Genomic Analyses Identify Hundreds of Variants Associated with Age at Menarche and Support a Role for Puberty Timing in Cancer Risk

Day, Felix R.; Thompson, Deborah J.; Helgason, Hannes; Chasman, Daniel I.; Finucane, Hilary; Sulem, Patrick; Ruth, Katherine S.; Whalen, Sean; Sarkar, Abhishek K.; Albrecht, Eva; Altmaier, Elisabeth; Amini, Marzyeh; Barbieri, Caterina M.; Boutin, Thibaud; Campbell, Archie; Demerath, Ellen; Giri, Ayush; He, Chunyan; Hottenga, Jouke J.; Karlsson, Robert; Kolcic, Ivana; Loh, Po-Ru; Lunetta, Kathryn L.; Mangino, Massimo; Marco, Brumat; McMahon, George; Medland, Sarah E.; Nolte, Ilja M.; Noordam, Raymond; Nutile, Teresa; Paternoster, Lavinia; Perjakova, Natalia; Porcu, Eleonora; Rose, Lynda M.; Schraut, Katharina E.; Segre, Ayellet V.; Smith, Albert V.; Stolk, Lisette; Teumer, Alexander; Andrulis, Irene L.; Bandinelli, Stefania; Beckmann, Matthias W.; Benitez, Javier; Bergmann, Sven; Bochud, Murielle; Boerwinkle, Eric A.; Bojesen, Stig E.; Bolla, Manjeet K.; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broer, Linda; Bruning, Thomas; Buring, Julie E.; Campbell, Harry; Catamo, Eulalia; Chanock, Stephen; Chenevix-Trench, Georgia; Corre, Tanguy; Couch, Fergus J.; Cousminer, Diana L.; Cox, Angela; Crisponi, Laura; Czene, Kamila; Davey Smith, George; de Geus, Eco J. C. N.; de Mutsert, Renee; De Vivo, Immaculata; Dennis, Joe; Devilee, Peter; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Eriksson, Johan G.; Fasching, Peter A.; Fernandez-Rhodes, Lindsay; Ferrucci, Luigi; Flesch-Janys, Dieter; Franke, Lude; Gabrielson, Marike; Gandin, Ilaria; Giles, Graham G.; Grallert, Harald; Gudbjartsson, Daniel F.; Guenel, Pascal; Hall, Per; Hallberg, Emily; Hamann, Ute; Harris, Tamara B.; Hartman, Catharina A.; Heiss, Gerardo M.; Hooning, Maartje J.; Hopper, John L.; Hu, Frank; Hunter, David J.; Ikram, M. Arfan; Im, Hae Kyung; Jarvelin, Marjo-Riitta; Joshi, Peter K.; Karasik, David; Kellis, Manolis; Kutalik, Zoltan; LaChance, Genevieve; Lambrechts, Diether; Langenberg, Claudia; Launer, Lenore J.; Laven, Joop S. E.; Lenarduzzi, Stefania; Li, Jingmei; Lind, Penelope A.; Lindstrom, Sara; Liu, YongMei; Luan, Jian'an; Magi, Reedik; Mannermaa, Arto; Mbarek, Hamdi; McCarthy, Mark I.; Meisinger, Christa; Meitinger, Thomas; Menni, Cristina; Metspalu, Andres; Michailidou, Kyriaki; Milani, Lili; Milne, Roger L.; Montgomery, Grant W.; Mulligan, Anna M.; Nalls, Mike A.; Navarro, Pau; Nevanlinna, Heli; Nyholt, Dale R.; Oldehinkel, Albertine J.; O'Mara, Tracy A.; Padmanabhan, Sandosh; Palotie, Aarno; Pedersen, Nancy; Peters, Annette; Peto, Julian; Pharoah, Paul D. P.; Pouta, Anneli; Radice, Paolo; Rahman, Iffat; Ring, Susan M.; Robino, Antonietta; Rosendaal, Frits R.; Rudan, Igor; Rueedi, Rico; Ruggiero, Daniela; Sala, Cinzia F.; Schmidt, Marjanka K.; Scott, Robert A.; Shah, Mitul; Sorice, Rossella; Southey, Melissa C.; Sovio, Ulla; Stampfer, Meir; Steri, Maristella; Strauch, Konstantin; Tanaka, Toshiko; Tikkanen, Emmi; Timpson, Nicholas J.; Traglia, Michela; Truong, Therese; Tyrer, Jonathan P.; Uitterlinden, Andre G.; Edwards, Digna R. Velez; Vitart, Veronique; Volker, Uwe; Vollenweider, Peter; Wang, Qin; Widen, Elisabeth; van Dijk, Ko Willems; Willemsen, Gonneke; Winqvist, Robert; Wolffenbuttel, Bruce H. R.; Zhao, Jing Hua; Zoledziewska, Magdalena; Zygmunt, Marek; Alizadeh, Behrooz Z.; Boomsma, Dorret I.; Ciullo, Marina; Cucca, Francesco; Esko, Tonu; Franceschini, Nora; Gieger, Christian; Gudnason, Vilmundur; Hayward, Caroline; Kraft, Peter; Lawlor, Debbie A.; Magnusson, Patrik K. E.; Martin, Nicholas G.; Mook-Kanamori, Dennis O.; Nohr, Ellen A.; Polasek, Ozren; Porteous, David; Price, Alkes L.; Ridker, Paul M.; Snieder, Harold; Spector, Tim D.; Stockl, Doris; Toniolo, Daniela; Ulivi, Sheila; Visser, Jenny A.; Volzke, Henry; Wareham, Nicholas J.; Wilson, James F.; Study, LifeLines Cohort; the InterAct Consortium; kConFab/AOCS Investigators; Endometrial Cancer Association Consortium; Ovarian Cancer Association Consortium; PRACTICAL Consortium; Spurdle, Amanda B.; Thorsteindottir, Unnur; Pollard, Katherine S.; Easton, Douglas F.; Tung, Joyce Y.; Chang-Claude, Jenny; Hinds, David; Murray, Anna; Murabito, Joanne M.; Stefansson, Kari; Ong, Ken K.; & Perry, John R. B. (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), 834-41. PMCID: PMC5841952

Day, Felix R.; Thompson, Deborah J.; Helgason, Hannes; Chasman, Daniel I.; Finucane, Hilary; Sulem, Patrick; Ruth, Katherine S.; Whalen, Sean; Sarkar, Abhishek K.; Albrecht, Eva; Altmaier, Elisabeth; Amini, Marzyeh; Barbieri, Caterina M.; Boutin, Thibaud; Campbell, Archie; Demerath, Ellen; Giri, Ayush; He, Chunyan; Hottenga, Jouke J.; Karlsson, Robert; Kolcic, Ivana; Loh, Po-Ru; Lunetta, Kathryn L.; Mangino, Massimo; Marco, Brumat; McMahon, George; Medland, Sarah E.; Nolte, Ilja M.; Noordam, Raymond; Nutile, Teresa; Paternoster, Lavinia; Perjakova, Natalia; Porcu, Eleonora; Rose, Lynda M.; Schraut, Katharina E.; Segre, Ayellet V.; Smith, Albert V.; Stolk, Lisette; Teumer, Alexander; Andrulis, Irene L.; Bandinelli, Stefania; Beckmann, Matthias W.; Benitez, Javier; Bergmann, Sven; Bochud, Murielle; Boerwinkle, Eric A.; Bojesen, Stig E.; Bolla, Manjeet K.; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broer, Linda; Bruning, Thomas; Buring, Julie E.; Campbell, Harry; Catamo, Eulalia; Chanock, Stephen; Chenevix-Trench, Georgia; Corre, Tanguy; Couch, Fergus J.; Cousminer, Diana L.; Cox, Angela; Crisponi, Laura; Czene, Kamila; Davey Smith, George; de Geus, Eco J. C. N.; de Mutsert, Renee; De Vivo, Immaculata; Dennis, Joe; Devilee, Peter; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Eriksson, Johan G.; Fasching, Peter A.; Fernandez-Rhodes, Lindsay; Ferrucci, Luigi; Flesch-Janys, Dieter; Franke, Lude; Gabrielson, Marike; Gandin, Ilaria; Giles, Graham G.; Grallert, Harald; Gudbjartsson, Daniel F.; Guenel, Pascal; Hall, Per; Hallberg, Emily; Hamann, Ute; Harris, Tamara B.; Hartman, Catharina A.; Heiss, Gerardo M.; Hooning, Maartje J.; Hopper, John L.; Hu, Frank; Hunter, David J.; Ikram, M. Arfan; Im, Hae Kyung; Jarvelin, Marjo-Riitta; Joshi, Peter K.; Karasik, David; Kellis, Manolis; Kutalik, Zoltan; LaChance, Genevieve; Lambrechts, Diether; Langenberg, Claudia; Launer, Lenore J.; Laven, Joop S. E.; Lenarduzzi, Stefania; Li, Jingmei; Lind, Penelope A.; Lindstrom, Sara; Liu, YongMei; Luan, Jian'an; Magi, Reedik; Mannermaa, Arto; Mbarek, Hamdi; McCarthy, Mark I.; Meisinger, Christa; Meitinger, Thomas; Menni, Cristina; Metspalu, Andres; Michailidou, Kyriaki; Milani, Lili; Milne, Roger L.; Montgomery, Grant W.; Mulligan, Anna M.; Nalls, Mike A.; Navarro, Pau; Nevanlinna, Heli; Nyholt, Dale R.; Oldehinkel, Albertine J.; O'Mara, Tracy A.; Padmanabhan, Sandosh; Palotie, Aarno; Pedersen, Nancy; Peters, Annette; Peto, Julian; Pharoah, Paul D. P.; Pouta, Anneli; Radice, Paolo; Rahman, Iffat; Ring, Susan M.; Robino, Antonietta; Rosendaal, Frits R.; Rudan, Igor; Rueedi, Rico; Ruggiero, Daniela; Sala, Cinzia F.; Schmidt, Marjanka K.; Scott, Robert A.; Shah, Mitul; Sorice, Rossella; Southey, Melissa C.; Sovio, Ulla; Stampfer, Meir; Steri, Maristella; Strauch, Konstantin; Tanaka, Toshiko; Tikkanen, Emmi; Timpson, Nicholas J.; Traglia, Michela; Truong, Therese; Tyrer, Jonathan P.; Uitterlinden, Andre G.; Edwards, Digna R. Velez; Vitart, Veronique; Volker, Uwe; Vollenweider, Peter; Wang, Qin; Widen, Elisabeth; van Dijk, Ko Willems; Willemsen, Gonneke; Winqvist, Robert; Wolffenbuttel, Bruce H. R.; Zhao, Jing Hua; Zoledziewska, Magdalena; Zygmunt, Marek; Alizadeh, Behrooz Z.; Boomsma, Dorret I.; Ciullo, Marina; Cucca, Francesco; Esko, Tonu; Franceschini, Nora; Gieger, Christian; Gudnason, Vilmundur; Hayward, Caroline; Kraft, Peter; Lawlor, Debbie A.; Magnusson, Patrik K. E.; Martin, Nicholas G.; Mook-Kanamori, Dennis O.; Nohr, Ellen A.; Polasek, Ozren; Porteous, David; Price, Alkes L.; Ridker, Paul M.; Snieder, Harold; Spector, Tim D.; Stockl, Doris; Toniolo, Daniela; Ulivi, Sheila; Visser, Jenny A.; Volzke, Henry; Wareham, Nicholas J.; Wilson, James F.; Study, LifeLines Cohort; the InterAct Consortium; kConFab/AOCS Investigators; Endometrial Cancer Association Consortium; Ovarian Cancer Association Consortium; PRACTICAL Consortium; Spurdle, Amanda B.; Thorsteindottir, Unnur; Pollard, Katherine S.; Easton, Douglas F.; Tung, Joyce Y.; Chang-Claude, Jenny; Hinds, David; Murray, Anna; Murabito, Joanne M.; Stefansson, Kari; Ong, Ken K.; & Perry, John R. B. (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), 834-41. PMCID: PMC5841952

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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 approximately 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 approximately 7.4% of the population variance in age at menarche, corresponding to approximately 25% of the estimated heritability. We implicate approximately 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.




JOUR



Day, Felix R.
Thompson, Deborah J.
Helgason, Hannes
Chasman, Daniel I.
Finucane, Hilary
Sulem, Patrick
Ruth, Katherine S.
Whalen, Sean
Sarkar, Abhishek K.
Albrecht, Eva
Altmaier, Elisabeth
Amini, Marzyeh
Barbieri, Caterina M.
Boutin, Thibaud
Campbell, Archie
Demerath, Ellen
Giri, Ayush
He, Chunyan
Hottenga, Jouke J.
Karlsson, Robert
Kolcic, Ivana
Loh, Po-Ru
Lunetta, Kathryn L.
Mangino, Massimo
Marco, Brumat
McMahon, George
Medland, Sarah E.
Nolte, Ilja M.
Noordam, Raymond
Nutile, Teresa
Paternoster, Lavinia
Perjakova, Natalia
Porcu, Eleonora
Rose, Lynda M.
Schraut, Katharina E.
Segre, Ayellet V.
Smith, Albert V.
Stolk, Lisette
Teumer, Alexander
Andrulis, Irene L.
Bandinelli, Stefania
Beckmann, Matthias W.
Benitez, Javier
Bergmann, Sven
Bochud, Murielle
Boerwinkle, Eric A.
Bojesen, Stig E.
Bolla, Manjeet K.
Brand, Judith S.
Brauch, Hiltrud
Brenner, Hermann
Broer, Linda
Bruning, Thomas
Buring, Julie E.
Campbell, Harry
Catamo, Eulalia
Chanock, Stephen
Chenevix-Trench, Georgia
Corre, Tanguy
Couch, Fergus J.
Cousminer, Diana L.
Cox, Angela
Crisponi, Laura
Czene, Kamila
Davey Smith, George
de Geus, Eco J. C. N.
de Mutsert, Renee
De Vivo, Immaculata
Dennis, Joe
Devilee, Peter
Dos-Santos-Silva, Isabel
Dunning, Alison M.
Eriksson, Johan G.
Fasching, Peter A.
Fernandez-Rhodes, Lindsay
Ferrucci, Luigi
Flesch-Janys, Dieter
Franke, Lude
Gabrielson, Marike
Gandin, Ilaria
Giles, Graham G.
Grallert, Harald
Gudbjartsson, Daniel F.
Guenel, Pascal
Hall, Per
Hallberg, Emily
Hamann, Ute
Harris, Tamara B.
Hartman, Catharina A.
Heiss, Gerardo M.
Hooning, Maartje J.
Hopper, John L.
Hu, Frank
Hunter, David J.
Ikram, M. Arfan
Im, Hae Kyung
Jarvelin, Marjo-Riitta
Joshi, Peter K.
Karasik, David
Kellis, Manolis
Kutalik, Zoltan
LaChance, Genevieve
Lambrechts, Diether
Langenberg, Claudia
Launer, Lenore J.
Laven, Joop S. E.
Lenarduzzi, Stefania
Li, Jingmei
Lind, Penelope A.
Lindstrom, Sara
Liu, YongMei
Luan, Jian'an
Magi, Reedik
Mannermaa, Arto
Mbarek, Hamdi
McCarthy, Mark I.
Meisinger, Christa
Meitinger, Thomas
Menni, Cristina
Metspalu, Andres
Michailidou, Kyriaki
Milani, Lili
Milne, Roger L.
Montgomery, Grant W.
Mulligan, Anna M.
Nalls, Mike A.
Navarro, Pau
Nevanlinna, Heli
Nyholt, Dale R.
Oldehinkel, Albertine J.
O'Mara, Tracy A.
Padmanabhan, Sandosh
Palotie, Aarno
Pedersen, Nancy
Peters, Annette
Peto, Julian
Pharoah, Paul D. P.
Pouta, Anneli
Radice, Paolo
Rahman, Iffat
Ring, Susan M.
Robino, Antonietta
Rosendaal, Frits R.
Rudan, Igor
Rueedi, Rico
Ruggiero, Daniela
Sala, Cinzia F.
Schmidt, Marjanka K.
Scott, Robert A.
Shah, Mitul
Sorice, Rossella
Southey, Melissa C.
Sovio, Ulla
Stampfer, Meir
Steri, Maristella
Strauch, Konstantin
Tanaka, Toshiko
Tikkanen, Emmi
Timpson, Nicholas J.
Traglia, Michela
Truong, Therese
Tyrer, Jonathan P.
Uitterlinden, Andre G.
Edwards, Digna R. Velez
Vitart, Veronique
Volker, Uwe
Vollenweider, Peter
Wang, Qin
Widen, Elisabeth
van Dijk, Ko Willems
Willemsen, Gonneke
Winqvist, Robert
Wolffenbuttel, Bruce H. R.
Zhao, Jing Hua
Zoledziewska, Magdalena
Zygmunt, Marek
Alizadeh, Behrooz Z.
Boomsma, Dorret I.
Ciullo, Marina
Cucca, Francesco
Esko, Tonu
Franceschini, Nora
Gieger, Christian
Gudnason, Vilmundur
Hayward, Caroline
Kraft, Peter
Lawlor, Debbie A.
Magnusson, Patrik K. E.
Martin, Nicholas G.
Mook-Kanamori, Dennis O.
Nohr, Ellen A.
Polasek, Ozren
Porteous, David
Price, Alkes L.
Ridker, Paul M.
Snieder, Harold
Spector, Tim D.
Stockl, Doris
Toniolo, Daniela
Ulivi, Sheila
Visser, Jenny A.
Volzke, Henry
Wareham, Nicholas J.
Wilson, James F.
Study, LifeLines Cohort
the InterAct Consortium
kConFab/AOCS Investigators
Endometrial Cancer Association Consortium
Ovarian Cancer Association Consortium
PRACTICAL Consortium
Spurdle, Amanda B.
Thorsteindottir, Unnur
Pollard, Katherine S.
Easton, Douglas F.
Tung, Joyce Y.
Chang-Claude, Jenny
Hinds, David
Murray, Anna
Murabito, Joanne M.
Stefansson, Kari
Ong, Ken K.
Perry, John R. B.



2017


Nature Genetics

49

6

834-41








PMC5841952


10742

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