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Genetic variation in LIN28B is associated with the timing of puberty

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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Figure 1: Regional plot of the locus around LIN28B associated with age at menarche.
Figure 2
Figure 3: Kaplan-Maier plot of survival in pre-pubertal status (Tanner breast stage 1) by age and LIN28B rs314276 genotype in ALSPAC girls (N = 3,233).
Figure 4: Adolescent growth in ALSPAC girls by LIN28B rs314276 genotype.

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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.

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Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Ken K Ong or Ruth J Loos.

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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).

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–3, Supplementary Note (PDF 354 kb)

Supplementary Table 4

Candidate gene SNP associations with age at menarche (XLS 136 kb)

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Ong, K., Elks, C., Li, S. et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat Genet 41, 729–733 (2009). https://doi.org/10.1038/ng.382

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