Firm matches Icelanders' genetic makeup with region they come from
Test tracking ancestry to island's geography is part of effort to unravel human diseases

Nicholas Wade, New York Times

Sunday, January 2, 2005

An Icelandic company has developed a genetic test for analyzing where in Iceland people come from or, if their parents or grandparents came from different places, how their ancestry is distributed over the island's 11 geographic regions.

The fine-scale matching of genetic makeup to geographic origins is made possible by the surprising immobility of human populations. At least until the last few decades, people have tended overwhelmingly to live, marry and die where they were born.

This stay-at-home behavior has been known for the world in general ever since geneticists learned to assess human variation through measurements of proteins and later DNA.

But it was not obvious that even in a small country like Iceland the residents of each small region would have developed a characteristic genetic signature.

These regional genetic differences have emerged even though Iceland has been inhabited only since the 10th century A.D., and its population as a whole -- derived from Norway, Britain and Ireland -- has rather little genetic diversity.

Decode Genetics, the Reykjavik company that developed the test, is using the Icelandic population as a source for hunting down the genetic roots of common human diseases.

Other researchers recently suggested that such attempts might be confounded if the population under study possessed any kind of systematic genetic difference. So Decode's researchers decided they needed to find out if there were regional genetic differences among Icelanders.

The company has constructed a genealogy of almost all living Icelanders and most of their ancestors back to 1650. The location of most of these individuals is known from parish records and censuses.

Looking at various age cohorts, the researchers found that Icelanders born from 1850 to 1875 tended to live in the same county as had their ancestors for five generations. This tendency was less marked among later age cohorts.

Because many Icelanders have now been genotyped, meaning their DNA has been analyzed at many sites spaced across the genome, the Decode researchers were able to pick a set of 40 sites where the DNA variations were diagnostic of geographic origin. Analyzing a person's DNA at these sites shows with reasonable probability which of Iceland's 11 geographic regions is the home of the person's parents and grandparents.

The findings are reported in the current Nature Genetics in an article by Dr. Agnar Helgason of Decode Genetics and others.

Dr. Kari Stefansson, the chief executive of Decode, said an analysis of his own genome showed he had genetic roots in the northeast and southeast corners of Iceland and on the west coast. "The pattern is exactly faithful to what I know of my ancestry," he said, explaining that his paternal grandparents lived in the first two regions and his maternal grandparents in the third.

The geographical stratification of Icelandic genes suggests that genetically based diseases should also show regional variations. Stefansson said that Decode was studying this possibility and had already seen signs that breast cancer was more common in people from the southern coast and that schizophrenia seemed more frequent in the southeast corner of the island.

Dr. Robert R. Sokal, a population geneticist at Stony Brook University in New York, said he was not surprised by the regional genetic variations in Iceland because in a survey of European populations using an older method he had found two genetic barriers that he could not explain by language or geography. One was in Greece and the other cut through Iceland, separating the western third from the eastern two-thirds.

By consulting the Icelandic Book of Settlement, which records the origins of the first households, Sokal inferred that the two parts of the islands had been settled by different groups, one coming directly from Norway and the other descendants of Vikings who had settled first in Ireland or Britain and married local women.

The Decode researchers say that larger countries, with older and more diverse populations, are likely to have a far greater degree of genetic structure. This is a problem in hunting for disease genes because genetic structure, the Decode researchers confirm, affects the statistical analyses used to associate genetic variations with the incidence of particular diseases.

Stefansson said that he had not had to restate the results of any genetic study done so far in Iceland, and that he would take account of the genetic structure in future studies. But he said he thought that it would be harder to make such adjustments in hunting for disease genes in populations like that of the United States, where the genetic structure is largely unknown.

"The fact of the matter is that you have to understand the population structure in detail to design association studies in a rational manner," he said.

Dr. David Altshuler, a medical geneticist at Massachusetts General Hospital, said he agreed with Stefansson that geography and ancestry had to be taken into account in association studies. But he did not agree that such studies would be harder to do in the United States than in Iceland.