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

• 成果类型: Article
• 署名作者: Staeger, Frederik Filip; Andersen, Mette K.; Li, Zilong; Hjerresen, Jasmin Pernille; He, Shixu; Santander, Cindy G.; Jensen, Rasmus Tanderup; Rex, Karsten Fleischer; Thuesen, Anne Cathrine Baun; Hanghoj, Kristian; Seiding, Inge Host; Jorsboe, Emil; Stinson, Sara Elizabeth; Rasmussen, Malthe Sebro; Balboa, Renzo F.; Larsen, Christina Viskum Lytken; Bjerregaard, Peter; Schubert, Mikkel; Meisner, Jonas; Linneberg, Allan; Grarup, Niels; Zeggini, Eleftheria; Nielsen, Rasmus; Jorgensen, Marit E.; Hansen, Torben; Moltke, Ida; Albrechtsen, Anders
• 署名单位: University of Copenhagen; University of Copenhagen; Aalborg University; Aalborg University Hospital; University of Oxford; University of Oxford; University of Southern Denmark; University of Copenhagen; Bispebjerg Hospital; Copenhagen University Hospital; University of Copenhagen; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Technical University of Munich; Technical University of Munich; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of Copenhagen
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2095
• DOI: 10.1038/s41586-024-08516-4
• 发表日期: 2025-03-13
• 关键词: diversity; genomes; common; inuit; sequence; variant; association; efficient; ancestry; insights

摘要

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.