Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Genetics volume 41, pages 734–738 (2009)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of the 6q21 locus based on the UCSC genome browser.
Figure 2: The association with AAM of SNPs previously reported to associate with anthropometric traits.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Onland-Moret, N.C. et al. Age at menarche in relation to adult height: the EPIC study. Am. J. Epidemiol. 162, 623–632 (2005).

    Article  CAS  Google Scholar 

  2. Kaplowitz, P.B. Link between body fat and the timing of puberty. Pediatrics 121 Suppl 3, S208–S217 (2008).

    Article  Google Scholar 

  3. Gudbjartsson, D.F. et al. Many sequence variants affecting diversity of adult human height. Nat. Genet. 40, 609–615 (2008).

    Article  CAS  Google Scholar 

  4. Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat. Genet. 40, 584–591 (2008).

    Article  CAS  Google Scholar 

  5. Weedon, M.N. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat. Genet. 40, 575–583 (2008).

    Article  CAS  Google Scholar 

  6. Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  CAS  Google Scholar 

  7. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).

    Article  CAS  Google Scholar 

  8. Hinney, A. et al. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS ONE 2, e1361 (2007).

    Article  Google Scholar 

  9. Loos, R.J. et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768–775 (2008).

    Article  CAS  Google Scholar 

  10. Thorleifsson, G. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009).

    Article  CAS  Google Scholar 

  11. Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

    Article  CAS  Google Scholar 

  12. Clavel-Chapelon, F. Differential effects of reproductive factors on the risk of pre- and postmenopausal breast cancer. Results from a large cohort of French women. Br. J. Cancer 86, 723–727 (2002).

    Article  CAS  Google Scholar 

  13. Jordan, S.J., Webb, P.M. & Green, A.C. Height, age at menarche, and risk of epithelial ovarian cancer. Cancer Epidemiol. Biomarkers Prev. 14, 2045–2048 (2005).

    Article  Google Scholar 

  14. Purdie, D.M. & Green, A.C. Epidemiology of endometrial cancer. Best Pract. Res. Clin. Obstet. Gynaecol. 15, 341–354 (2001).

    Article  CAS  Google Scholar 

  15. Eastell, R. Role of oestrogen in the regulation of bone turnover at the menarche. J. Endocrinol. 185, 223–234 (2005).

    Article  CAS  Google Scholar 

  16. Herman-Giddens, M.E. et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99, 505–512 (1997).

    Article  CAS  Google Scholar 

  17. Morabia, A. & Costanza, M.C. International variability in ages at menarche, first livebirth, and menopause. World Health Organization collaborative study of neoplasia and steroid contraceptives. Am. J. Epidemiol. 148, 1195–1205 (1998).

    Article  CAS  Google Scholar 

  18. Thomas, F., Renaud, F., Benefice, E., de Meeus, T. & Guegan, J.F. International variability of ages at menarche and menopause: patterns and main determinants. Hum. Biol. 73, 271–290 (2001).

    Article  CAS  Google Scholar 

  19. Tanner, J.M. Trend towards earlier menarche in London, Olso, Copenhagen, the Netherlands and Hungary. Nature 243, 95–96 (1973).

    Article  CAS  Google Scholar 

  20. Euling, S.Y. et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics 121 (Suppl. 3), S172–S191 (2008).

    Article  Google Scholar 

  21. Tryggvadottir, L., Tulinius, H. & Larusdottir, M. A decline and a halt in mean age at menarche in Iceland. Ann. Hum. Biol. 21, 179–186 (1994).

    Article  CAS  Google Scholar 

  22. van den Berg, S.M. & Boomsma, D.I. The familial clustering of age at menarche in extended twin families. Behav. Genet. 37, 661–667 (2007).

    Article  Google Scholar 

  23. Towne, B. et al. Heritability of age at menarche in girls from the Fels Longitudinal Study. Am. J. Phys. Anthropol. 128, 210–219 (2005).

    Article  Google Scholar 

  24. Anderson, C.A., Duffy, D.L., Martin, N.G. & Visscher, P.M. Estimation of variance components for age at menarche in twin families. Behav. Genet. 37, 668–677 (2007).

    Article  Google Scholar 

  25. Devlin, B., Bacanu, S.A. & Roeder, K. Genomic Control to the extreme. Nat. Genet. 36, 1129–1130; author reply 1131 (2004).

    Article  CAS  Google Scholar 

  26. Guo, Y. et al. Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma. Gene 384, 51–61 (2006).

    Article  CAS  Google Scholar 

  27. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  Google Scholar 

  28. The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  29. Lakshman, R. et al. Association between age at menarche and risk of diabetes in adults: results from the EPIC-Norfolk cohort study. Diabetologia 51, 781–786 (2008).

    Article  CAS  Google Scholar 

  30. Olsen, J. et al. The Danish National Birth Cohort–its background, structure and aim. Scand. J. Public Health 29, 300–307 (2001).

    Article  CAS  Google Scholar 

Download references

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

Author notes

  1. Patrick Sulem and Daniel F Gudbjartsson: These authors contributed equally to this work.

Authors and 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

Authors
  1. Patrick Sulem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel F Gudbjartsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thorunn Rafnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hilma Holm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elinborg J Olafsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gudridur H Olafsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thorvaldur Jonsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Alexandersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bjarke Feenstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Heather A Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Katja K Aben
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andre L M Verbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nel Roeleveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Aslaug Jonasdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Unnur Styrkarsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Valgerdur Steinthorsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Ari Karason
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Simon N Stacey
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Julius Gudmundsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Margret Jakobsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Gudmar Thorleifsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Gudmundur Hardarson
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Jeffrey Gulcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Augustine Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Lambertus A Kiemeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Mads Melbye
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Claus Christiansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Laufey Tryggvadottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Unnur Thorsteinsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Kari Stefansson
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Patrick Sulem or Kari Stefansson.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1–5, Supplementary Methods and Supplementary Note (PDF 307 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sulem, P., Gudbjartsson, D., Rafnar, T. et al. Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat Genet 41, 734–738 (2009). https://doi.org/10.1038/ng.383

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing