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

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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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.

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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 

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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.

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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.

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Correspondence to Patrick Sulem or Kari Stefansson.

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

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

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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

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