Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk
Open accessAbstract
John Perry, Ken Ong and colleagues analyze genotype data on ∼370,000 women and identify 389 independent signals that associate with age at menarche, implicating ∼250 genes. Their analyses suggest causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10−8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
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Among genes carrying fixed HHMCs, NCOA6 has been linked to age at menarche and onset of puberty, as well as placental function.
“Among the genes carrying fixed HHMCs, NCOA6 has also been linked to age at menarche and onset of puberty170, as well as placental function171.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [170]
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- Authors
- 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., Finucane, H., Sulem, P., Ruth, K. S., Whalen, S., Sarkar, A. K., Albrecht, E., Altmaier, E., Amini, M., Barbieri, C. M., Boutin, T., Campbell, A., Demerath, E., Giri, A., He, C., Hottenga, J. J., Karlsson, R., Kolcic, I., Loh, P.-R., Lunetta, K. L., Mangino, M., Marco, B., McMahon, G., Medland, S. E., Nolte, I. M., Noordam, R., Nutile, T., Paternoster, L., Perjakova, N., Porcu, E., Rose, L. M., Schraut, K. E., Segrè, A. V., Smith, A. V., Stolk, L., Teumer, A., Andrulis, I. L., Bandinelli, S., Beckmann, M. W., Benitez, J., Bergmann, S., Bochud, M., Boerwinkle, E., Bojesen, S. E., Bolla, M. K., Brand, J. S., Brauch, H., Brenner, H., Broer, L., Brüning, T., Buring, J. E., Campbell, H., Catamo, E., Chanock, S., Chenevix-Trench, G., Corre, T., Couch, F. J., Cousminer, D. L., Cox, A., Crisponi, L., Czene, K., Davey Smith, G., de Geus, E. J. C. N., de Mutsert, R., De Vivo, I., Dennis, J., Devilee, P., dos-Santos-Silva, I., Dunning, A. M., Eriksson, J. G., Fasching, P. A., Fernández-Rhodes, L., Ferrucci, L., Flesch-Janys, D., Franke, L., Gabrielson, M., Gandin, I., Giles, G. G., Grallert, H., Gudbjartsson, D. F., Guénel, P., Hall, P., Hallberg, E., Hamann, U., Harris, T. B., Hartman, C. A., Heiss, G., Hooning, M. J., Hopper, J. L., Hu, F., Hunter, D. J., Ikram, M. A., Im, H. K., Järvelin, M.-R., Joshi, P. K., Karasik, D., Kellis, M., Kutalik, Z., LaChance, G., Lambrechts, D., Langenberg, C., Launer, L. J., Laven, J. S. E., Lenarduzzi, S., Li, J., Lind, P. A., Lindstrom, S., Liu, Y., Luan, J., Mägi, R., Mannermaa, A., Mbarek, H., McCarthy, M. I., Meisinger, C., Meitinger, T., Menni, C., Metspalu, A., Michailidou, K., Milani, L., Milne, R. L., Montgomery, G. W., Mulligan, A. M., Nalls, M. A., Navarro, P., Nevanlinna, H., Nyholt, D. R., Oldehinkel, A. J., O'Mara, T. A., Padmanabhan, S., Palotie, A., Pedersen, N., Peters, A., Peto, J., Pharoah, P. D. P., Pouta, A., Radice, P., Rahman, I., Ring, S. M., Robino, A., Rosendaal, F. R., Rudan, I., Rueedi, R., Ruggiero, D., Sala, C. F., Schmidt, M. K., Scott, R. A., Shah, M., Sorice, R., Southey, M. C., Sovio, U., Stampfer, M., Steri, M., Strauch, K., Tanaka, T., Tikkanen, E., Timpson, N. J., Traglia, M., Truong, T., Tyrer, J. P., Uitterlinden, A. G., Edwards, D. R. V., Vitart, V., Völker, U., Vollenweider, P., Wang, Q., Widen, E., van Dijk, K. W., Willemsen, G., Winqvist, R., Wolffenbuttel, B. H. R., Zhao, J. H., Zoledziewska, M., Zygmunt, M., Alizadeh, B. Z., Boomsma, D. I., Ciullo, M., Cucca, F., Esko, T., Franceschini, N., Gieger, C., Gudnason, V., Hayward, C., Kraft, P., Lawlor, D. A., Magnusson, P. K. E., Martin, N. G., Mook-Kanamori, D. O., Nohr, E. A., Polasek, O., Porteous, D., Price, A. L., Ridker, P. M., Snieder, H., Spector, T. D., Stöckl, D., Toniolo, D., Ulivi, S., Visser, J. A., Völzke, H., Wareham, N. J., Wilson, J. F., Spurdle, A. B., Thorsteindottir, U., Pollard, K. S., Easton, D. F., Tung, J. Y., Chang-Claude, J., Hinds, D., Murray, A., Murabito, J. M., Stefansson, K., Ong, K. K., & Perry, J. R. B.
- Affiliations
- University of Cambridge (GB)
- deCODE Genetics (Iceland) (IS)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Gladstone Institutes (US)
- University of Exeter (GB)
- Broad Institute (US)
- University Medical Center Groningen (NL)
- Vita-Salute San Raffaele University (IT)
- University of Minnesota (US)
- Vanderbilt University (US)
- Indiana University Health (US)
- Vrije Universiteit Amsterdam (NL)
- Boston University (US)
- King's College London (GB)
- QIMR Berghofer Medical Research Institute (AU)
- Leiden University Medical Center (NL)
- Institute of Genetics and Biophysics (IT)
- University of Bristol (GB)
- Edinburgh Royal Infirmary (GB)
- University of Iceland (IS)
- Mount Sinai Hospital (CA)
- Universitätsmedizin Greifswald (DE)
- Spanish National Cancer Research Centre (ES)
- SIB Swiss Institute of Bioinformatics (CH)
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Copenhagen (DK)
- German Cancer Research Center (DE)
- Institute for Prevention and Occupational Medicine (DE)
- National Cancer Institute (US)
- Mayo Clinic (US)
- Children's Hospital of Philadelphia (US)
- Karolinska Institutet (SE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of North Carolina at Chapel Hill (US)
- University of California, Los Angeles (US)
- Cancer Council Victoria (AU)
- University of Trieste (IT)
- Inserm (FR)
- National Institutes of Health (US)
- Erasmus MC (NL)
- University of Chicago (US)
- University of Washington (US)
- Wake Forest University Health Sciences (US)
- University of Eastern Finland (FI)
- University of Tartu (EE)
- Helmholtz Munich (DE)
- Centre for Human Genetics (GB)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- University Health Network (CA)
- Queensland University of Technology (AU)
- Finnish Institute for Health and Welfare (FI)
- IRCCS Materno Infantile Burlo Garofolo (IT)
- The Netherlands Cancer Institute (NL)
- National Institute on Aging (US)
- University of Helsinki (FI)
- National Research Council (IT)
- University of Southern Denmark (DK)
- University of California, San Francisco (US)
- 23andMe (United States) (US)
- Corresponding author
- Ong, Ken K
- Perry, John R B
- ORCID
- Day, Felix R
- Thompson, Deborah J
- Chasman, Daniel I
- Finucane, Hilary
- Sulem, Patrick
- Ruth, Katherine S
- Whalen, Sean
- Sarkar, Abhishek K
- Amini, Marzyeh
- Barbieri, Caterina M
- Boutin, Thibaud
- Campbell, Archie
- Demerath, Ellen
- Giri, Ayush
- He, Chunyan
- Hottenga, Jouke J
- Karlsson, Robert
- Loh, Po-Ru
- Lunetta, Kathryn L
- Mangino, Massimo
- Medland, Sarah E
- Nolte, Ilja M
- Noordam, Raymond
- Nutile, Teresa
- Paternoster, Lavinia
- Porcu, Eleonora
- Rose, Lynda M
- Segrè, Ayellet V
- Smith, Albert V
- Teumer, Alexander
- Andrulis, Irene L
- Bandinelli, Stefania
- Beckmann, Matthias W
- Benitez, Javier
- Bergmann, Sven
- Bochud, Murielle
- Boerwinkle, Eric
- Bojesen, Stig E
- Bolla, Manjeet K
- Brand, Judith S
- Brauch, Hiltrud
- Brenner, Hermann
- Broer, Linda
- Brüning, Thomas
- Buring, Julie E
- Catamo, Eulalia
- Chanock, Stephen
- Corre, Tanguy
- Couch, Fergus J
- Cox, Angela
- Crisponi, Laura
- Czene, Kamila
- Dennis, Joe
- Devilee, Peter
- Dunning, Alison M
- Eriksson, Johan G
- Fasching, Peter A
- Ferrucci, Luigi
- Franke, Lude
- Gabrielson, Marike
- Gandin, Ilaria
- Giles, Graham G
- Grallert, Harald
- Gudbjartsson, Daniel F
- Guénel, Pascal
- Hall, Per
- Hamann, Ute
- Harris, Tamara B
- Hartman, Catharina A
- Heiss, Gerardo
- Hooning, Maartje J
- Hopper, John L
- Hu, Frank
- Ikram, M Arfan
- Im, Hae Kyung
- Järvelin, Marjo-Riitta
- Joshi, Peter K
- Karasik, David
- Kellis, Manolis
- Lambrechts, Diether
- Langenberg, Claudia
- Launer, Lenore J
- Laven, Joop S E
- Lenarduzzi, Stefania
- Li, Jingmei
- Lind, Penelope A
- Luan, Jian'an
- Mägi, Reedik
- Mbarek, Hamdi
- McCarthy, Mark I
- Meisinger, Christa
- Meitinger, Thomas
- Menni, Cristina
- Metspalu, Andres
- Michailidou, Kyriaki
- Milani, Lili
- Milne, Roger L
- Montgomery, Grant W
- Mulligan, Anna M
- Nalls, Mike A
- Navarro, Pau
- Nevanlinna, Heli
- Nyholt, Dale R
- Oldehinkel, Albertine J
- Padmanabhan, Sandosh
- Palotie, Aarno
- Pedersen, Nancy
- Peters, Annette
- Peto, Julian
- Pharoah, Paul D P
- Radice, Paolo
- Rahman, Iffat
- Ring, Susan M
- Robino, Antonietta
- Rosendaal, Frits R
- Rudan, Igor
- Rueedi, Rico
- Ruggiero, Daniela
- Sala, Cinzia F
- Schmidt, Marjanka K
- Shah, Mitul
- Southey, Melissa C
- Sovio, Ulla
- Stampfer, Meir
- Steri, Maristella
- Strauch, Konstantin
- Tanaka, Toshiko
- Tikkanen, Emmi
- Timpson, Nicholas J
- Traglia, Michela
- Truong, Thérèse
- Tyrer, Jonathan P
- Uitterlinden, André G
- Edwards, Digna R Velez
- Völker, Uwe
- Wang, Qin
- Willemsen, Gonneke
- Winqvist, Robert
- Wolffenbuttel, Bruce H R
- Zhao, Jing Hua
- Zygmunt, Marek
- Alizadeh, Behrooz Z
- Boomsma, Dorret I
- Ciullo, Marina
- Cucca, Francesco
- Esko, Tõnu
- Franceschini, Nora
- Gieger, Christian
- Gudnason, Vilmundur
- Hayward, Caroline
- Kraft, Peter
- Lawlor, Debbie A
- Magnusson, Patrik K E
- Martin, Nicholas G
- Nohr, Ellen A
- Porteous, David
- Price, Alkes L
- Ridker, Paul M
- Snieder, Harold
- Spector, Tim D
- Toniolo, Daniela
- Ulivi, Sheila
- Völzke, Henry
- Wareham, Nicholas J
- Wilson, James F
- Spurdle, Amanda B
- Pollard, Katherine S
- Easton, Douglas F
- Tung, Joyce Y
- Chang-Claude, Jenny
- Hinds, David
- Murray, Anna
- Murabito, Joanne M
- Ong, Ken K
- Perry, John R B
- Venue
- Nature Genetics
- Published
- 2017-04-24
- Volume
- 49
- Issue
- 6
- Pages
- 834-841
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5841952
- OpenAlex
- W2608920382
- Cited by
- 587
- References
- 46
- Citations by year
- 2026: 43 · 2025: 41 · 2024: 75 · 2023: 75 · 2022: 74 · 2021: 72 · 2020: 73 · 2019: 57 · 2018: 54 · 2017: 20
- FWCI
- 64.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Explore Bristol Research (publishedVersion, other-oa)
- VU Research Portal (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- Bristol Research (University of Bristol) (acceptedVersion, other-oa)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Leiden Repository (Leiden University) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion)
- IRIS (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Lirias (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (202802/Z/16/Z)
- Francis Crick Institute (10124)
- Cancer Research UK (16561, 16565, 14136, 10124)
- National Institute for Health and Care Research (NF-SI-0611-10099, NF-SI-0512-10114, NF-SI-0512-10135)
- British Heart Foundation (SP/07/008/24066)
- National Institutes of Health
- Medical Research Council (MC_PC_13046, MC_PC_13048, MR/J012165/1, MC_EX_MR/L100002/1, MC_UU_12015/2, MR/N003284/1, MC_UU_12015/1)
- National Institute on Aging (R56AG029451, Z01AG006000)
- National Heart, Lung, and Blood Institute (T32HL007055)
- National Cancer Institute (R01CA192393, UM1CA182913)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P2CHD050924)
- 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 phenotypic traits in livestock
- Keywords
- age at menarche, puberty timing, polygenic risk, breast cancer, endometrial cancer, prostate cancer, cancer risk, Mendelian randomization, causal inference, imprinted genes, MKRN3, DLK1, rare variants, heritability, body mass index
- MeSH terms
- Adolescent, Age Factors, Calcium-Binding Proteins, Female, Humans, Male, Membrane Proteins, Menarche, Neoplasms, Puberty, Ribonucleoproteins, Risk Factors, Body Mass Index, Genomic Imprinting, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Databases, Genetic, Intercellular Signaling Peptides and Proteins, Quantitative Trait Loci, Ubiquitin-Protein Ligases, Genome-Wide Association Study
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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.
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