Abstract

Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants1 on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10−10), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10−11 and 7.3% per allele, P = 7.5 × 10−18, respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r2 = 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.

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Acknowledgements

The authors thank the subjects of the Icelandic deCODE study and the Iranian study for their participation. We also thank the staff at deCODE Genetics core facilities and all our colleagues for their contributions to this work. This research project has been supported by grant no. 121 NRCI Research Project and with the support of the National Research Council of the Islamic Republic of Iran.

Author information

Affiliations

  1. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

    • Erna V Ivarsdottir
    • , Valgerdur Steinthorsdottir
    • , Gudmar Thorleifsson
    • , Patrick Sulem
    • , Hilma Holm
    • , Snaevar Sigurdsson
    • , Unnur Thorsteinsdottir
    • , Daniel F Gudbjartsson
    •  & Kari Stefansson
  2. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.

    • Erna V Ivarsdottir
    •  & Daniel F Gudbjartsson
  3. Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

    • Maryam S Daneshpour
  4. Department of Endocrinology and Metabolic Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.

    • Astradur B Hreidarsson
    • , Gunnar Sigurdsson
    •  & Rafn Benediktsson
  5. Children's Medical Center, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.

    • Ragnar Bjarnason
    •  & Arni V Thorsson
  6. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

    • Ragnar Bjarnason
    • , Rafn Benediktsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  7. Laboratory in Mjodd, RAM, Reykjavik, Iceland.

    • Gudmundur Eyjolfsson
  8. Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.

    • Olof Sigurdardottir
  9. Department of Clinical Biochemistry, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.

    • Isleifur Olafsson
  10. Iranian Molecular Medicine Network, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.

    • Sirous Zeinali
  11. Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

    • Fereidoun Azizi

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Contributions

E.V.I., V.S., P.S., H.H., U.T., D.F.G. and K.S. designed the study and interpreted the results. E.V.I. and D.F.G. performed statistical analysis. M.S.D., G.T., S.S., A.B.H., G.S., R. Bjarnason, A.V.T., R. Benediktsson, G.E., O.S., I.O., S.Z. and F.A. performed recruitment and phenotyping. The manuscript was drafted by E.V.I., V.S., D.F.G. and K.S. All authors contributed to the final version of the manuscript.

Competing interests

E.V.I., V.S., G.T., P.S., H.H., S.S., U.T., D.F.G. and K.S. are employees of deCODE Genetics/Amgen, Inc.

Corresponding authors

Correspondence to Daniel F Gudbjartsson or Kari Stefansson.

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DOI

https://doi.org/10.1038/ng.3928

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