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Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

Nature Genetics volume 46, pages 294–298 (2014)Cite this article

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Abstract

Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10−21) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10−12 and 0.56 kg/m2 per allele, P = 6.5 × 10−7, respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10−10 and OR = 1.47, P = 1.7 × 10−5, respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10−7).

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Figure 1: Manhattan plots of association results.

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Acknowledgements

We thank the subjects of the Icelandic deCODE study, the Danish studies and the Iranian study for their participation. We also thank the staff at the deCODE Genetics core facilities and all our colleagues for their important contributions to this work. The Danish studies were supported by the Lundbeck Foundation (Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp), http://www.lucamp.org/) and the Danish Council for Independent Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/).

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Authors and Affiliations

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

    Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Patrick Sulem, Hannes Helgason, Asgeir Sigurdsson, Hafdis T Helgadottir, Hrefna Johannsdottir, Olafur T Magnusson, Sigurjon A Gudjonsson, Gisli Masson, Agnar Helgason, Augustine Kong, Daniel F Gudbjartsson, Unnur Thorsteinsdottir & Kari Stefansson

  2. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    Hannes Helgason, Augustine Kong & Daniel F Gudbjartsson

  3. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Niels Grarup, Johanne M Justesen, Marie N Harder, Henrik Vestergaard, Torben Hansen & Oluf Pedersen

  4. Steno Diabetes Center, Gentofte, Denmark

    Marit E Jørgensen

  5. Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark

    Cramer Christensen

  6. Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark

    Ivan Brandslund

  7. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark

    Ivan Brandslund

  8. Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark

    Annelli Sandbæk & Torsten Lauritzen

  9. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark

    Allan Linneberg & Torben Jørgensen

  10. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Torben Jørgensen

  11. Faculty of Medicine, University of Aalborg, Aalborg, Denmark

    Torben Jørgensen

  12. Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Maryam S Daneshpour & Mohammad-Sadegh Fallah

  13. Department of Endocrinology and Metabolism, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland

    Astradur B Hreidarsson, Gunnar Sigurdsson & Rafn Benediktsson

  14. Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fereidoun Azizi

  15. Department of Anthropology, University of Iceland, Reykjavik, Iceland

    Agnar Helgason

  16. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Unnur Thorsteinsdottir & Kari Stefansson

Authors
  1. Valgerdur Steinthorsdottir
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  2. Gudmar Thorleifsson
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Contributions

V.S., G.T., D.F.G., A.K., U.T. and K.S. designed the study and interpreted the results. G.T., P.S., H.H., D.F.G., O.T.M., A.H., A.K. and G.M. performed analysis of sequence data, imputation and association analysis. N.G., J.M.J., M.N.H., T.H., G.T. and O.P. performed analysis and interpretation of Danish clinical and physiological data. Subject recruitment, phenotype analysis and biological material collection were organized and carried out by A.B.H., G.S. and R.B. in Iceland; T.J., A.L., M.E.J., C.C., I.B., A. Sandbæk, T.L., H.V., T.H. and O.P. in Denmark; and M.S.D., M.-S.F. and F.A. in Iran. O.T.M. and U.T. supervised sequencing and genotyping. N.G., T.H. and O.P. supervised genotyping of Danish samples. S.A.G. performed bioinformatics analyses. A. Sigurdsson, H.T.H. and H.J. performed and analyzed data from Sanger sequencing and Centaurus genotyping. G.T. and A. Sigurdsson performed and analyzed data from expression experiments. V.S., G.T., N.G., O.P., U.T. and K.S. drafted the manuscript. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Unnur Thorsteinsdottir or Kari Stefansson.

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Competing interests

V.S., G.T., P.S., H.H., A. Sigurdsson, A.H., H.T.H., H.J., O.T.M., S.A.G., G.M., D.F.G., A.K., U.T. and K.S. are employees of deCODE Genetics/Amgen, Inc.

Integrated supplementary information

Supplementary Figure 1 Correlation between genotypes of rs76895963 and the expression of CCND2 in adipose tissue samples from 637 individuals.

The vertical axis shows the average relative expression, i.e. 10^(average MLR), where MLR is the mean log expression ratio, and the average is over individuals with a particular genotypes. The error bars indicate the standard error of the mean. Regressing the MLR values on the number of at-risk alleles rs76895963-G that an individual carries, adjusting for the effects of age, sex and BMI by including those as explanatory variables, yields an estimated 38% increase in expression per allele carried (P = 0.000011). All P values were adjusted for the relatedness of the individuals by simulating genotypes through the Icelandic genealogy. The resulting adjustment factors for the χ2 statistic were 1.08 for adipose. We also tested the correlation of the expression of CCND2 with all variants in a 1-Mb region centered on the gene to compare with the observed correlation with rs76895963.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–7 and Supplementary Figure 1 (PDF 760 kb)

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Steinthorsdottir, V., Thorleifsson, G., Sulem, P. et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat Genet 46, 294–298 (2014). https://doi.org/10.1038/ng.2882

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