For generations, Greenlanders have endured one of the world’s harshest environments – and their genes carry the imprint of that survival. A groundbreaking genetic map now reveals how unique DNA traits, shaped by millennia of isolation and adaptation, influence human health in Greenland today. The findings pave the way for more precise healthcare tailored to the genetic landscape of this resilient population.
Greenland’s vast glaciers, punishing weather and scarce food comprise some of the harshest living conditions in the world – and the people who call it home carry a legacy of survival in their genes.
The Inuit ancestors of modern Greenlanders settled the world’s largest island nearly a thousand years ago, and the demands of life made a unique suite of genetic traits – including an unusual modification to how energy from food is metabolised – an advantage for survival. But millennia of separation from the population of mainland Europe mean that European genetic reference panels researchers use to predict disease risk and identify the cause of health conditions are not accurate for Greenlanders.
New research published in Nature is the first to map the full genetic architecture of Greenlanders, promising to help scientists pinpoint the causes of disease. “The broad genetic variation in the Greenlandic population has never been mapped before,” says co-author Torben Hansen, Professor at the Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Denmark. “Now we can start relating it to health.”
An epic migration
Scientists studying everything from disease susceptibility to ancestry rely on genetic architecture – maps of how genetic variants are distributed throughout a population – to understand how common or rare a certain trait is in a community, Torben Hansen explains.
To understand Greenland’s genetic architecture today, researchers need to look back hundreds of generations.
The ancestors of modern-day Greenlanders left Siberia about 20,000 years ago, gradually making their way across Alaska and the Canadian Arctic before arriving in Greenland about a thousand years ago. During this epic migration, Torben Hansen says, the group nearly died out on multiple occasions. These population bottlenecks have reduced the variation in the genes of their present-day descendants.
And since most genetic research has been conducted on ethnic Europeans, the genetic screens doctors rely on to predict disease risk do not work as well for Greenlanders, Torben Hansen explains. Some genetic landmarks for Europeans are absent for Greenlanders, and Greenlanders have a suite of their own landmarks unknown for Europeans.
Over the last thousand years, “Greenlanders have been exposed to probably the harshest shaping of their genome compared with other populations,” he says. “Some variants behave very differently compared with those of Europeans.”
Decades of volunteers
To map Greenland’s genetic architecture, Torben Hansen and his colleagues turned to a bank of DNA samples donated by Greenlanders participating in health surveys since 1999. Altogether, the team assembled nearly 6,000 DNA samples from Greenland residents collected between 1999 and 2019 – some with exclusively Inuit ancestry but most with a combination of Inuit and European ancestors.
To capture the population’s genetic diversity, Torben Hansen and his team first sequenced the complete genome – all 3 billion base pairs – for 448 individuals. Analysis of these full genomes revealed that each Greenlander had multiple genetic variants not present in European populations, Torben Hansen says.
This means that when a problem arises – for example, an unusual heart condition – researchers working with a European reference genome will struggle to determine which mutation might be associated with the condition. “If you have a strong reference genome, then you might know that, of 13 variants, 11 are common in the population and are not the root of the problem,” leaving just two for researchers to explore. “If you do not have this reference, then you need to evaluate all 13 variants – and even then, you might not be able to give effective advice and counselling to the family.”
To make further use of the new Greenlander-specific reference genome, the researchers analyzed the DNA of the other 5,548 participants to look for thousands of genetic landmarks called single nucleotide polymorphisms – one-letter variations in DNA that can be tied to variants.
Next, to better understand how these genetic variants affect health, they paired this information with personal health data from the participants – including data on their height, weight and history of metabolic disorders such as diabetes.
High-impact variants
Using the single nucleotide polymorphisms data, Torben Hansen and his colleagues confirmed that several genetic variants seem to strongly affect metabolic disorders among Inuit Greenlanders.
Today, Greenlanders experience high rates of metabolic disorders, with some estimates placing their risk of diabetes at double that of ethnic Danes. But Torben Hansen and his colleagues found that these metabolic variants are much more common than expected, suggesting that the same genetic variants that cause health problems in modern life might have benefitted their ancestors.
One of the biggest differences is how Greenlanders process fatty acid chains, which are rich in animal foods. “Living in the far north, you mostly have access to fish and animal food and nearly no carbohydrate,” Torben Hansen says.
Another difference is how some Greenlanders handle glucose. After a meal, energy in the form of glucose floods the bloodstream. Normally, the release of insulin prompts skeletal muscles to absorb much of this blood sugar, storing it for later use. But in people with a genetic variant in a gene called TBC1D4, insulin cannot stimulate glucose uptake in the muscles, meaning glucose remains in the blood longer. “People with this variant will have elevated glucose levels every time they eat,” says Torben Hansen.
Keeping blood sugar high might help to preserve brain function
Researchers suspect that these genetic variants could have helped ancient Greenlanders survive periods of starvation – keeping blood sugar high might help to preserve brain function.
“This is speculation, but it might be when you did not have carbohydrate and mainly had protein and fat, then you protected the glucose levels in your circulation for the brain,” Torben Hansen says.
The TBC1D4 variant was identified nearly a decade ago, but mapping the genetic architecture of Greenland has revealed that it is much more widespread than researchers anticipated.
“It turns out that around 4% of the population is lacking a functional copy of this gene,” Torben Hansen says. “This is the most common variant in diabetes, with the largest effect size ever reported. It does not exist among Europeans but explains more than 10% of all diabetes in Greenland.”
A roadmap for future clinicians
Genetic reference panels built from European populations were not as accurate at predicting metabolic disorders in the Greenlanders in the study, Torben Hansen and his colleagues found.
However, incorporating Arctic-specific genetic variants—discovered through mapping Greenland’s unique genetic landscape—increased the predictive accuracy to match, or even surpass, that seen in people of European descent, he says. As a result, a known genetic cause of diabetes can now be identified in one out of every five Greenlanders, he says.
This is a heartening moment for Torben Hansen, who has been studying metabolic disorders among Greenlanders since 1998. He says he hopes that this new genetic reference panel will be a roadmap clinicians can use to decipher determinants of health for Greenlanders and provide more effective health advice to their patients.
“If you do not study the Greenlandic genome, it is unfair to Greenlanders,” Torben Hansen says.
