In Iceland’s DNA, New Clues to Disease-Causing Genes

Scientists in Iceland have produced an unprecedented snapshot of a nation’s genetic makeup, discovering a host of previously unknown gene mutations that may play roles in ailments as diverse as Alzheimer’s disease, heart disease and gallstones.

“This is amazing work, there’s no question about it,” said Daniel G. MacArthur, a geneticist at Massachusetts General Hospital who was not involved in the research. “They’ve now managed to get more genetic data on a much larger chunk of the population than in any other country in the world.”

In a series of papers published on Wednesday in the journal Nature Genetics, researchers at Decode, an Icelandic genetics firm owned by Amgen, described sequencing the genomes — the complete DNA — of 2,636 Icelanders, the largest collection ever analyzed in a single human population.

With this trove of genetic information, the scientists were able to accurately infer the genomes of more than 100,000 other Icelanders, or almost a third of the entire country.

“From the technical point of view, these papers are a tour-de-force,” said David Reich, a geneticist at Harvard Medical School who was not involved in the research.

While some diseases, like cystic fibrosis, are caused by a single genetic mutation, the most common ones are not. Instead, mutations to a number of different genes can each raise the risk of getting, say, heart disease or breast cancer. Discovering these mutations can shed light on these diseases and point to potential treatments. But many of them are rare, making it necessary to search large groups of people to find them.

The wealth of data created in Iceland may enable scientists to begin doing that.

In their new study, the researchers at Decode present several such revealing mutations. For example, they found eight people in Iceland who shared a mutation on a gene called MYL4. Medical records showed that they also have early onset atrial fibrillation, a type of irregular heartbeat.

Gilian McVean, a geneticist at the University of Oxford who was not involved in the study, said that discovering a rare association this way “is a bit of a holy grail” for geneticists.

Luke Jostins, also at Oxford, was intrigued by another rare mutation discovered by Decode, one that influences the level of a hormone that stimulates the thyroid gland.

When Icelanders get the mutation from their mother, they make more of the hormone, the researcher found. But when they get it from their father, they make less.

Dr. Jostins called the discovery “super-weird” and wants to see the result replicated elsewhere. “If it is real, it is quite the find, the sort of thing that could really inform some new biology,” he said.

The scientists also found a rare mutation to a gene called ABDB4 that raises the risk of gallstones. And they identified a gene called ABCA7 as a risk factor for Alzheimer’s disease.

Previous studies had suggested a gene in the genetic neighborhood of ABCA7 was associated with the disease.

But the Icelandic study pinpointed the gene itself — and even the specific mutation involved.

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. Scientists call them human knockouts.

The Decode researchers looked for human knockouts in Iceland — and found a lot of them. Nearly 8 percent of Icelanders lack a working version of a gene. All told, the Decode team identified 1,171 genes shut down in Icelandic knockouts.

In a 2012 study, Dr. MacArthur and his colleagues were able to identify just 253 genes knocked out in humans.

In an interview, Dr. Kari Stefansson, the founder of Decode, said that he and his colleagues are now getting in touch with the Icelandic knockouts to see if they will consent to more studies designed to figure out the physiological consequences of the missing genes.

Since Dr. Stefansson and his colleagues submitted their initial results for publication, they have continued gathering DNA from Icelanders.

The scientists now have full genomes from about 10,000 Icelanders and partial genetic information on 150,000 more.

With a technique called imputation, the researchers say they are able to ascertain the full genomes of people they have not even examined. Dr. Stefansson said that means that his firm could generate a report for genetic disease on every person in Iceland.

With the push of a button, for instance, the firm can identify every person with the well-known BRCA2 mutation, which dramatically raises the risk of breast and ovarian cancer — even if they have not submitted to genetic testing themselves.

Currently, that information is withheld from Icelanders, but Dr. Stefansson hopes that the government will change its policy. “It’s a crime not to approach these people,” he said.

Iceland is a particularly fertile country for doing genetics research. It was founded by a small number of settlers from Europe arriving about 1,100 years ago. Between 8,000 and 20,000 people came mainly from Scandinavia, Ireland and Scotland.

The country remained isolated for the next thousand years, and so living Icelanders have a relatively low level of genetic diversity. This makes it easier for scientists to detect genetic variants that raise the risk of disease, because there are fewer of them to examine.

Iceland also has impressive genealogical records. Through epic poems and historical documents, many Icelanders can trace their ancestry back to the nation’s earliest arrivals. Geneticists use national genealogy databases to look for diseases that are unusually common in relatives — a sign that they share a mutation.

Dr. Stefansson founded Decode in 1996 to explore the genetic landscape of his country. Over the next few years, the government set up regulations enabling Icelanders to consent to have their DNA analyzed and compared with their medical records.

Initially, Decode researchers looked for a set of genetic markers known to vary from person to person. But promising links did not lead to new treatments, and in 2009 Decode filed for bankruptcy.

In 2012, the biotechnology giant Amgen bought Decode for $415 million. The company is looking at the newly published results for clues to effective new drugs.

Sean E. Harper, the head of research and development at Amgen, said that the company is now investigating a gene, found by Decode, with a strong link to cardiovascular disease in Iceland. (He declined to name the gene.)

While many researchers are trying to treat heart disease by targeting cholesterol levels, this new mutation seems to affect heart disease through a different route.

Dr. Harper said that he expected many more insights from the DNA of Icelanders.

“They can be guiding lights for us,” he said.