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

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

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dc.creator	Day, FR
dc.creator	Thompson, DJ
dc.creator	Helgason, H
dc.creator	Chasman, DI
dc.creator	Finucane, H
dc.creator	Sulem, P
dc.creator	Ruth, KS
dc.creator	Whalen, S
dc.creator	Sarkar, AK
dc.creator	Albrecht, E
dc.creator	Altmaier, E
dc.creator	Amini, M
dc.creator	Barbieri, CM
dc.creator	Boutin, T
dc.creator	Campbell, A
dc.creator	Demerath, E
dc.creator	Giri, A
dc.creator	He, C
dc.creator	Hottenga, JJ
dc.creator	Karlsson, R
dc.creator	Kolcic, I
dc.creator	Loh, P-R
dc.creator	Lunetta, KL
dc.creator	Mangino, M
dc.creator	Marco, B
dc.creator	McMahon, G
dc.creator	Medland, SE
dc.creator	Nolte, IM
dc.creator	Noordam, R
dc.creator	Nutile, T
dc.creator	Paternoster, L
dc.creator	Perjakova, N
dc.creator	Porcu, E
dc.creator	Rose, LM
dc.creator	Schraut, KE
dc.creator	Segrè, AV
dc.creator	Smith, AV
dc.creator	Stolk, L
dc.creator	Teumer, A
dc.creator	Andrulis, IL
dc.creator	Bandinelli, S
dc.creator	Beckmann, MW
dc.creator	Benitez, J
dc.creator	Bergmann, S
dc.creator	Bochud, M
dc.creator	Boerwinkle, E
dc.creator	Bojesen, SE
dc.creator	Bolla, MK
dc.creator	Brand, JS
dc.creator	Brauch, H
dc.creator	Brenner, H
dc.creator	Broer, L
dc.creator	Brüning, T
dc.creator	Buring, JE
dc.creator	Campbell, H
dc.creator	Catamo, E
dc.creator	Chanock, S
dc.creator	Chenevix-Trench, G
dc.creator	Corre, T
dc.creator	Couch, FJ
dc.creator	Cousminer, DL
dc.creator	Cox, A
dc.creator	Crisponi, L
dc.creator	Czene, K
dc.creator	Davey Smith, G
dc.creator	de Geus, EJCN
dc.creator	de Mutsert, R
dc.creator	De Vivo, I
dc.creator	Dennis, J
dc.creator	Devilee, P
dc.creator	Dos-Santos-Silva, I
dc.creator	Dunning, AM
dc.creator	Eriksson, JG
dc.creator	Fasching, PA
dc.creator	Fernández-Rhodes, L
dc.creator	Ferrucci, L
dc.creator	Flesch-Janys, D
dc.creator	Franke, L
dc.creator	Gabrielson, M
dc.creator	Gandin, I
dc.creator	Giles, GG
dc.creator	Grallert, H
dc.creator	Gudbjartsson, DF
dc.creator	Guénel, P
dc.creator	Hall, P
dc.creator	Hallberg, E
dc.creator	Hamann, U
dc.creator	Harris, TB
dc.creator	Hartman, CA
dc.creator	Heiss, G
dc.creator	Hooning, MJ
dc.creator	Hopper, JL
dc.creator	Hu, F
dc.creator	Hunter, DJ
dc.creator	Ikram, MA
dc.creator	Im, HK
dc.creator	Järvelin, M-R
dc.creator	Joshi, PK
dc.creator	Karasik, D
dc.creator	Kellis, M
dc.creator	Kutalik, Z
dc.creator	LaChance, G
dc.creator	Lambrechts, D
dc.creator	Langenberg, C
dc.creator	Launer, LJ
dc.creator	Laven, JSE
dc.creator	Lenarduzzi, S
dc.creator	Li, J
dc.creator	Lind, PA
dc.creator	Lindstrom, S
dc.creator	Liu, Y
dc.creator	Luan, J
dc.creator	Mägi, R
dc.creator	Mannermaa, A
dc.creator	Mbarek, H
dc.creator	McCarthy, MI
dc.creator	Meisinger, C
dc.creator	Meitinger, T
dc.creator	Menni, C
dc.creator	Metspalu, A
dc.creator	Michailidou, K
dc.creator	Milani, L
dc.creator	Milne, RL
dc.creator	Montgomery, GW
dc.creator	Mulligan, AM
dc.creator	Nalls, MA
dc.creator	Navarro, P
dc.creator	Nevanlinna, H
dc.creator	Nyholt, DR
dc.creator	Oldehinkel, AJ
dc.creator	O'Mara, TA
dc.creator	Padmanabhan, S
dc.creator	Palotie, A
dc.creator	Pedersen, N
dc.creator	Peters, A
dc.creator	Peto, J
dc.creator	Pharoah, PDP
dc.creator	Pouta, A
dc.creator	Radice, P
dc.creator	Rahman, I
dc.creator	Ring, SM
dc.creator	Robino, A
dc.creator	Rosendaal, FR
dc.creator	Rudan, I
dc.creator	Rueedi, R
dc.creator	Ruggiero, D
dc.creator	Sala, CF
dc.creator	Schmidt, MK
dc.creator	Scott, RA
dc.creator	Shah, M
dc.creator	Sorice, R
dc.creator	Southey, MC
dc.creator	Sovio, U
dc.creator	Stampfer, M
dc.creator	Steri, M
dc.creator	Strauch, K
dc.creator	Tanaka, T
dc.creator	Tikkanen, E
dc.creator	Timpson, NJ
dc.creator	Traglia, M
dc.creator	Truong, T
dc.creator	Tyrer, JP
dc.creator	Uitterlinden, AG
dc.creator	Edwards, DRV
dc.creator	Vitart, V
dc.creator	Völker, U
dc.creator	Vollenweider, P
dc.creator	Wang, Q
dc.creator	Widen, E
dc.creator	van Dijk, KW
dc.creator	Willemsen, G
dc.creator	Winqvist, R
dc.creator	Wolffenbuttel, BHR
dc.creator	Zhao, JH
dc.creator	Zoledziewska, M
dc.creator	Zygmunt, M
dc.creator	Alizadeh, BZ
dc.creator	Boomsma, DI
dc.creator	Ciullo, M
dc.creator	Cucca, F
dc.creator	Esko, T
dc.creator	Franceschini, N
dc.creator	Gieger, C
dc.creator	Gudnason, V
dc.creator	Hayward, C
dc.creator	Kraft, P
dc.creator	Lawlor, DA
dc.creator	Magnusson, PKE
dc.creator	Martin, NG
dc.creator	Mook-Kanamori, DO
dc.creator	Nohr, EA
dc.creator	Polasek, O
dc.creator	Porteous, D
dc.creator	Price, AL
dc.creator	Ridker, PM
dc.creator	Snieder, H
dc.creator	Spector, TD
dc.creator	Stöckl, D
dc.creator	Toniolo, D
dc.creator	Ulivi, S
dc.creator	Visser, JA
dc.creator	Völzke, H
dc.creator	Wareham, NJ
dc.creator	Wilson, JF
dc.creator	LifeLines Cohort Study
dc.creator	InterAct Consortium
dc.creator	kConFab/AOCS Investigators
dc.creator	Endometrial Cancer Association Consortium
dc.creator	Ovarian Cancer Association Consortium
dc.creator	PRACTICAL consortium
dc.creator	Spurdle, AB
dc.creator	Thorsteindottir, U
dc.creator	Pollard, KS
dc.creator	Easton, DF
dc.creator	Tung, JY
dc.creator	Chang-Claude, J
dc.creator	Hinds, D
dc.creator	Murray, A
dc.creator	Murabito, JM
dc.creator	Stefansson, K
dc.creator	Ong, KK
dc.creator	Perry, JRB
dc.date	2017-07-04T10:38:47Z
dc.date	2017-04-24
dc.date	2017-07-04T10:38:47Z
dc.identifier	Vol. 49, pp. 834 - 841
dc.identifier	10.1038/ng.3841
dc.identifier	http://hdl.handle.net/10871/28300
dc.identifier	Nature Genetics
dc.description	This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.
dc.description	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.
dc.description	This research has been conducted using the UK Biobank Resource under applications 5122 and 9797. Full study-specific acknowledgments can be found in the Supplementary Note.: https://www.nature.com/article-assets/npg/ng/journal/v49/n6/extref/ng.3841-S1.pdf
dc.language	eng
dc.relation	https://www.ncbi.nlm.nih.gov/pubmed/28436984
dc.relation	https://www.nature.com/article-assets/npg/ng/journal/v49/n6/extref/ng.3841-S1.pdf
dc.rights	2017-10-24
dc.rights	Publisher policy
dc.subject	Cancer
dc.subject	Genome-wide association studies
dc.subject	Reproductive disorders
dc.title	Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.
dc.type	Article

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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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