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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.

Publication ,  Journal Article
Day, FR; Thompson, DJ; Helgason, H; Chasman, DI; Finucane, H; Sulem, P; Ruth, KS; Whalen, S; Sarkar, AK; Albrecht, E; Altmaier, E; Amini, M ...
Published in: Nat Genet
June 2017

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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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

June 2017

Volume

49

Issue

6

Start / End Page

834 / 841

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Risk Factors
  • Ribonucleoproteins
  • Quantitative Trait Loci
  • Puberty
  • Polymorphism, Single Nucleotide
  • Neoplasms
  • Menarche
  • Membrane Proteins
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
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. Nat Genet, 49(6), 834–841. https://doi.org/10.1038/ng.3841
Day, Felix R., Deborah J. Thompson, Hannes Helgason, Daniel I. Chasman, Hilary Finucane, Patrick Sulem, Katherine S. Ruth, et al. “Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.Nat Genet 49, no. 6 (June 2017): 834–41. https://doi.org/10.1038/ng.3841.
Day FR, Thompson DJ, Helgason H, Chasman DI, Finucane H, Sulem P, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet. 2017 Jun;49(6):834–41.
Day, Felix R., et al. “Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.Nat Genet, vol. 49, no. 6, June 2017, pp. 834–41. Pubmed, doi:10.1038/ng.3841.
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 P-R, 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 M-R, 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 J, 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, LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, 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. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet. 2017 Jun;49(6):834–841.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

June 2017

Volume

49

Issue

6

Start / End Page

834 / 841

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Risk Factors
  • Ribonucleoproteins
  • Quantitative Trait Loci
  • Puberty
  • Polymorphism, Single Nucleotide
  • Neoplasms
  • Menarche
  • Membrane Proteins
  • Male