Genetic data from an island population proves to be a useful tool in understanding disease

With fewer than 4,000 residents, the genetically isolated Micronesian island of Kosrae, in the West Pacific, provides an ideal population in which to research heritability of disease.

Over the last 12 years, Rockefeller University researchers have been collecting blood samples and other data from the island's residents, and have put together a giant family tree connecting just about everyone on the island. Now, in a pair of new studies, this data is beginning to yield intriguing results about the strength of whole genome studies in isolated populations and their usefulness in uncovering the genetic basis of complex disease.

The Kosrae project is not scientists' first attempt to use a catalog of genetic data to link genes to disease. When the first results of the International HapMap Project = an immense catalog of human genetic variations based on four distinct populations = were published late last year, they were heralded as a potent tool in the quest to understand the impact of genes on health. The study left an open question, however, as to whether the information provided by the results could be applied to any racial group other than the four in the original study. But now, as described in a paper in Nature Genetics 38: 214-217 (February, 2006), Rockefeller lab heads Jeffrey Friedman, Markus Stoffel and Jan Breslow have demonstrated HapMap's applicability: Using markers from the HapMap project as guideposts, they have earmarked the island population of Kosrae as a powerful resource for whole-genome studies.

After choosing 30 Kosraen trios (each of which consisted of two parents and one child), the group used DNA chips to determine the genetic makeup, or "genotype," of each participant. When they compared selected results to those from the HapMap project, they found that more than 98 percent of the data points matched = providing evidence that the HapMap data can likely be used for whole-genome studies in groups beyond the four initial study populations. And, likely due to the islanders' isolation, the analysis yielded two other important results: reduced genetic diversity and longer-than-normal segments of linked DNA variations, something called linkage disequilibrium. In other words, Kosrae's citizens offer a tool that may be even more powerful than the HapMap. "With less diversity and longer segments of linkage disequilibrium, you can extract more information than from other populations," says Friedman, head of the Laboratory of Molecular Genetics and director of the university's Starr Center for Human Genetics.

The first clue that the residents of Kosrae might provide a key perspective on the impact of genetics on disease came in a study published by Breslow and his colleagues in 2004, which announced the discovery of a mutant gene that affects a person's cholesterol absorption. But looking at more complex diseases, which involve multiple genes or genes that respond to environmental influence, requires an immense set of data. So, using the same chips that they used to genotype the parent-child trios, Friedman, Breslow and Stoffel have now genotyped nearly every resident of the island, more than 3,000 in all.

In the second paper, published in the Proceedings of the National Academy of Sciences 103(10): 3502-3509 (March 7, 2006), the three researchers analyzed the island's extended family tree in combination with genotype data from 2,188 of their participants. They were looking for the potential genetic locations of a group of conditions that, when combined, are referred to as metabolic syndrome or Syndrome X. The symptoms typically include obesity, insulin resistance and high blood pressure, and they increase a person's risk of developing diabetes and heart disease. "When you look at inheritance patterns on the island, there's clear heritability of these disorders," Friedman says. "So we'd very much like to know if we can figure out what the causal genes are."

He and his colleagues were able to map the chromosomal locations for a number of the traits involved in metabolic syndrome, pinpointing blood pressure, cholesterol, weight, body mass index, fasting blood sugar levels, and other attributes. And all of those attributes appear to be inherited as a group. This may be just the tip of the iceberg. Now that Friedman, Breslow and Stoffel have genotyped every Kosrae resident, they're collaborating with colleagues at the Broad Institute in Boston to analyze the data much more extensively and they believe that it could yield important results. "The hope is that we can begin to establish the basis for different diseases on the island," Friedman says.