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Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche

Nature Genetics 41, 734–738 (2009) | Download Citation

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Abstract

Earlier menarche correlates with shorter adult height1 and higher childhood body fat2. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10−14). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height3,4. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height3,4,5, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI)6,7,8,9,10,11 and 5 of those associated with earlier AAM.

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Acknowledgements

The Danish National Research Foundation has established the Danish Epidemiology Science Centre, which initiated and created the Danish National Birth Cohort. The cohort was established with the support of a major grant from this foundation. Additional support for the Danish National Birth Cohort has been obtained from the Danish Pharmacists' Fund, the Egmont Foundation the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies.

Author information

    • Patrick Sulem
    •  & Daniel F Gudbjartsson

    These authors contributed equally to this work.

Affiliations

  1. deCODE Genetics, Reykjavik, Iceland.

    • Patrick Sulem
    • , Daniel F Gudbjartsson
    • , Thorunn Rafnar
    • , Hilma Holm
    • , Aslaug Jonasdottir
    • , Unnur Styrkarsdottir
    • , Valgerdur Steinthorsdottir
    • , Ari Karason
    • , Simon N Stacey
    • , Julius Gudmundsson
    • , Margret Jakobsdottir
    • , Gudmar Thorleifsson
    • , Gudmundur Hardarson
    • , Jeffrey Gulcher
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson

  2. Department of Internal Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Hilma Holm

  3. Icelandic Cancer Registry, Reykjavik, Iceland.

    • Elinborg J Olafsdottir
    • , Gudridur H Olafsdottir
    •  & Laufey Tryggvadottir

  4. Department of Surgery, University Hospital, Reykjavik, Iceland.

    • Thorvaldur Jonsson

  5. Center for Clinical and Basic Research A/S, Ballerup, Denmark.

    • Peter Alexandersen

  6. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

    • Bjarke Feenstra
    • , Heather A Boyd
    •  & Mads Melbye

  7. Comprehensive Cancer Centre East, Nijmegen, The Netherlands.

    • Katja K Aben
    •  & Lambertus A Kiemeney

  8. Radboud University Nijmegen Medical Center Department of Epidemiology & Biostatistics, Nijmegen, The Netherlands.

    • Andre L M Verbeek
    • , Nel Roeleveld
    •  & Lambertus A Kiemeney

  9. Radboud University Nijmegen Department of Urology, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney

  10. Nordic bioscience A/S, Herlev, Denmark.

    • Claus Christiansen

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

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson

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Contributions

P.S., D.F.G., T.R., H.H. and K.S. wrote the first draft of the paper. P.S., D.F.G., G.T. and A.K. analyzed the data. T.R., E.J.O., G.H.O., T.J., U.S., V.S., A.K., S.N.S., J.G. and L.T. collected the Icelandic data. A.J. peformed expression measurements. M.J., G.H. and U.T. carried out the genotyping. P.A., B.F., H.A.B., M.M. and C.C. collected the Danish data. K.K.A., A.L.M.V., N.R. and L.A.K. collected the Dutch data. P.S., D.F.G., T.R., J.G., L.A.K., M.M., C.C., L.T., U.T. and K.S. planned and supervised the work.

Competing interests

Some of the authors employed by deCODE genetics own stock or stock options in the company.

Corresponding authors

Correspondence to Patrick Sulem or Kari Stefansson.

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DOI

https://doi.org/10.1038/ng.383

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