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

Day, F. R., 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., Segre, A. V., Smith, A. V., Stolk, L., Teumer, A., Andrulis, I. L., Bandinelli, S., Beckmann, M. W., Benitez, J., Bergmann, S., Franke, L., Hartman, C. A., Oldehinkel, A. J., Wolffenbuttel, B. H. R., Alizadeh, B. Z., Snieder, H., InterAct Consortium, KConFab AOCS Investigators, Endometrial Canc Accoc Consortium, Ovarian Canc Accoc Consortium & PRACTICAl Consortium, Jun-2017, In : Nature Genetics. 49, 6, p. 834-841 11 p.

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

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  • 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 Karlsson
  • Ivana 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. Segre
  • Albert V. Smith
  • Lisette Stolk
  • Alexander Teumer
  • Irene L. Andrulis
  • Stefania Bandinelli
  • Matthias W. Beckmann
  • Javier Benitez
  • Sven Bergmann
  • Lude Franke
  • Catharina A. Hartman
  • Albertine J. Oldehinkel
  • Bruce H. R. Wolffenbuttel
  • Behrooz Z. Alizadeh
  • Harold Snieder
  • InterAct Consortium
  • KConFab AOCS Investigators
  • Endometrial Canc Accoc Consortium
  • Ovarian Canc Accoc Consortium
  • PRACTICAl Consortium

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 similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 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
Pages (from-to)834-841
Number of pages11
JournalNature Genetics
Volume49
Issue number6
Publication statusPublished - Jun-2017

    Keywords

  • BODY-MASS INDEX, WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, TRAITS, GROWTH, LOCI, METAANALYSIS, INHERITANCE, METABOLISM, REGRESSION
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