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Genetic variation in LIN28B is associated with the timing of puberty

Nature Genetics 41, 729–733 (2009) | Download Citation

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Abstract

The timing of puberty is highly variable1. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 × 10−8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 × 10−10; combined P = 3.6 × 10−16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 × 10−7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing2, as the first genetic determinant regulating the timing of human pubertal growth and development.

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References

  1. 1.

    et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 24, 668–693 (2003).

  2. 2.

    , & Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).

  3. 3.

    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).

  4. 4.

    , & What controls the timing of puberty? An update on progress from genetic investigation. Curr. Opin. Endocrinol. Diabetes Obes. 16, 16–24 (2009).

  5. 5.

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

  6. 6.

    , , , & Changes in the male voice at puberty. Arch. Dis. Child. 77, 445–447 (1997).

  7. 7.

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

  8. 8.

    & Heterochronic mutants of the nematode Caenorhabditis elegans. Science 226, 409–416 (1984).

  9. 9.

    , & The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA. Cell 88, 637–646 (1997).

  10. 10.

    et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

  11. 11.

    et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br. J. Cancer 80 (Suppl. 1), 95–103 (1999).

  12. 12.

    et al. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc. Disord. 8, 6 (2008).

  13. 13.

    , & ALSPAC — the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr. Perinat. Epidemiol. 15, 74–87 (2001).

  14. 14.

    , , & Cohort Profile: The 1946 National Birth Cohort (MRC National Survey of Health and Development). Int. J. Epidemiol. 35, 49–54 (2006).

  15. 15.

    et al. Genetic and environmental influences on pubertal timing assessed by height growth. Am. J. Hum. Biol. 20, 417–423 (2008).

Download references

Acknowledgements

We are grateful to all of the participants in each of the studies contributing to this effort. Full acknowledgments can be found in the Supplementary Note.

Support for this research was provided by: the UK Medical Research Council; the Wellcome Trust; University of Bristol; the Faculty of Biology and Medicine of Lausanne, Switzerland; and GlaxoSmithKline.

Author information

Affiliations

  1. Medical Research Council (MRC) Epidemiology Unit, Addenbrooke's Hospital, Cambridge, UK.

    • Ken K Ong
    • , Cathy E Elks
    • , Shengxu Li
    • , Jing Hua Zhao
    • , Jian'an Luan
    • , Soren Brage
    • , Ulf Ekelund
    • , Christopher J Gillson
    • , Matthew A Sims
    • , Ruth J Loos
    •  & Nicholas J Wareham

  2. Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Ken K Ong
    • , Cathy E Elks
    • , Shengxu Li
    • , Jing Hua Zhao
    • , Jian'an Luan
    • , Soren Brage
    • , Ulf Ekelund
    • , Christopher J Gillson
    • , Matthew A Sims
    • , Ruth J Loos
    •  & Nicholas J Wareham

  3. Department of Paediatrics, University of Cambridge, Cambridge, UK.

    • Ken K Ong

  4. Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.

    • Lars B Andersen

  5. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge, UK.

    • Sheila A Bingham

  6. MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Cambridge, UK.

    • Sheila A Bingham

  7. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK.

    • George Davey Smith
    •  & Beate Glaser

  8. School of Health and Medical Sciences, Örebro University, Örebro, Sweden.

    • Ulf Ekelund

  9. Avon Longitudinal Study of Parents and Children (ALSPAC), Department of Community Based Medicine, University of Bristol, Bristol, UK.

    • Jean Golding

  10. MRC Unit for Lifelong Health and Ageing, London, UK.

    • Rebecca Hardy
    • , Diana Kuh
    •  & Andrew Wong

  11. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
    •  & Robert Luben

  12. National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

    • Michele Marcus
    • , Michael A McGeehin
    •  & Carol Rubin

  13. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

    • Michele Marcus

  14. Departments of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

    • Michele Marcus

  15. Department of Oral and Dental Science, University of Bristol, Bristol, UK.

    • Andrew R Ness

  16. ALSPAC, Department of Social Medicine, University of Bristol, Bristol, UK.

    • Kate Northstone
    •  & Susan M Ring

  17. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Kijoung Song
    • , Dawn M Waterworth
    •  & Vincent Mooser

  18. Division of Community Health Sciences, St. George's, University of London, London, UK.

    • David P Strachan

  19. Department of Internal Medicine, BH-10 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber

  20. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Panagiotis Deloukas
    •  & Inês Barroso

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Contributions

Writing group: C.E.E., R.J.L., S.L., K.K.O., N.J.W.

Genome-wide association analyses and meta-analyses: I.B., P.D., C.E.E., S.L., R.J.L., V.M., K.K.O., N.J.W., J.H.Z.

Oversight of contributing cohorts: L.B.A., S.B., U.E., J.G., D.K., K.-T.K., S.A.B., V.M., A.R.N., D.P.S., G.D.S., P.V., N.J.W.

Phenotype preparation and analyses in contributing cohorts: S.B., U.E., B.G., J.G., R.H., S.L., J.L., R.L., R.J.L., M.M., M.A.M., A.R.N., K.N., K.K.O., C.R., D.P.S., K.S., G.W., D.M.W., J.H.Z.

Generating new genotype data: C.J.G., S.M.R., M.A.S., A.W.

Competing interests

Vincent Mooser, Dawn Waterworth and Kijoung Song are full-time employees of GlaxoSmithKline. Peter Vollenweider and Gérard Waeber received financial support from GlaxoSmithKline to build the CoLaus study. Inês Barroso owns stock in the companies GlaxoSmithKline (GSK) and Incyte (INCY).

Corresponding authors

Correspondence to Ken K Ong or Ruth J Loos.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3 and Supplementary Tables 1–3, Supplementary Note

Excel files

  1. 1.

    Supplementary Table 4

    Candidate gene SNP associations with age at menarche

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DOI

https://doi.org/10.1038/ng.382

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