Abstract

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years1. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l−1, P = 2.5 × 10−35) and serum insulin (β = 165 pmol l−1, P = 1.5 × 10−20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = −0.18 mmol l−1, P = 1.1 × 10−6) and fasting serum insulin (β = −8.3 pmol l−1, P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10−24). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l−1, P = 5.3 × 10−5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2,3,4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

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Acknowledgements

We thank I. Kleist, as well as all colleagues at the Physician’s Clinic, Nuuk, Greenland. We also thank J. F. Wojtaszewski for comments and X. Zhou for discussions about GEMMA. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen and is partly funded by an unrestricted donation from the Novo Nordisk Foundation. This project was also funded by the Danish Council for Independent Research (Medical Sciences), the Steno Diabetes Center and the Villum Foundation. The IHIT study was supported by Karen Elise Jensen’s Foundation, NunaFonden, the Medical Research Council of Denmark, the Medical Research Council of Greenland and the Commission for Scientific Research in Greenland. None of the funding agencies had any role in the study design or in the collection or interpretation of the data.

Author information

Author notes

    • Ida Moltke
    •  & Niels Grarup

    These authors contributed equally to this work.

Affiliations

  1. The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark

    • Ida Moltke
    •  & Anders Albrechtsen
  2. Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA

    • Ida Moltke
  3. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark

    • Niels Grarup
    • , Nikolaj T. Krarup
    • , Anette P. Gjesing
    • , Jun Wang
    • , Oluf Pedersen
    •  & Torben Hansen
  4. Steno Diabetes Center, 2820 Gentofte, Denmark

    • Marit E. Jørgensen
  5. National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen, Denmark

    • Peter Bjerregaard
  6. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark

    • Jonas T. Treebak
    • , Marianne A. Andersen
    • , Thomas S. Nielsen
    •  & Juleen R. Zierath
  7. Department of Integrative Biology, University of California, Berkeley, California 94720, USA

    • Matteo Fumagalli
    •  & Rasmus Nielsen
  8. Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark

    • Thorfinn S. Korneliussen
  9. Department of Molecular Medicine and Surgery, Karolinska Institute, 171 77 Stockholm, Sweden

    • Juleen R. Zierath
  10. Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark

    • Allan Linneberg
  11. BGI-Shenzhen, Shenzhen 518083, China

    • Xueli Wu
    • , Guangqing Sun
    • , Xin Jin
    • , Jumana Al-Aama
    •  & Jun Wang
  12. The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia

    • Jumana Al-Aama
    •  & Jun Wang
  13. Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark

    • Jun Wang
  14. Macau University of Science and Technology, Macau 999078, China

    • Jun Wang
  15. Holbaek Hospital, 4300 Holbaek, Denmark

    • Knut Borch-Johnsen
  16. Department of Statistics, University of California, Berkeley, California 94720, USA

    • Rasmus Nielsen
  17. Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark

    • Torben Hansen

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Contributions

T.H. and A.A. conceived and headed the project. I.M., R.N. and A.A. designed the statistical set-up, and T.H., N.G., A.P.G. and O.P. designed the experimental set-up for the DNA extraction, genotyping and sequencing. A.L. provided the Danish samples. M.E.J., P.B. and K.B.-J. provided the Greenlandic samples, collected and defined the phenotypes and provided context for these samples. I.M. and A.A. performed the admixture, relatedness and linkage disequilibrium analyses. I.M. carried out the statistical part of the association analysis and N.G. carried out the medical part, with input from A.A., T.H., O.P. and R.N. The Chinese samples were analysed by X.W., G.S., X.J., J.A.-A. and J.W. N.G. analysed the Danish samples. X.W., G.S., X.J., J.A.-A. and J.W. performed the library constructions and sequencing. T.S.K. performed the mapping and genotyping for the sequencing data. M.F. and R.N. performed the selection analysis. N.T.K. collected muscle biopsies, and J.T.T., T.S.N., M.A.A. and J.R.Z. experimentally analysed and interpreted the TBC1D4 and GLUT4 expression data. N.G., I.M., A.A. and T.H. wrote most of the manuscript, with input from R.N., O.P., M.E.J. and P.B. All authors approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Anders Albrechtsen or Torben Hansen.

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    Supplementary Notes

    This file contains a brief description of the methods applied in selection analysis and the outcome of the analysis.

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DOI

https://doi.org/10.1038/nature13425

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