types of variants into account.

About 10% of carriers died before reaching the age 69, for instance, compared to 10% of non-carriers who died before reaching the age of 73 years. Those with cancer-related variants also had a median lifespan three years shorter than those without them. One BRCA2 variant in particular was linked to seven years fewer of life, while another variant thought to raise the risk of high cholesterol and cardiovascular disease was linked to six years fewer.

The team’s findings are published Wednesday in the New England Journal of Medicine.

The results do have their caveats. The analysis was only conducted on people from Iceland, which is a less genetically diverse country than many others. That said, other studies of large genomic datasets have found a similar percentage of harmful variants within a population. A 2020 study conducted in the U.S. found that about 3% of participants carried them, for instance (for context, if extrapolated to the U.S. as a whole, that would roughly amount to 10 million Americans). The lower starting diversity in Iceland—a phenomenon known as the founder effect—might still explain the higher percentage seen in the current study, the researchers acknowledge, since lower diversity does increase the risk of harmful genetic mutations showing up in a population.

A big, ongoing debate in medicine is whether it’s worthwhile to implement or recommend widespread population screening for these actionable genes. The authors say that their findings should show the possible benefits of doing so.

“The identification and disclosure of actionable genotypes to participants can guide clinical decision-making, which may result in improved patient outcomes,” they wrote. “This knowledge therefore has significant potential to mitigate disease burden for individuals and society as a whole”

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