Genetic architecture in Greenland is shaped by demography, structure and selection

Frederik Filip Stæger, Mette K. Andersen, Zilong Li, Jasmin Pernille Hjerresen, Shixu He, Cindy G. Santander, Rasmus Tanderup Jensen, Karsten Fleischer Rex, Anne Cathrine Baun Thuesen, Kristian Hanghøj, Inge Høst Seiding, Emil Jørsboe, Sara Elizabeth Stinson, Malthe Sebro Rasmussen, Renzo F. Balboa, Christina Viskum Lytken Larsen, Peter Bjerregaard, Mikkel Schubert, Jonas Meisner, Allan Linneberg, Niels Grarup, Eleftheria Zeggini, Rasmus Nielsen, Marit E. Jørgensen, Torben Hansen (), Ida Moltke () and Anders Albrechtsen ()
Additional contact information
Frederik Filip Stæger: Section for Computational and RNA Biology, University of Copenhagen
Mette K. Andersen: Faculty of Health and Medical Sciences, University of Copenhagen
Zilong Li: Section for Computational and RNA Biology, University of Copenhagen
Jasmin Pernille Hjerresen: Faculty of Health and Medical Sciences, University of Copenhagen
Shixu He: Section for Computational and RNA Biology, University of Copenhagen
Cindy G. Santander: Section for Computational and RNA Biology, University of Copenhagen
Rasmus Tanderup Jensen: Faculty of Health and Medical Sciences, University of Copenhagen
Karsten Fleischer Rex: Queen Ingrid’s Hospital
Anne Cathrine Baun Thuesen: Faculty of Health and Medical Sciences, University of Copenhagen
Kristian Hanghøj: Section for Computational and RNA Biology, University of Copenhagen
Inge Høst Seiding: Ilisimatusarfik - University of Greenland
Emil Jørsboe: Faculty of Health and Medical Sciences, University of Copenhagen
Sara Elizabeth Stinson: Faculty of Health and Medical Sciences, University of Copenhagen
Malthe Sebro Rasmussen: Section for Computational and RNA Biology, University of Copenhagen
Renzo F. Balboa: Section for Computational and RNA Biology, University of Copenhagen
Christina Viskum Lytken Larsen: National Institute of Public Health, University of Southern Denmark
Peter Bjerregaard: National Institute of Public Health, University of Southern Denmark
Mikkel Schubert: Faculty of Health and Medical Sciences, University of Copenhagen
Jonas Meisner: Faculty of Health and Medical Sciences, University of Copenhagen
Allan Linneberg: Bispebjerg and Frederiksberg Hospital, The Capital Region of Denmark
Niels Grarup: Faculty of Health and Medical Sciences, University of Copenhagen
Eleftheria Zeggini: Helmholtz Zentrum München – German Research Center for Environmental Health
Rasmus Nielsen: University of California at Berkeley
Marit E. Jørgensen: National Institute of Public Health, University of Southern Denmark
Torben Hansen: Faculty of Health and Medical Sciences, University of Copenhagen
Ida Moltke: Section for Computational and RNA Biology, University of Copenhagen
Anders Albrechtsen: Section for Computational and RNA Biology, University of Copenhagen

Nature, 2025, vol. 639, issue 8054, 404-410

Abstract: Abstract Greenlandic Inuit and other indigenous populations are underrepresented in genetic research1,2, leading to inequity in healthcare opportunities. To address this, we performed analyses of sequenced or imputed genomes of 5,996 Greenlanders with extensive phenotypes. We quantified their historical population bottleneck and how it has shaped their genetic architecture to have fewer, but more common, variable sites. Consequently, we find twice as many high-impact genome-wide associations to metabolic traits in Greenland compared with Europe. We infer that the high-impact variants arose after the population split from Native Americans and thus are Arctic-specific, and show that some of them are common due to not only genetic drift but also selection. We also find that European-derived polygenic scores for metabolic traits are only half as accurate in Greenlanders as in Europeans, and that adding Arctic-specific variants improves the overall accuracy to the same level as in Europeans. Similarly, lack of representation in public genetic databases makes genetic clinical screening harder in Greenlandic Inuit, but inclusion of Greenlandic data remedies this by reducing the number of non-causal candidate variants by sixfold. Finally, we identify pronounced genetic fine structure that explains differences in prevalence of monogenic diseases in Greenland and, together with recent changes in mobility, leads to a predicted future reduction in risk for certain recessive diseases. These results illustrate how including data from Greenlanders can greatly reduce inequity in genomic-based healthcare.

Date: 2025
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DOI: 10.1038/s41586-024-08516-4

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