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


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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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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Authors and Affiliations



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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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).

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