Genetic variation in LIN28B is associated with the timing of puberty
Open accessAbstract
The timing of puberty is highly variable. 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 processing, as the first genetic determinant regulating the timing of human pubertal growth and development.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
LIN28B was significant in the meta-analysis and has been linked to age at menarche.
“The lin-28 homolog b (LIN28B) gene was significant in our meta-analysis and has been associated with age of menarche 37.”
From Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions (2019) · cites this paper as [37]
In 2009, genome-wide association studies identified an association between the locus 6q21 (in or near the LIN28B gene) and age at menarche and height.
“In 2009, genome-wide association studies identified an association between the locus 6q21 (in or near the LIN28B gene) with age at menarche and height.81–84”
From Pubertal development and regulation (2016) · cites this paper as [84]
Common variants in LIN28B were associated with age at menarche in four independent genome-wide association studies.
“common variants in LIN28B were associated with age at menarche in four independent genome-wide association studies (GWAS)8–11”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [9]
Previous studies comprising up to 17,510 women had detected only one or two genome-wide significant signals.
“Previous studies comprising up to 17,510 women had detected only one or two genome-wide significant signals8–11.”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [9]
The known menarche locus in LIN28B was shown to also influence the onset of breast development in girls, the timing of pubic hair development and voice breaking in boys, and the timing of the pubertal growth spurt in both boys and girls.
“The known menarche locus in LIN28B was shown to also influence the onset of breast development in girls, the timing of pubic hair development and voice breaking in boys9, and the timing of the pubertal growth spurt in both boys and girls41.”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [9]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells
Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., et al. (2007) · Science · doi:10.1126/science.1151526 · Cited by 10,310 · see citing works
Parent, A.-S., Teilmann, G., Juul, A., Skakkebaek, N. E., Toppari, J., & Bourguignon, J.-P. (2003) · Endocrine Reviews · doi:10.1210/er.2002-0019 · Cited by 1,762 · see citing works
ALSPAC–The Avon Longitudinal Study of Parents and Children
Golding, Pembrey, Jones, & The Alspac Study Team (2001) · Paediatric and Perinatal Epidemiology · doi:10.1046/j.1365-3016.2001.00325.x · Cited by 1,549 · see citing works
Selective Blockade of MicroRNA Processing by Lin28
Viswanathan, S. R., Daley, G. Q., & Gregory, R. I. (2008) · Science · doi:10.1126/science.1154040 · Cited by 1,442 · see citing works
Heterochronic Mutants of the Nematode <i>Caenorhabditis elegans</i>
Ambros, V., & Horvitz, H. R. (1984) · Science · doi:10.1126/science.6494891 · Cited by 797 · see citing works
Day, N., Oakes, S., Luben, R., Khaw, K., Bingham, S., Welch, A., & Wareham, N. (1999) · Nature · doi:10.17863/cam.89388 · Cited by 780 · see citing works
Self-citationMoss, E. G., Lee, R. C., & Ambros, V. (1997) · Cell · doi:10.1016/s0092-8674(00)81906-6 · Cited by 723 · see citing works
Firmann, M., Mayor, V., Marques-Vidal, P. M., Bochud, M., Pécoud, A. R., Hayoz, D., Paccaud, F. M., Preisig, M., Song, K. S., Yuan, X., et al. (2008) · BMC Cardiovascular Disorders · doi:10.1186/1471-2261-8-6 · Cited by 715 · see citing works
Self-citationIdentification of ten loci associated with height highlights new biological pathways in human growth
Initiative, T. D. G., Lettre, G., FUSION, KORA, The Prostate, L. C. A. O. C. S. T., Study, T. N. H., SardiNIA, Jackson, A., Gieger, C., Schumacher, F. R., et al. (2008) · Nature Genetics · doi:10.1038/ng.125 · Cited by 583 · see citing works
Cohort Profile: The 1946 National Birth Cohort (MRC National Survey of Health and Development)
Wadsworth, M., Kuh, D., Richards, M., & Hardy, R. (2006) · International Journal of Epidemiology · doi:10.1093/ije/dyi201 · Cited by 515 · see citing works
Self-citationIdentification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma
Guo, Y., Chen, Y., Ito, H., Watanabe, A., Ge, X., Kodama, T., & Aburatani, H. (2006) · Gene · doi:10.1016/j.gene.2006.07.011 · Cited by 291 · see citing works
Lakshman, R., Forouhi, N. G., Luben, R., Bingham, S. A., Khaw, K., Wareham, N. J., & Ong, K. K. (2008) · Diabetologia · doi:10.1007/s00125-008-0948-5 · Cited by 203 · see citing works
Self-citationChanges in the male voice at puberty
Harries, M. L., Walker, J. M., Williams, D., Hawkins, S., & Hughes, I. A. (1997) · Archives of Disease in Childhood · doi:10.1136/adc.77.5.445 · Cited by 179 · see citing works
What controls the timing of puberty? An update on progress from genetic investigation
Gajdos, Z. K. Z., Hirschhorn, J. N., & Palmert, M. R. (2009) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e328320253c · Cited by 94 · see citing works
Genetic and environmental influences on pubertal timing assessed by height growth
Wehkalampi, K., Silventoinen, K., Kaprio, J. A., Dick, D. M., Rose, R. J., Pulkkinen, L., & Dunkel, L. (2008) · American Journal of Human Biology · doi:10.1002/ajhb.20748 · Cited by 87 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0326-7 · Cited by 2,565 · see citing works
Pubertal development and regulation
Abreu, A. P., & Kaiser, U. B. (2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00418-0 · Cited by 611 · see citing works
Study, T. L. C., Day, F. R., The InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Thompson, D. J., Helgason, H., Chasman, D. I., et al. (2017) · Nature Genetics · doi:10.1038/ng.3841 · Cited by 587 · see citing works
Self-citationThirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
The GIANT Consortium, Elks, C. E., Perry, J. R. B., Sulem, P., Chasman, D. I., Franceschini, N., He, C., Lunetta, K. L., Visser, J. A., Byrne, E. M., et al. (2010) · Nature Genetics · doi:10.1038/ng.714 · Cited by 504 · see citing works
Self-citationParent, A.-S., Franssen, D., Fudvoye, J., Gérard, A., & Bourguignon, J.-P. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.12.004 · Cited by 175 · see citing works
Lee, Y. T., de Vasconcellos, J. F., Yuan, J., Byrnes, C., Noh, S.-J., Meier, E. R., Kim, K. S., Rabel, A., Kaushal, M., Muljo, S. A., et al. (2013) · Blood · doi:10.1182/blood-2012-12-472308 · Cited by 142 · see citing works
Epigenetic regulation of female puberty
Lomniczi, A., Wright, H., & Ojeda, S. R. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.08.003 · Cited by 136 · see citing works
Genetic determinants of pubertal timing in the general population
Gajdos, Z. K. Z., Henderson, K. D., Hirschhorn, J. N., & Palmert, M. R. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.01.038 · Cited by 121 · see citing works
Distinct Variants at LIN28B Influence Growth in Height from Birth to Adulthood
Widén, E., Ripatti, S., Cousminer, D. L., Surakka, I., Lappalainen, T., Järvelin, M.-R., Eriksson, J. G., Raitakari, O., Salomaa, V., Sovio, U., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.03.010 · Cited by 88 · see citing works
LIN28B in constitutional delay of growth and puberty
Tommiska, J., Wehkalampi, K., Vaaralahti, K., Laitinen, E.-M., Raivio, T., & Dunkel, L. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2344 · Cited by 53 · see citing works
Silveira-Neto, A. P., Leal, L. F., Emerman, A. B., Henderson, K. D., Piskounova, E., Henderson, B. E., Gregory, R. I., Silveira, L. F. G., Hirschhorn, J. N., Nguyen, T. T., et al. (2012) · Hormone Research in Paediatrics · doi:10.1159/000342212 · Cited by 34 · see citing works
- Authors
- Ong, K. K., Elks, C. E., Li, S., Zhao, J. H., Luan, J., Andersen, L. B., Bingham, S. A., Brage, S., Smith, G. D., Ekelund, U., Gillson, C. J., Glaser, B., Golding, J., Hardy, R., Khaw, K.-T., Kuh, D., Luben, R., Marcus, M., McGeehin, M. A., Ness, A. R., Northstone, K., Ring, S. M., Rubin, C., Sims, M. A., Song, K., Strachan, D. P., Vollenweider, P., Waeber, G., Waterworth, D. M., Wong, A., Deloukas, P., Barroso, I., Mooser, V., Loos, R. J., & Wareham, N. J.
- Affiliations
- Addenbrooke's Hospital (GB)
- University of Southern Denmark (DK)
- MRC Mitochondrial Biology Unit (GB)
- University of Bristol (GB)
- Örebro University (SE)
- MRC Unit for Lifelong Health and Ageing (GB)
- University of Cambridge (GB)
- Centers for Disease Control and Prevention (US)
- GlaxoSmithKline (United States) (US)
- St George's, University of London (GB)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Ong, Ken K
- Loos, Ruth J
- ORCID
- Ong, Ken K
- Li, Shengxu
- Zhao, Jing Hua
- Luan, Jian'an
- Andersen, Lars B
- Smith, George Davey
- Ekelund, Ulf
- Golding, Jean
- Hardy, Rebecca
- Khaw, Kay-Tee
- Kuh, Diana
- Luben, Robert
- Marcus, Michele
- Northstone, Kate
- Ring, Susan M
- Strachan, David P
- Waterworth, Dawn M
- Wong, Andrew
- Barroso, Inês
- Mooser, Vincent
- Loos, Ruth J
- Wareham, Nicholas J
- Venue
- Nature Genetics
- Published
- 2009-05-17
- Volume
- 41
- Issue
- 6
- Pages
- 729-733
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3000552
- OpenAlex
- W2094323986
- Cited by
- 366
- References
- 15
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 22 · 2023: 16 · 2022: 12 · 2021: 12 · 2020: 21 · 2019: 20 · 2018: 22 · 2017: 17 · 2016: 22 · 2015: 30 · 2014: 20 · 2013: 39 · 2012: 35
- FWCI
- 37.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Funders
- GlaxoSmithKline
- Wellcome Trust (068545/Z/02), 077011, 079996, 077016, 077016/Z/05/Z, 076467/Z05/z, 068049)
- Cancer Research UK
- University of Bristol
- Medical Research Council
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- LIN28B, age at menarche, puberty timing, pubertal growth, breast development, pubic hair development, adult height, microRNA processing, genetic association
- MeSH terms
- Adult, Body Height, Breast, Chromosomes, Human, Pair 6, DNA-Binding Proteins, Female, Genitalia, Hair, Humans, Male, Mothers, Puberty, Regression Analysis, Meta-Analysis as Topic, RNA-Binding Proteins, Polymorphism, Single Nucleotide, MicroRNAs
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
