It may not look like King Tut’s tomb, but there’s a modern-day treasure in these blood samples provided by some 3,000 Icelanders. They are being used to help scientists track genes and mutations behind some of today’s most puzzling diseases, including Alzheimer’s. After being collected and analyzed by consent, the samples have been cross-checked with individual medical records. The project represents two decades’ worth of work by the Icelandic firm, Decode, and already has led to discovery of a mutation associated with Alzheimer’s. Still ahead lie issues of disclosure, as well as development of new treatments to block the effects of risk-conferring mutations.
Last week, researchers in Iceland announced the completion of a large project to sequence the genomes (or complete DNA) of 2,636 of their fellow countrymen. Having captured the complete genetic information for this sizable group, scientists are able to use a technique called imputation to “tease out” the genomes of people they have not sampled. Using this technique, they have already assembled full genomes from about 10,000 Icelanders and partial genetic information on 150,000 more, representing about half the country. Eventually they expect to be able to generate a report for genetic disease on every person in Iceland.
The work was done by the Icelandic research firm, Decode, which is owned by Amgen. Results were published online March 25 in the journal, Nature Genetics.
The Icelandic data base is being called a “treasure trove” of information that will further scientists’ understanding of diseases that are not caused by one single genetic mutation, but instead to mutations on several different genes. Such mutations often work together with environment and lifestyle factors to increase a person’s risk of getting the disease, with no one factor being predictive.
Diseases like this, with so-called “multifactorial” origins, include some of the most common types of heart disease and cancer. They also include the most prevalent, age-related forms of Alzheimer’s disease, macular degeneration, and glaucoma—all the diseases that make up BrightFocus’ raison d’etre and receive research funds from BrightFocus donors.
Multifactorial disease can be difficult to study because, among the numerous genetic mutations that contribute to them, some are quite rare. That makes it necessary to search large groups of people to find some of the elusive pieces of a puzzle that lead to a disease’s onset.
Already, the Icelandic project has led to identification of a gene called ABCA7 as a risk factor for Alzheimer’s disease. Previous studies had suggested a gene in the same “neighborhood” be involved, but Decode’s work went further, to pinpoint the gene itself and the specific mutation.
In recent years, geneticists have been searching for causes of disease not just by seeking out people who carry mutations, but also those who lack a working copy of a particular gene, called “human knockouts.” Decode has found that nearly 8 percent of Icelanders lack a working version of a gene, and that 1,171 genes have been shut down in Icelandic knockouts. By contrast, a similar effort in 2012 to map human knockouts yielded just 253 genes.
Big data techniques like imputation, as well as the nature of Iceland itself, have accelerated Decode’s progress. Iceland was founded by Scottish, Irish, and Scandinavian settlers about 1,100 years ago, and until the past 100 years has been relatively isolated. As a result, Icelanders have a relatively low level of genetic diversity and that makes it easier for scientists to detect genetic variants that raise the risk of disease. Iceland also has impressive genealogical records and geneticists can use national genealogy databases to look for diseases that are unusually common in relatives—a sign that they share a mutation.
As the flip side of all this, the factors that make Iceland “just right” for rapid genetic research may have unanticipated consequences. After being relatively isolated for a millenium, Iceland may find itself forced to come to grips rapidly, and much sooner than other nations, with laws around disclosure of genetic information, which are expected to become a key issue of our time.
In a New York Times interview, Kári Stefánsson, MD, the founder of Decode (and senior author on the study), said his firm is now capable of generating a report for genetic disease on every person in Iceland. For example, with the push of a button, they could identify every person in Iceland who has the BRCA2 mutation, which dramatically raises the risk of breast and ovarian cancer. However, due to federal laws, that information currently is withheld from Icelanders.
Stefansson, a former professor of neurology at Harvard and University of Chicago, said he hopes Iceland’s policies will change to permit disclosure to individual carriers.
However, it also may be necessary to temper expectations, not only in Iceland, but everywhere, about the fact that treatments currently lag behind most genetic discoveries. This is not by accident, but to be expected. Only by identifying rare mutations, and tracking their impact on a disease’s development and course, can scientists custom design treatments to block a mutation’s biological action.
Part of this lesson has already been learned, at least at Decode. After Stefánsson founded the company, in 1996, the government set up regulations enabling Icelanders to consent to have their DNA analyzed and compared with their medical records. However, in part because the genetic markers they identified did not lead immediately to new treatments, Decode was forced into bankruptcy in 2009. It was acquired by the biotechnology giant, Amgen, in 2012, with the hopes these genetic discoveries will provide clues for drug development.
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