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 K Finucane; Patrick Sulem; Katherine S Ruth; Sean Whalen; Abhishek K Sarkar; Eva Albrecht; Elisabeth Altmaier; Marzyeh Amini; Caterina M Barbieri; Thibaud S Boutin; Archie Campbell; Ellen Demerath; Ayush Giri; Chunyan He; Jouke Jan 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 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; Jing Hua Zhao; LifeLines Cohort Study

doi: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

Felix R Day, Deborah J Thompson, Hannes Helgason, Daniel I Chasman, Hilary K Finucane, Patrick Sulem, Katherine S Ruth, Sean Whalen, Abhishek K Sarkar, Eva Albrecht, Elisabeth Altmaier, Marzyeh Amini, Caterina M Barbieri, Thibaud S Boutin, Archie Campbell, Ellen Demerath, Ayush Giri, Chunyan He, Jouke Jan 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, Jing Hua Zhao, LifeLines Cohort Study

Department of Clinical Medicine

184 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 language	English
Journal	Nature Genetics
Volume	49
Issue number	6
Pages (from-to)	834-841
Number of pages	8
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3841
Publication status	Published - 1 Jun 2017

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3841

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Day, F. R., Thompson, D. J., Helgason, H., Chasman, D. I., Finucane, H. K., Sulem, P., Ruth, K. S., Whalen, S., Sarkar, A. K., Albrecht, E., Altmaier, E., Amini, M., Barbieri, C. M., Boutin, T. S., Campbell, A., Demerath, E., Giri, A., He, C., Hottenga, J. J., ... LifeLines Cohort Study (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

Day, FR, Thompson, DJ, Helgason, H, Chasman, DI, Finucane, HK, Sulem, P, Ruth, KS, Whalen, S, Sarkar, AK, Albrecht, E, Altmaier, E, Amini, M, Barbieri, CM, Boutin, TS, 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, Zhao, JH & LifeLines Cohort Study 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

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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.",

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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 K

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 S

AU - Campbell, Archie

AU - Demerath, Ellen

AU - Giri, Ayush

AU - He, Chunyan

AU - Hottenga, Jouke Jan

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 - Zhao, Jing Hua

AU - LifeLines Cohort Study

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.

KW - Journal Article

U2 - 10.1038/ng.3841

DO - 10.1038/ng.3841

M3 - Journal article

C2 - 28436984

SN - 1061-4036

VL - 49

SP - 834

EP - 841

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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