Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Felix R. Day, Deborah J. Thompson, Hannes Helgason, Daniel I. Chasman, Hilary Finucane, Patrick Sulem, Katherine S. Ruth, Sean Whalen, Abhishek K. Sarkar, Eva Albrecht, Elisabeth Altmaier, Marzyeh Amini, Caterina M. Barbieri, Thibaud Boutin, Archie Campbell, Ellen Demerath, Ayush Giri, Chunyan He, Jouke J. Hottenga, Robert KarlssonIvana Kolcic, Po Ru Loh, Kathryn L. Lunetta, Massimo Mangino, Brumat Marco, George McMahon, Sarah E. Medland, Ilja M. Nolte, Raymond Noordam, Teresa Nutile, Lavinia Paternoster, Natalia Perjakova, Eleonora Porcu, Lynda M. Rose, Katharina E. Schraut, Ayellet V. Segrè, Albert V. Smith, Lisette Stolk, Alexander Teumer, Irene L. Andrulis, Stefania Bandinelli, Matthias W. Beckmann, Javier Benitez, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E. Bojesen, Manjeet K. Bolla, Judith S. Brand, Hiltrud Brauch, Hermann Brenner, Linda Broer, Thomas Brüning, Julie E. Buring, Harry Campbell, Eulalia Catamo, Stephen Chanock, Georgia Chenevix-Trench, Tanguy Corre, Fergus J Couch, Diana L. Cousminer, Angela Cox, Laura Crisponi, Kamila Czene, George Davey Smith, Eco J.C.N. De Geus, Renée De Mutsert, Immaculata De Vivo, Joe Dennis, Peter Devilee, Isabel Dos-Santos-Silva, Alison M. Dunning, Johan G. Eriksson, Peter A. Fasching, Lindsay Fernández-Rhodes, Luigi Ferrucci, Dieter Flesch-Janys, Lude Franke, Marike Gabrielson, Ilaria Gandin, Graham G. Giles, Harald Grallert, Daniel F. Gudbjartsson, Pascal Guénel, Per Hall, Emily Hallberg, Ute Hamann, Tamara B. Harris, Catharina A. Hartman, Gerardo Heiss, Maartje J. Hooning, John L. Hopper, Frank Hu, David J. Hunter, M. Arfan Ikram, Hae Kyung Im, Marjo Riitta Järvelin, Peter K. Joshi, David Karasik, Manolis Kellis, Zoltan Kutalik, Genevieve Lachance, Diether Lambrechts, Claudia Langenberg, Lenore J. Launer, Joop S.E. Laven, Stefania Lenarduzzi, Jingmei Li, Penelope A. Lind, Sara Lindstrom, Yongmei Liu, Jian'An Luan, Reedik Mägi, Arto Mannermaa, Hamdi Mbarek, Mark I. McCarthy, Christa Meisinger, Thomas Meitinger, Cristina Menni, Andres Metspalu, Kyriaki Michailidou, Lili Milani, Roger L. Milne, Grant W. Montgomery, Anna M. Mulligan, Mike A. Nalls, Pau Navarro, Heli Nevanlinna, Dale R. Nyholt, Albertine J. Oldehinkel, Tracy A. O'Mara, Sandosh Padmanabhan, Aarno Palotie, Nancy Pedersen, Annette Peters, Julian Peto, Paul D.P. Pharoah, Anneli Pouta, Paolo Radice, Iffat Rahman, Susan M. Ring, Antonietta Robino, Frits R. Rosendaal, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Cinzia F. Sala, Marjanka K. Schmidt, Robert A. Scott, Mitul Shah, Rossella Sorice, Melissa C. Southey, Ulla Sovio, Meir Stampfer, Maristella Steri, Konstantin Strauch, Toshiko Tanaka, Emmi Tikkanen, Nicholas J. Timpson, Michela Traglia, Thérèse Truong, Jonathan P. Tyrer, André G. Uitterlinden, Digna R.Velez Edwards, Veronique Vitart, Uwe Völker, Peter Vollenweider, Qin Wang, Elisabeth Widen, Ko Willems Van Dijk, Gonneke Willemsen, Robert Winqvist, Bruce H.R. Wolffenbuttel, Jing Hua Zhao, Magdalena Zoledziewska, Marek Zygmunt, Behrooz Z. Alizadeh, Dorret I. Boomsma, Marina Ciullo, Francesco Cucca, Tõnu Esko, Nora Franceschini, Christian Gieger, Vilmundur Gudnason, Caroline Hayward, Peter Kraft, Debbie A. Lawlor, Patrik K.E. Magnusson, Nicholas G. Martin, Dennis O. Mook-Kanamori, Ellen A. Nohr, Ozren Polasek, David Porteous, Alkes L. Price, Paul M. Ridker, Harold Snieder, Tim D. Spector, Doris Stöckl, Daniela Toniolo, Sheila Ulivi, Jenny A. Visser, Henry Völzke, Nicholas J. Wareham, James F. Wilson, Amanda B. Spurdle, Unnur Thorsteindottir, Katherine S. Pollard, Douglas F. Easton, Joyce Y. Tung, Jenny Chang-Claude, David Hinds, Anna Murray, Joanne M. Murabito, Kari Stefansson, Ken K. Ong, John R.B. Perry

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)834-841
Number of pages8
JournalNature Genetics
Volume49
Issue number6
DOIs
StatePublished - Jun 1 2017

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Menarche
Puberty
Mendelian Randomization Analysis
Multifactorial Inheritance
Neoplasms
Endometrial Neoplasms
Genes
Prostatic Neoplasms
Body Mass Index
Genotype
Genome
Breast Neoplasms
Population

ASJC Scopus subject areas

  • Genetics

Cite this

Day, F. R., Thompson, D. J., Helgason, H., Chasman, D. I., Finucane, H., Sulem, P., ... Perry, J. R. B. (2017). Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nature Genetics, 49(6), 834-841. https://doi.org/10.1038/ng.3841

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. / Day, Felix R.; Thompson, Deborah J.; Helgason, Hannes; Chasman, Daniel I.; Finucane, Hilary; Sulem, Patrick; Ruth, Katherine S.; Whalen, Sean; Sarkar, Abhishek K.; Albrecht, Eva; Altmaier, Elisabeth; Amini, Marzyeh; Barbieri, Caterina M.; Boutin, Thibaud; Campbell, Archie; Demerath, Ellen; Giri, Ayush; He, Chunyan; Hottenga, Jouke J.; Karlsson, Robert; Kolcic, Ivana; Loh, Po Ru; Lunetta, Kathryn L.; Mangino, Massimo; Marco, Brumat; McMahon, George; Medland, Sarah E.; Nolte, Ilja M.; Noordam, Raymond; Nutile, Teresa; Paternoster, Lavinia; Perjakova, Natalia; Porcu, Eleonora; Rose, Lynda M.; Schraut, Katharina E.; Segrè, Ayellet V.; Smith, Albert V.; Stolk, Lisette; 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.; Campbell, Harry; Catamo, Eulalia; Chanock, Stephen; Chenevix-Trench, Georgia; Corre, Tanguy; Couch, Fergus J; Cousminer, Diana L.; Cox, Angela; Crisponi, Laura; Czene, Kamila; Davey Smith, George; De Geus, Eco J.C.N.; De Mutsert, Renée; De Vivo, Immaculata; Dennis, Joe; Devilee, Peter; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Eriksson, Johan G.; Fasching, Peter A.; Fernández-Rhodes, Lindsay; Ferrucci, Luigi; Flesch-Janys, Dieter; Franke, Lude; Gabrielson, Marike; Gandin, Ilaria; Giles, Graham G.; Grallert, Harald; Gudbjartsson, Daniel F.; Guénel, Pascal; Hall, Per; Hallberg, Emily; Hamann, Ute; Harris, Tamara B.; Hartman, Catharina A.; Heiss, Gerardo; Hooning, Maartje J.; Hopper, John L.; Hu, Frank; Hunter, David J.; Ikram, M. Arfan; Im, Hae Kyung; Järvelin, Marjo Riitta; Joshi, Peter K.; Karasik, David; Kellis, Manolis; Kutalik, Zoltan; Lachance, Genevieve; Lambrechts, Diether; Langenberg, Claudia; Launer, Lenore J.; Laven, Joop S.E.; Lenarduzzi, Stefania; Li, Jingmei; Lind, Penelope A.; Lindstrom, Sara; Liu, Yongmei; Luan, Jian'An; Mägi, Reedik; Mannermaa, Arto; 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.; O'Mara, Tracy A.; Padmanabhan, Sandosh; Palotie, Aarno; Pedersen, Nancy; Peters, Annette; Peto, Julian; Pharoah, Paul D.P.; Pouta, Anneli; Radice, Paolo; Rahman, Iffat; Ring, Susan M.; Robino, Antonietta; Rosendaal, Frits R.; Rudan, Igor; Rueedi, Rico; Ruggiero, Daniela; Sala, Cinzia F.; Schmidt, Marjanka K.; Scott, Robert A.; Shah, Mitul; Sorice, Rossella; 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; Vitart, Veronique; Völker, Uwe; Vollenweider, Peter; Wang, Qin; Widen, Elisabeth; Van Dijk, Ko Willems; Willemsen, Gonneke; Winqvist, Robert; Wolffenbuttel, Bruce H.R.; Zhao, Jing Hua; Zoledziewska, Magdalena; 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.; Mook-Kanamori, Dennis O.; Nohr, Ellen A.; Polasek, Ozren; Porteous, David; Price, Alkes L.; Ridker, Paul M.; Snieder, Harold; Spector, Tim D.; Stöckl, Doris; Toniolo, Daniela; Ulivi, Sheila; Visser, Jenny A.; Völzke, Henry; Wareham, Nicholas J.; Wilson, James F.; Spurdle, Amanda B.; Thorsteindottir, Unnur; Pollard, Katherine S.; Easton, Douglas F.; Tung, Joyce Y.; Chang-Claude, Jenny; Hinds, David; Murray, Anna; Murabito, Joanne M.; Stefansson, Kari; Ong, Ken K.; Perry, John R.B.

In: Nature Genetics, Vol. 49, No. 6, 01.06.2017, p. 834-841.

Research output: Contribution to journalArticle

Day, FR, Thompson, DJ, Helgason, H, Chasman, DI, Finucane, H, Sulem, P, Ruth, KS, Whalen, S, Sarkar, AK, Albrecht, E, Altmaier, E, Amini, M, Barbieri, CM, Boutin, T, Campbell, A, Demerath, E, Giri, A, He, C, Hottenga, JJ, Karlsson, R, Kolcic, I, Loh, PR, Lunetta, KL, Mangino, M, Marco, B, McMahon, G, Medland, SE, Nolte, IM, Noordam, R, Nutile, T, Paternoster, L, Perjakova, N, Porcu, E, Rose, LM, Schraut, KE, Segrè, AV, Smith, AV, Stolk, L, Teumer, A, Andrulis, IL, Bandinelli, S, Beckmann, MW, Benitez, J, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Brand, JS, Brauch, H, Brenner, H, Broer, L, Brüning, T, Buring, JE, Campbell, H, Catamo, E, Chanock, S, Chenevix-Trench, G, Corre, T, Couch, FJ, Cousminer, DL, Cox, A, Crisponi, L, Czene, K, Davey Smith, G, De Geus, EJCN, De Mutsert, R, De Vivo, I, Dennis, J, Devilee, P, Dos-Santos-Silva, I, Dunning, AM, Eriksson, JG, Fasching, PA, Fernández-Rhodes, L, Ferrucci, L, Flesch-Janys, D, Franke, L, Gabrielson, M, Gandin, I, Giles, GG, Grallert, H, Gudbjartsson, DF, Guénel, P, Hall, P, Hallberg, E, Hamann, U, Harris, TB, Hartman, CA, Heiss, G, Hooning, MJ, Hopper, JL, Hu, F, Hunter, DJ, Ikram, MA, Im, HK, Järvelin, MR, Joshi, PK, Karasik, D, Kellis, M, Kutalik, Z, Lachance, G, Lambrechts, D, Langenberg, C, Launer, LJ, Laven, JSE, Lenarduzzi, S, Li, J, Lind, PA, Lindstrom, S, Liu, Y, Luan, JA, Mägi, R, Mannermaa, A, Mbarek, H, McCarthy, MI, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Michailidou, K, Milani, L, Milne, RL, Montgomery, GW, Mulligan, AM, Nalls, MA, Navarro, P, Nevanlinna, H, Nyholt, DR, Oldehinkel, AJ, O'Mara, TA, Padmanabhan, S, Palotie, A, Pedersen, N, Peters, A, Peto, J, Pharoah, PDP, Pouta, A, Radice, P, Rahman, I, Ring, SM, Robino, A, Rosendaal, FR, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Schmidt, MK, Scott, RA, Shah, M, Sorice, R, Southey, MC, Sovio, U, Stampfer, M, Steri, M, Strauch, K, Tanaka, T, Tikkanen, E, Timpson, NJ, Traglia, M, Truong, T, Tyrer, JP, Uitterlinden, AG, Edwards, DRV, Vitart, V, Völker, U, Vollenweider, P, Wang, Q, Widen, E, Van Dijk, KW, Willemsen, G, Winqvist, R, Wolffenbuttel, BHR, Zhao, JH, Zoledziewska, M, Zygmunt, M, Alizadeh, BZ, Boomsma, DI, Ciullo, M, Cucca, F, Esko, T, Franceschini, N, Gieger, C, Gudnason, V, Hayward, C, Kraft, P, Lawlor, DA, Magnusson, PKE, Martin, NG, Mook-Kanamori, DO, Nohr, EA, Polasek, O, Porteous, D, Price, AL, Ridker, PM, Snieder, H, Spector, TD, Stöckl, D, Toniolo, D, Ulivi, S, Visser, JA, Völzke, H, Wareham, NJ, Wilson, JF, Spurdle, AB, Thorsteindottir, U, Pollard, KS, Easton, DF, Tung, JY, Chang-Claude, J, Hinds, D, Murray, A, Murabito, JM, Stefansson, K, Ong, KK & Perry, JRB 2017, 'Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk', Nature Genetics, vol. 49, no. 6, pp. 834-841. https://doi.org/10.1038/ng.3841
Day, Felix R. ; Thompson, Deborah J. ; Helgason, Hannes ; Chasman, Daniel I. ; Finucane, Hilary ; Sulem, Patrick ; Ruth, Katherine S. ; Whalen, Sean ; Sarkar, Abhishek K. ; Albrecht, Eva ; Altmaier, Elisabeth ; Amini, Marzyeh ; Barbieri, Caterina M. ; Boutin, Thibaud ; Campbell, Archie ; Demerath, Ellen ; Giri, Ayush ; He, Chunyan ; Hottenga, Jouke J. ; Karlsson, Robert ; Kolcic, Ivana ; Loh, Po Ru ; Lunetta, Kathryn L. ; Mangino, Massimo ; Marco, Brumat ; McMahon, George ; Medland, Sarah E. ; Nolte, Ilja M. ; Noordam, Raymond ; Nutile, Teresa ; Paternoster, Lavinia ; Perjakova, Natalia ; Porcu, Eleonora ; Rose, Lynda M. ; Schraut, Katharina E. ; Segrè, Ayellet V. ; Smith, Albert V. ; Stolk, Lisette ; 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. ; Campbell, Harry ; Catamo, Eulalia ; Chanock, Stephen ; Chenevix-Trench, Georgia ; Corre, Tanguy ; Couch, Fergus J ; Cousminer, Diana L. ; Cox, Angela ; Crisponi, Laura ; Czene, Kamila ; Davey Smith, George ; De Geus, Eco J.C.N. ; De Mutsert, Renée ; De Vivo, Immaculata ; Dennis, Joe ; Devilee, Peter ; Dos-Santos-Silva, Isabel ; Dunning, Alison M. ; Eriksson, Johan G. ; Fasching, Peter A. ; Fernández-Rhodes, Lindsay ; Ferrucci, Luigi ; Flesch-Janys, Dieter ; Franke, Lude ; Gabrielson, Marike ; Gandin, Ilaria ; Giles, Graham G. ; Grallert, Harald ; Gudbjartsson, Daniel F. ; Guénel, Pascal ; Hall, Per ; Hallberg, Emily ; Hamann, Ute ; Harris, Tamara B. ; Hartman, Catharina A. ; Heiss, Gerardo ; Hooning, Maartje J. ; Hopper, John L. ; Hu, Frank ; Hunter, David J. ; Ikram, M. Arfan ; Im, Hae Kyung ; Järvelin, Marjo Riitta ; Joshi, Peter K. ; Karasik, David ; Kellis, Manolis ; Kutalik, Zoltan ; Lachance, Genevieve ; Lambrechts, Diether ; Langenberg, Claudia ; Launer, Lenore J. ; Laven, Joop S.E. ; Lenarduzzi, Stefania ; Li, Jingmei ; Lind, Penelope A. ; Lindstrom, Sara ; Liu, Yongmei ; Luan, Jian'An ; Mägi, Reedik ; Mannermaa, Arto ; 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. ; O'Mara, Tracy A. ; Padmanabhan, Sandosh ; Palotie, Aarno ; Pedersen, Nancy ; Peters, Annette ; Peto, Julian ; Pharoah, Paul D.P. ; Pouta, Anneli ; Radice, Paolo ; Rahman, Iffat ; Ring, Susan M. ; Robino, Antonietta ; Rosendaal, Frits R. ; Rudan, Igor ; Rueedi, Rico ; Ruggiero, Daniela ; Sala, Cinzia F. ; Schmidt, Marjanka K. ; Scott, Robert A. ; Shah, Mitul ; Sorice, Rossella ; 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 ; Vitart, Veronique ; Völker, Uwe ; Vollenweider, Peter ; Wang, Qin ; Widen, Elisabeth ; Van Dijk, Ko Willems ; Willemsen, Gonneke ; Winqvist, Robert ; Wolffenbuttel, Bruce H.R. ; Zhao, Jing Hua ; Zoledziewska, Magdalena ; 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. ; Mook-Kanamori, Dennis O. ; Nohr, Ellen A. ; Polasek, Ozren ; Porteous, David ; Price, Alkes L. ; Ridker, Paul M. ; Snieder, Harold ; Spector, Tim D. ; Stöckl, Doris ; Toniolo, Daniela ; Ulivi, Sheila ; Visser, Jenny A. ; Völzke, Henry ; Wareham, Nicholas J. ; Wilson, James F. ; Spurdle, Amanda B. ; Thorsteindottir, Unnur ; Pollard, Katherine S. ; Easton, Douglas F. ; Tung, Joyce Y. ; Chang-Claude, Jenny ; Hinds, David ; Murray, Anna ; Murabito, Joanne M. ; Stefansson, Kari ; Ong, Ken K. ; Perry, John R.B. / Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. In: Nature Genetics. 2017 ; Vol. 49, No. 6. pp. 834-841.
@article{f203720a3abc4dfeab7b2d2216e9defc,
title = "Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk",
abstract = "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.",
author = "Day, {Felix R.} and Thompson, {Deborah J.} and Hannes Helgason and Chasman, {Daniel I.} and Hilary Finucane and Patrick Sulem and Ruth, {Katherine S.} and Sean Whalen and Sarkar, {Abhishek K.} and Eva Albrecht and Elisabeth Altmaier and Marzyeh Amini and Barbieri, {Caterina M.} and Thibaud Boutin and Archie Campbell and Ellen Demerath and Ayush Giri and Chunyan He and Hottenga, {Jouke J.} and Robert Karlsson and Ivana Kolcic and Loh, {Po Ru} and Lunetta, {Kathryn L.} and Massimo Mangino and Brumat Marco and George McMahon and Medland, {Sarah E.} and Nolte, {Ilja M.} and Raymond Noordam and Teresa Nutile and Lavinia Paternoster and Natalia Perjakova and Eleonora Porcu and Rose, {Lynda M.} and Schraut, {Katharina E.} and Segr{\`e}, {Ayellet V.} and Smith, {Albert V.} and Lisette Stolk and Alexander Teumer and Andrulis, {Irene L.} and Stefania Bandinelli and Beckmann, {Matthias W.} and Javier Benitez and Sven Bergmann and Murielle Bochud and Eric Boerwinkle and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Brand, {Judith S.} and Hiltrud Brauch and Hermann Brenner and Linda Broer and Thomas Br{\"u}ning and Buring, {Julie E.} and Harry Campbell and Eulalia Catamo and Stephen Chanock and Georgia Chenevix-Trench and Tanguy Corre and Couch, {Fergus J} and Cousminer, {Diana L.} and Angela Cox and Laura Crisponi and Kamila Czene and {Davey Smith}, George and {De Geus}, {Eco J.C.N.} and {De Mutsert}, Ren{\'e}e and {De Vivo}, Immaculata and Joe Dennis and Peter Devilee and Isabel Dos-Santos-Silva and Dunning, {Alison M.} and Eriksson, {Johan G.} and Fasching, {Peter A.} and Lindsay Fern{\'a}ndez-Rhodes and Luigi Ferrucci and Dieter Flesch-Janys and Lude Franke and Marike Gabrielson and Ilaria Gandin and Giles, {Graham G.} and Harald Grallert and Gudbjartsson, {Daniel F.} and Pascal Gu{\'e}nel and Per Hall and Emily Hallberg and Ute Hamann and Harris, {Tamara B.} and Hartman, {Catharina A.} and Gerardo Heiss and Hooning, {Maartje J.} and Hopper, {John L.} and Frank Hu and Hunter, {David J.} and Ikram, {M. Arfan} and Im, {Hae Kyung} and J{\"a}rvelin, {Marjo Riitta} and Joshi, {Peter K.} and David Karasik and Manolis Kellis and Zoltan Kutalik and Genevieve Lachance and Diether Lambrechts and Claudia Langenberg and Launer, {Lenore J.} and Laven, {Joop S.E.} and Stefania Lenarduzzi and Jingmei Li and Lind, {Penelope A.} and Sara Lindstrom and Yongmei Liu and Jian'An Luan and Reedik M{\"a}gi and Arto Mannermaa and Hamdi Mbarek and McCarthy, {Mark I.} and Christa Meisinger and Thomas Meitinger and Cristina Menni and Andres Metspalu and Kyriaki Michailidou and Lili Milani and Milne, {Roger L.} and Montgomery, {Grant W.} and Mulligan, {Anna M.} and Nalls, {Mike A.} and Pau Navarro and Heli Nevanlinna and Nyholt, {Dale R.} and Oldehinkel, {Albertine J.} and O'Mara, {Tracy A.} and Sandosh Padmanabhan and Aarno Palotie and Nancy Pedersen and Annette Peters and Julian Peto and Pharoah, {Paul D.P.} and Anneli Pouta and Paolo Radice and Iffat Rahman and Ring, {Susan M.} and Antonietta Robino and Rosendaal, {Frits R.} and Igor Rudan and Rico Rueedi and Daniela Ruggiero and Sala, {Cinzia F.} and Schmidt, {Marjanka K.} and Scott, {Robert A.} and Mitul Shah and Rossella Sorice and Southey, {Melissa C.} and Ulla Sovio and Meir Stampfer and Maristella Steri and Konstantin Strauch and Toshiko Tanaka and Emmi Tikkanen and Timpson, {Nicholas J.} and Michela Traglia and Th{\'e}r{\`e}se Truong and Tyrer, {Jonathan P.} and Uitterlinden, {Andr{\'e} G.} and Edwards, {Digna R.Velez} and Veronique Vitart and Uwe V{\"o}lker and Peter Vollenweider and Qin Wang and Elisabeth Widen and {Van Dijk}, {Ko Willems} and Gonneke Willemsen and Robert Winqvist and Wolffenbuttel, {Bruce H.R.} and Zhao, {Jing Hua} and Magdalena Zoledziewska and Marek Zygmunt and Alizadeh, {Behrooz Z.} and Boomsma, {Dorret I.} and Marina Ciullo and Francesco Cucca and T{\~o}nu Esko and Nora Franceschini and Christian Gieger and Vilmundur Gudnason and Caroline Hayward and Peter Kraft and Lawlor, {Debbie A.} and Magnusson, {Patrik K.E.} and Martin, {Nicholas G.} and Mook-Kanamori, {Dennis O.} and Nohr, {Ellen A.} and Ozren Polasek and David Porteous and Price, {Alkes L.} and Ridker, {Paul M.} and Harold Snieder and Spector, {Tim D.} and Doris St{\"o}ckl and Daniela Toniolo and Sheila Ulivi and Visser, {Jenny A.} and Henry V{\"o}lzke and Wareham, {Nicholas J.} and Wilson, {James F.} and Spurdle, {Amanda B.} and Unnur Thorsteindottir and Pollard, {Katherine S.} and Easton, {Douglas F.} and Tung, {Joyce Y.} and Jenny Chang-Claude and David Hinds and Anna Murray and Murabito, {Joanne M.} and Kari Stefansson and Ong, {Ken K.} and Perry, {John R.B.}",
year = "2017",
month = "6",
day = "1",
doi = "10.1038/ng.3841",
language = "English (US)",
volume = "49",
pages = "834--841",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

AU - Day, Felix R.

AU - Thompson, Deborah J.

AU - Helgason, Hannes

AU - Chasman, Daniel I.

AU - Finucane, Hilary

AU - Sulem, Patrick

AU - Ruth, Katherine S.

AU - Whalen, Sean

AU - Sarkar, Abhishek K.

AU - Albrecht, Eva

AU - Altmaier, Elisabeth

AU - Amini, Marzyeh

AU - Barbieri, Caterina M.

AU - Boutin, Thibaud

AU - Campbell, Archie

AU - Demerath, Ellen

AU - Giri, Ayush

AU - He, Chunyan

AU - Hottenga, Jouke J.

AU - Karlsson, Robert

AU - Kolcic, Ivana

AU - Loh, Po Ru

AU - Lunetta, Kathryn L.

AU - Mangino, Massimo

AU - Marco, Brumat

AU - McMahon, George

AU - Medland, Sarah E.

AU - Nolte, Ilja M.

AU - Noordam, Raymond

AU - Nutile, Teresa

AU - Paternoster, Lavinia

AU - Perjakova, Natalia

AU - Porcu, Eleonora

AU - Rose, Lynda M.

AU - Schraut, Katharina E.

AU - Segrè, Ayellet V.

AU - Smith, Albert V.

AU - Stolk, Lisette

AU - Teumer, Alexander

AU - Andrulis, Irene L.

AU - Bandinelli, Stefania

AU - Beckmann, Matthias W.

AU - Benitez, Javier

AU - Bergmann, Sven

AU - Bochud, Murielle

AU - Boerwinkle, Eric

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Brand, Judith S.

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Broer, Linda

AU - Brüning, Thomas

AU - Buring, Julie E.

AU - Campbell, Harry

AU - Catamo, Eulalia

AU - Chanock, Stephen

AU - Chenevix-Trench, Georgia

AU - Corre, Tanguy

AU - Couch, Fergus J

AU - Cousminer, Diana L.

AU - Cox, Angela

AU - Crisponi, Laura

AU - Czene, Kamila

AU - Davey Smith, George

AU - De Geus, Eco J.C.N.

AU - De Mutsert, Renée

AU - De Vivo, Immaculata

AU - Dennis, Joe

AU - Devilee, Peter

AU - Dos-Santos-Silva, Isabel

AU - Dunning, Alison M.

AU - Eriksson, Johan G.

AU - Fasching, Peter A.

AU - Fernández-Rhodes, Lindsay

AU - Ferrucci, Luigi

AU - Flesch-Janys, Dieter

AU - Franke, Lude

AU - Gabrielson, Marike

AU - Gandin, Ilaria

AU - Giles, Graham G.

AU - Grallert, Harald

AU - Gudbjartsson, Daniel F.

AU - Guénel, Pascal

AU - Hall, Per

AU - Hallberg, Emily

AU - Hamann, Ute

AU - Harris, Tamara B.

AU - Hartman, Catharina A.

AU - Heiss, Gerardo

AU - Hooning, Maartje J.

AU - Hopper, John L.

AU - Hu, Frank

AU - Hunter, David J.

AU - Ikram, M. Arfan

AU - Im, Hae Kyung

AU - Järvelin, Marjo Riitta

AU - Joshi, Peter K.

AU - Karasik, David

AU - Kellis, Manolis

AU - Kutalik, Zoltan

AU - Lachance, Genevieve

AU - Lambrechts, Diether

AU - Langenberg, Claudia

AU - Launer, Lenore J.

AU - Laven, Joop S.E.

AU - Lenarduzzi, Stefania

AU - Li, Jingmei

AU - Lind, Penelope A.

AU - Lindstrom, Sara

AU - Liu, Yongmei

AU - Luan, Jian'An

AU - Mägi, Reedik

AU - Mannermaa, Arto

AU - Mbarek, Hamdi

AU - McCarthy, Mark I.

AU - Meisinger, Christa

AU - Meitinger, Thomas

AU - Menni, Cristina

AU - Metspalu, Andres

AU - Michailidou, Kyriaki

AU - Milani, Lili

AU - Milne, Roger L.

AU - Montgomery, Grant W.

AU - Mulligan, Anna M.

AU - Nalls, Mike A.

AU - Navarro, Pau

AU - Nevanlinna, Heli

AU - Nyholt, Dale R.

AU - Oldehinkel, Albertine J.

AU - O'Mara, Tracy A.

AU - Padmanabhan, Sandosh

AU - Palotie, Aarno

AU - Pedersen, Nancy

AU - Peters, Annette

AU - Peto, Julian

AU - Pharoah, Paul D.P.

AU - Pouta, Anneli

AU - Radice, Paolo

AU - Rahman, Iffat

AU - Ring, Susan M.

AU - Robino, Antonietta

AU - Rosendaal, Frits R.

AU - Rudan, Igor

AU - Rueedi, Rico

AU - Ruggiero, Daniela

AU - Sala, Cinzia F.

AU - Schmidt, Marjanka K.

AU - Scott, Robert A.

AU - Shah, Mitul

AU - Sorice, Rossella

AU - Southey, Melissa C.

AU - Sovio, Ulla

AU - Stampfer, Meir

AU - Steri, Maristella

AU - Strauch, Konstantin

AU - Tanaka, Toshiko

AU - Tikkanen, Emmi

AU - Timpson, Nicholas J.

AU - Traglia, Michela

AU - Truong, Thérèse

AU - Tyrer, Jonathan P.

AU - Uitterlinden, André G.

AU - Edwards, Digna R.Velez

AU - Vitart, Veronique

AU - Völker, Uwe

AU - Vollenweider, Peter

AU - Wang, Qin

AU - Widen, Elisabeth

AU - Van Dijk, Ko Willems

AU - Willemsen, Gonneke

AU - Winqvist, Robert

AU - Wolffenbuttel, Bruce H.R.

AU - Zhao, Jing Hua

AU - Zoledziewska, Magdalena

AU - Zygmunt, Marek

AU - Alizadeh, Behrooz Z.

AU - Boomsma, Dorret I.

AU - Ciullo, Marina

AU - Cucca, Francesco

AU - Esko, Tõnu

AU - Franceschini, Nora

AU - Gieger, Christian

AU - Gudnason, Vilmundur

AU - Hayward, Caroline

AU - Kraft, Peter

AU - Lawlor, Debbie A.

AU - Magnusson, Patrik K.E.

AU - Martin, Nicholas G.

AU - Mook-Kanamori, Dennis O.

AU - Nohr, Ellen A.

AU - Polasek, Ozren

AU - Porteous, David

AU - Price, Alkes L.

AU - Ridker, Paul M.

AU - Snieder, Harold

AU - Spector, Tim D.

AU - Stöckl, Doris

AU - Toniolo, Daniela

AU - Ulivi, Sheila

AU - Visser, Jenny A.

AU - Völzke, Henry

AU - Wareham, Nicholas J.

AU - Wilson, James F.

AU - Spurdle, Amanda B.

AU - Thorsteindottir, Unnur

AU - Pollard, Katherine S.

AU - Easton, Douglas F.

AU - Tung, Joyce Y.

AU - Chang-Claude, Jenny

AU - Hinds, David

AU - Murray, Anna

AU - Murabito, Joanne M.

AU - Stefansson, Kari

AU - Ong, Ken K.

AU - Perry, John R.B.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85018441896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018441896&partnerID=8YFLogxK

U2 - 10.1038/ng.3841

DO - 10.1038/ng.3841

M3 - Article

C2 - 28436984

AN - SCOPUS:85018441896

VL - 49

SP - 834

EP - 841

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -