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.

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk / F. Day, D. Thompson, H. Helgason, D. Chasman, H. Finucane, P. Sulem, K. Ruth, S. Whalen, A. Sarkar, E. Albrecht, E. Altmaier, M. Amini, C. Barbieri, T. Boutin, A. Campbell, E. Demerath, A. Giri, C. He, J. Hottenga, R. Karlsson, I. Kolcic, P. Loh, K. Lunetta, M. Mangino, B. Marco, G. Mcmahon, S. Medland, I. Nolte, R. Noordam, T. Nutile, L. Paternoster, N. Perjakova, E. Porcu, L. Rose, K. Schraut, A. Segre, A. Smith, L. Stolk, A. Teumer, I. Andrulis, S. Bandinelli, M. Beckmann, J. Benitez, S. Bergmann, M. Bochud, E. Boerwinkle, S. Bojesen, M. Bolla, J. Brand, H. Brauch, H. Brenner, L. Broer, T. Bruning, J. Buring, H. Campbell, E. Catamo, S. Chanock, G. Chenevix-Trench, T. Corre, F. Couch, D. Cousminer, A. Cox, L. Crisponi, K. Czene, G. Smith, E. de Geus, R. de Mutsert, I. De Vivo, J. Dennis, P. Devilee, I. dos-Santos-Silva, A. Dunning, J. Eriksson, P. Fasching, L. Fernandez-Rhodes, L. Ferrucci, D. Flesch-Janys, L. Franke, M. Gabrielson, I. Gandin, G. Giles, H. Grallert, D. Gudbjartsson, P. Guenel, P. Hall, E. Hallberg, U. Hamann, T. Harris, C. Hartman, G. Heiss, M. Hooning, J. Hopper, F. Hu, D. Hunter, M. Ikram, H. Im, M. Jarvelin, P. Joshi, D. Karasik, M. Kellis, Z. Kutalik, G. Lachance, D. Lambrechts, C. Langenberg, L. Launer, J. Laven, S. Lenarduzzi, J. Li, P. Lind, S. Lindstrom, Y. Liu, J. Luan, R. Magi, A. Mannermaa, H. Mbarek, M. Mccarthy, C. Meisinger, T. Meitinger, C. Menni, A. Metspalu, K. Michailidou, L. Milani, R. Milne, G. Montgomery, A. Mulligan, M. Nalls, P. Navarro, H. Nevanlinna, D. Nyholt, A. Oldehinkel, T. O'Mara, S. Padmanabhan, A. Palotie, N. Pedersen, A. Peters, J. Peto, P. Pharoah, A. Pouta, P. Radice, I. Rahman, S. Ring, A. Robino, F. Rosendaal, I. Rudan, R. Rueedi, D. Ruggiero, C. Sala, M. Schmidt, R. Scott, M. Shah, R. Sorice, M. Southey, U. Sovio, M. Stampfer, M. Steri, K. Strauch, T. Tanaka, E. Tikkanen, N. Timpson, M. Traglia, T. Truong, J. Tyrer, A. Uitterlinden, D. Edwards, V. Vitart, U. Volker, P. Vollenweider, Q. Wang, E. Widen, K. van Dijk, G. Willemsen, R. Winqvist, B. Wolffenbuttel, J. Zhao, M. Zoledziewska, M. Zygmunt, B. Alizadeh, D. Boomsma, M. Ciullo, F. Cucca, T. Esko, N. Franceschini, C. Gieger, V. Gudnason, C. Hayward, P. Kraft, D. Lawlor, P. Magnusson, N. Martin, D. Mook-Kanamori, E. Nohr, O. Polasek, D. Porteous, A. Price, P. Ridker, H. Snieder, T. Spector, D. Stockl, D. Toniolo, S. Ulivi, J. Visser, H. Volzke, N. Wareham, J. Wilson, A. Spurdle, U. Thorsteindottir, K. Pollard, D. Easton, J. Tung, J. Chang-Claude, D. Hinds, A. Murray, J. Murabito, K. Stefansson, K. Ong, J. Perry. - In: NATURE GENETICS. - ISSN 1061-4036. - 49:6(2017), pp. 834-841. [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

C. Menni;
2017

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.
Settore MED/01 - Statistica Medica
Settore MEDS-24/A - Statistica medica
2017
Article (author)
File in questo prodotto:
File Dimensione Formato  
nihms902232.pdf

accesso aperto

Tipologia: Pre-print (manoscritto inviato all'editore)
Dimensione 1.75 MB
Formato Adobe PDF
1.75 MB Adobe PDF Visualizza/Apri
ng.3841.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 759.51 kB
Formato Adobe PDF
759.51 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1097008
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 381
  • ???jsp.display-item.citation.isi??? 187
social impact