Scientists who sequenced the entire genomes of 2,636 people in Iceland have produced a trove of valuable information about the nature, location and frequency of human genetic variations.
The new research not only sheds light on the range of human genetic variability; it will help researchers draw more direct lines between genes and diseases.
For instance, genetic abnormalities long thought to guarantee early death now appear to be more common than previously believed, the researchers found. They also discovered new genetic contributors to such varied afflictions as Alzheimer's disease, liver disease and atrial fibrillation.
These and other findings appeared in a package of articles published this week in the journal Nature Genetics.
By sequencing the full genomes of so many Icelanders and comparing the results with less extensive genotype data from more than 104,000 of their countrymen, the scientists identified more than 20 million genetic variants.
Then they cross-checked those variants against Iceland's extensive genealogical and medical records. That helped them see how specific DNA variants contributed to particular diseases. It also allowed them to see how a single disease passed through generations of a given family.
Future researchers are likely to find more such links as they comb through the data released by the project, which was funded by Amgen's DeCode Genetics, a biopharmaceutical company based in the Icelandic capital of Reykjavik.
Armed with the new findings, "we can turn the tables," said DeCode President Kari Stefansson, a senior author on all four of the studies.
In addition to starting with a disease and hunting for its origins in a population's DNA — a needle-in-a-haystack approach called the genome-wide association study — scientists can use the genetic clues found by DeCode to replicate diseases in animals, Stefansson said.
When scientists can see exactly how illness emerges from a specific genetic variation, it should speed the process of finding treatments for those afflictions, he said.
The approach will also make it easier to identify DNA variants that confer protection from diseases, Stefansson added.
Some of the genetic transcription errors found in the Icelandic population may not be as deadly as once believed, the new research suggests.
One of the studies looked for genetic "knockouts" — gene deletions that scientists had thought would do irreparable harm to the people who had them. The team identified 1,171 different knockouts, and they found more than 8,000 Icelanders who have completely lost the function of at least one gene as a result of a knockout.
Genes responsible for our ability to discriminate between scents were the most commonly knocked-out class. The team found far fewer knockouts in genes that are very active in the brain — suggesting that a gene deletion there would be more harmful.
The Icelandic project also turned up new and highly reliable genetic markers for onset of atrial fibrillation before the age of 60, and for a rare syndrome — affecting just four Icelanders — that results in blindness and balance problems.
Combing through the DNA of 8,258 Icelanders with gall bladder diseases, researchers found a pair of rare genetic variants at work.
A separate team examined the DNA of 3,419 Icelanders with Alzheimer's disease and more than 150,000 others with no such diagnosis. That helped them identify eight rare variants that appear to make the condition more likely. The variants influence the production of proteins that are key in the cleanup and disposal of waste in the brain.
In follow-up work, the researchers found that six of those variants were more common in Alzheimer's patients from Finland, Germany, Norway and the United States.
As scientists mine these data, they're likely to glean new insights into which genes are indispensable and which are linked to disease.
Lisa Brooks, co-director of the Genetic Variation Program at the National Human Genome Research Institute in Bethesda, Md., said the Icelandic project is particularly valuable for its ability to detect uncommon variants that contribute to diseases, or help protect against them. Some of these variants may work in conjunction with better-known mutations.
The Icelandic findings will help scientists devise disease-risk estimates that are fine-tuned to individuals, furthering the goals of the Obama administration's new Precision Medicine Initiative. That, in turn, will allow patients and their physicians to take steps to prevent those diseases or treat them in a targeted way, said Brooks, who was not involved in the DeCode studies.
While Iceland's small and homogeneous population was a factor in making such discoveries possible, the benefits of DeCode's findings are not limited to Icelanders, said Harvard University geneticist Steven McCarroll, who was not involved in the research.
By first finding a genetic variant and only then looking for its manifestation, DeCode's scientists have uncovered relationships that are likely to be universal in humans, however different their genetic lineage may be, McCarroll said.
"The things that they're learning about what genes contribute to disease are generally biologically true," he said.
McCarroll praised Iceland — and other countries, including Sweden, Finland and Estonia — that are not only provide excellent national healthcare but also maintain comprehensive records on matters pertaining to citizens' health, including kinship relations and, now, genetic information.
"Countries like Iceland are really going to be the leaders in the genomic medicine movement," he said. Meanwhile, nations like the United States, with fragmented healthcare systems and decentralized record-keeping, "are going to be playing catch-up."
If U.S. scientists were to undertake a similar project, the nation's genetic diversity "would be a towering strength," McCarroll said.
Brooks of the NHGRI also emphasized the importance of conducting large-scale genome-sequencing projects not just in small homogeneous countries such as Iceland, but in the United States.
"You really want to include people of all different ethnicities," she said. "There's a lot of genetic variance in the U.S. population that is not in Icelanders."
Beyond that, she said, studies conducted in the United States could help tease out how environmental factors — including diet, exercise, pollution and other toxic exposures — can influence gene expression.