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Understanding the genetic complexity of puberty timing across the allele frequency spectrum

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Understanding the genetic complexity of puberty timing across the allele frequency spectrum. / Kentistou, Katherine A; Kaisinger, Lena R; Stankovic, Stasa; Vaudel, Marc; de Oliveira, Edson M; Messina, Andrea; Walters, Robin G; Liu, Xiaoxi; Busch, Alexander S; Helgason, Hannes; Thompson, Deborah J; Santon, Federico; Petricek, Konstantin M; Zouaghi, Yassine; Huang-Doran, Isabel; Gudbjartsson, Daniel F; Bratland, Eirik; Lin, Kuang; Gardner, Eugene J; Zhao, Yajie; Jia, Raina; Terao, Chikashi; Riggan, Margie; Bolla, Manjeet K; Yazdanpanah, Mojgan; Yazdanpanah, Nahid; Bradfield, Jonath P; Broer, Linda; Campbell, Archie; Chasman, Daniel I; Cousminer, Diana L; Franceschini, Nora; Franke, Lude H; Girotto, Giorgia; He, Chunyan; Järvelin, Marjo-Riitta; Joshi, Peter K; Kamatani, Yoichiro; Karlsson, Robert; Luan, Jian'an; Lunetta, Kathryn L; Mägi, Reedik; Mangino, Massimo; Medland, Sarah E; Meisinger, Christa; Noordam, Raymond; Nutile, Teresa; Concas, Maria Pina; Polašek, Ozren; Porcu, Eleonora; Ring, Susan M; Sala, Cinzia; Smith, Albert V; Tanaka, Toshiko; van der Most, Peter J; Vitart, Veronique; Wang, Carol A; Willemsen, Gonneke; Zygmunt, Marek; Ahearn, Thomas U; Andrulis, Irene L; Anton-Culver, Hoda; Antoniou, Antonis C; Auer, Paul L; Barnes, Catriona Lk; Beckmann, Matthias W; Berrington, Amy; Bogdanova, Natalia V; Bojesen, Stig E; Brenner, Hermann; Buring, Julie E; Canzian, Federico; Chang-Claude, Jenny; Couch, Fergus J; Cox, Angela; Crisponi, Laura; Czene, Kamila; Daly, Mary B; Demerath, Ellen W; Dennis, Joe; Devilee, Peter; Vivo, Immaculata De; Dörk, Thilo; Dunning, Alison M; Dwek, Miriam; Eriksson, Johan G; Fasching, Peter A; Fernandez-Rhodes, Lindsay; Ferreli, Liana; Fletcher, Olivia; Gago-Dominguez, Manuela; García-Closas, Montserrat; García-Sáenz, José A; González-Neira, Anna; Grallert, Harald; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hakonarson, Hakon; Hart, Roger J; Hickey, Martha; Hooning, Maartje J; Hoppe, Reiner; Hopper, John L; Hottenga, Jouke-Jan; Hu, Frank B; Hübner, Hanna; Hunter, David J; Jernström, Helena; John, Esther M; Karasik, David; Khusnutdinova, Elza K; Kristensen, Vessela N; Lacey, James V; Lambrechts, Diether; Launer, Lenore J; Lind, Penelope A; Lindblom, Annika; Magnusson, Patrik Ke; Mannermaa, Arto; McCarthy, Mark I; Meitinger, Thomas; Menni, Cristina; Michailidou, Kyriaki; Millwood, Iona Y; Milne, Roger L; Montgomery, Grant W; Nevanlinna, Heli; Nolte, Ilja M; Nyholt, Dale R; Obi, Nadia; O'Brien, Katie M; Offit, Kenneth; Oldehinkel, Albertine J; Ostrowski, Sisse R; Palotie, Aarno; Pedersen, Ole B; Peters, Annette; Pianigiani, Giulia; Plaseska-Karanfilska, Dijana; Pouta, Anneli; Pozarickij, Alfred; Radice, Paolo; Rennert, Gad; Rosendaal, Frits R; Ruggiero, Daniela; Saloustros, Emmanouil; Sandler, Dale P; Schipf, Sabine; Schmidt, Carsten O; Small, Kerrin; Spedicati, Beatrice; Stampfer, Meir; Stone, Jennifer; Tamimi, Rulla M; Teras, Lauren R; Tikkanen, Emmi; Turman, Constance; Vachon, Celine M; Wang, Qin; Winqvist, Robert; Wolk, Alicja; Zemel, Babette S; Zheng, Wei; van Dijk, Ko W; Alizadeh, Behrooz Z; Bandinelli, Stefania; Boerwinkle, Eric; Boomsma, Dorret I; Ciullo, Marina; Chenevix-Trench, Georgia; Cucca, Francesco; Esko, Tõnu; Gieger, Christian; Grant, Struan Fa; Gudnason, Vilmundur; Hayward, Caroline; Kolčić, Ivana; Kraft, Peter; Lawlor, Deborah A; Martin, Nicholas G; Nøhr, Ellen A; Pedersen, Nancy L; Pennell, Craig E; Ridker, Paul M; Robino, Antonietta; Snieder, Harold; Sovio, Ulla; Spector, Tim D; Stöckl, Doris; Sudlow, Cathie; Timpson, Nic J; Toniolo, Daniela; Uitterlinden, André; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J; Widen, Elisabeth; Wilson, James F; Pharoah, Paul Dp; Li, Liming; Easton, Douglas F; Njølstad, Pål; Sulem, Patrick; Murabito, Joanne M; Murray, Anna; Manousaki, Despoina; Juul, Anders; Erikstrup, Christian; Stefansson, Kari; Horikoshi, Momoko; Chen, Zhengming; Farooqi, I Sadaf; Pitteloud, Nelly; Johansson, Stefan; Day, Felix R; Perry, John Rb; Ong, Ken K; ABCTB Investigators.

medRxiv, 2023.

Research output: Working paper › Preprint

Harvard

Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, de Oliveira, EM, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santon, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, R, Terao, C, Riggan, M, Bolla, MK, Yazdanpanah, M, Yazdanpanah, N, Bradfield, JP, Broer, L, Campbell, A, Chasman, DI, Cousminer, DL, Franceschini, N, Franke, LH, Girotto, G, He, C, Järvelin, M-R, Joshi, PK, Kamatani, Y, Karlsson, R, Luan, J, Lunetta, KL, Mägi, R, Mangino, M, Medland, SE, Meisinger, C, Noordam, R, Nutile, T, Concas, MP, Polašek, O, Porcu, E, Ring, SM, Sala, C, Smith, AV, Tanaka, T, van der Most, PJ, Vitart, V, Wang, CA, Willemsen, G, Zygmunt, M, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Auer, PL, Barnes, CL, Beckmann, MW, Berrington, A, Bogdanova, NV, Bojesen, SE, Brenner, H, Buring, JE, Canzian, F, Chang-Claude, J, Couch, FJ, Cox, A, Crisponi, L, Czene, K, Daly, MB, Demerath, EW, Dennis, J, Devilee, P, Vivo, ID, Dörk, T, Dunning, AM, Dwek, M, Eriksson, JG, Fasching, PA, Fernandez-Rhodes, L, Ferreli, L, Fletcher, O, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, González-Neira, A, Grallert, H, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Hakonarson, H, Hart, RJ, Hickey, M, Hooning, MJ, Hoppe, R, Hopper, JL, Hottenga, J-J, Hu, FB, Hübner, H, Hunter, DJ, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PK, Mannermaa, A, McCarthy, MI, Meitinger, T, Menni, C, Michailidou, K, Millwood, IY, Milne, RL, Montgomery, GW, Nevanlinna, H, Nolte, IM, Nyholt, DR, Obi, N, O'Brien, KM, Offit, K, Oldehinkel, AJ, Ostrowski, SR, Palotie, A, Pedersen, OB, Peters, A, Pianigiani, G, Plaseska-Karanfilska, D, Pouta, A, Pozarickij, A, Radice, P, Rennert, G, Rosendaal, FR, Ruggiero, D, Saloustros, E, Sandler, DP, Schipf, S, Schmidt, CO, Small, K, Spedicati, B, Stampfer, M, Stone, J, Tamimi, RM, Teras, LR, Tikkanen, E, Turman, C, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Zemel, BS, Zheng, W, van Dijk, KW, Alizadeh, BZ, Bandinelli, S, Boerwinkle, E, Boomsma, DI, Ciullo, M, Chenevix-Trench, G, Cucca, F, Esko, T, Gieger, C, Grant, SF, Gudnason, V, Hayward, C, Kolčić, I, Kraft, P, Lawlor, DA, Martin, NG, Nøhr, EA, Pedersen, NL, Pennell, CE, Ridker, PM, Robino, A, Snieder, H, Sovio, U, Spector, TD, Stöckl, D, Sudlow, C, Timpson, NJ, Toniolo, D, Uitterlinden, A, Ulivi, S, Völzke, H, Wareham, NJ, Widen, E, Wilson, JF, Pharoah, PD, Li, L, Easton, DF, Njølstad, P, Sulem, P, Murabito, JM, Murray, A, Manousaki, D, Juul, A, Erikstrup, C, Stefansson, K, Horikoshi, M, Chen, Z, Farooqi, IS, Pitteloud, N, Johansson, S, Day, FR, Perry, JR, Ong, KK & ABCTB Investigators 2023 'Understanding the genetic complexity of puberty timing across the allele frequency spectrum' medRxiv. https://doi.org/10.1101/2023.06.14.23291322

APA

Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., de Oliveira, E. M., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santon, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., ... ABCTB Investigators (2023). Understanding the genetic complexity of puberty timing across the allele frequency spectrum. medRxiv. https://doi.org/10.1101/2023.06.14.23291322

Vancouver

Kentistou KA, Kaisinger LR, Stankovic S, Vaudel M, de Oliveira EM, Messina A et al. Understanding the genetic complexity of puberty timing across the allele frequency spectrum. medRxiv. 2023 Jun 20. https://doi.org/10.1101/2023.06.14.23291322

Bibtex

@techreport{0734e22d48a54c668d7171fed64804d9,
title = "Understanding the genetic complexity of puberty timing across the allele frequency spectrum",
abstract = "Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.",
author = "Kentistou, {Katherine A} and Kaisinger, {Lena R} and Stasa Stankovic and Marc Vaudel and {de Oliveira}, {Edson M} and Andrea Messina and Walters, {Robin G} and Xiaoxi Liu and Busch, {Alexander S} and Hannes Helgason and Thompson, {Deborah J} and Federico Santon and Petricek, {Konstantin M} and Yassine Zouaghi and Isabel Huang-Doran and Gudbjartsson, {Daniel F} and Eirik Bratland and Kuang Lin and Gardner, {Eugene J} and Yajie Zhao and Raina Jia and Chikashi Terao and Margie Riggan and Bolla, {Manjeet K} and Mojgan Yazdanpanah and Nahid Yazdanpanah and Bradfield, {Jonath P} and Linda Broer and Archie Campbell and Chasman, {Daniel I} and Cousminer, {Diana L} and Nora Franceschini and Franke, {Lude H} and Giorgia Girotto and Chunyan He and Marjo-Riitta J{\"a}rvelin and Joshi, {Peter K} and Yoichiro Kamatani and Robert Karlsson and Jian'an Luan and Lunetta, {Kathryn L} and Reedik M{\"a}gi and Massimo Mangino and Medland, {Sarah E} and Christa Meisinger and Raymond Noordam and Teresa Nutile and Concas, {Maria Pina} and Ozren Pola{\v s}ek and Eleonora Porcu and Ring, {Susan M} and Cinzia Sala and Smith, {Albert V} and Toshiko Tanaka and {van der Most}, {Peter J} and Veronique Vitart and Wang, {Carol A} and Gonneke Willemsen and Marek Zygmunt and Ahearn, {Thomas U} and Andrulis, {Irene L} and Hoda Anton-Culver and Antoniou, {Antonis C} and Auer, {Paul L} and Barnes, {Catriona Lk} and Beckmann, {Matthias W} and Amy Berrington and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Hermann Brenner and Buring, {Julie E} and Federico Canzian and Jenny Chang-Claude and Couch, {Fergus J} and Angela Cox and Laura Crisponi and Kamila Czene and Daly, {Mary B} and Demerath, {Ellen W} and Joe Dennis and Peter Devilee and Vivo, {Immaculata De} and Thilo D{\"o}rk and Dunning, {Alison M} and Miriam Dwek and Eriksson, {Johan G} and Fasching, {Peter A} and Lindsay Fernandez-Rhodes and Liana Ferreli and Olivia Fletcher and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Garc{\'i}a-S{\'a}enz, {Jos{\'e} A} and Anna Gonz{\'a}lez-Neira and Harald Grallert and Pascal Gu{\'e}nel and Haiman, {Christopher A} and Per Hall and Ute Hamann and Hakon Hakonarson and Hart, {Roger J} and Martha Hickey and Hooning, {Maartje J} and Reiner Hoppe and Hopper, {John L} and Jouke-Jan Hottenga and Hu, {Frank B} and Hanna H{\"u}bner and Hunter, {David J} and Helena Jernstr{\"o}m and John, {Esther M} and David Karasik and Khusnutdinova, {Elza K} and Kristensen, {Vessela N} and Lacey, {James V} and Diether Lambrechts and Launer, {Lenore J} and Lind, {Penelope A} and Annika Lindblom and Magnusson, {Patrik Ke} and Arto Mannermaa and McCarthy, {Mark I} and Thomas Meitinger and Cristina Menni and Kyriaki Michailidou and Millwood, {Iona Y} and Milne, {Roger L} and Montgomery, {Grant W} and Heli Nevanlinna and Nolte, {Ilja M} and Nyholt, {Dale R} and Nadia Obi and O'Brien, {Katie M} and Kenneth Offit and Oldehinkel, {Albertine J} and Ostrowski, {Sisse R} and Aarno Palotie and Pedersen, {Ole B} and Annette Peters and Giulia Pianigiani and Dijana Plaseska-Karanfilska and Anneli Pouta and Alfred Pozarickij and Paolo Radice and Gad Rennert and Rosendaal, {Frits R} and Daniela Ruggiero and Emmanouil Saloustros and Sandler, {Dale P} and Sabine Schipf and Schmidt, {Carsten O} and Kerrin Small and Beatrice Spedicati and Meir Stampfer and Jennifer Stone and Tamimi, {Rulla M} and Teras, {Lauren R} and Emmi Tikkanen and Constance Turman and Vachon, {Celine M} and Qin Wang and Robert Winqvist and Alicja Wolk and Zemel, {Babette S} and Wei Zheng and {van Dijk}, {Ko W} and Alizadeh, {Behrooz Z} and Stefania Bandinelli and Eric Boerwinkle and Boomsma, {Dorret I} and Marina Ciullo and Georgia Chenevix-Trench and Francesco Cucca and T{\~o}nu Esko and Christian Gieger and Grant, {Struan Fa} and Vilmundur Gudnason and Caroline Hayward and Ivana Kol{\v c}i{\'c} and Peter Kraft and Lawlor, {Deborah A} and Martin, {Nicholas G} and N{\o}hr, {Ellen A} and Pedersen, {Nancy L} and Pennell, {Craig E} and Ridker, {Paul M} and Antonietta Robino and Harold Snieder and Ulla Sovio and Spector, {Tim D} and Doris St{\"o}ckl and Cathie Sudlow and Timpson, {Nic J} and Daniela Toniolo and Andr{\'e} Uitterlinden and Sheila Ulivi and Henry V{\"o}lzke and Wareham, {Nicholas J} and Elisabeth Widen and Wilson, {James F} and Pharoah, {Paul Dp} and Liming Li and Easton, {Douglas F} and P{\aa}l Nj{\o}lstad and Patrick Sulem and Murabito, {Joanne M} and Anna Murray and Despoina Manousaki and Anders Juul and Christian Erikstrup and Kari Stefansson and Momoko Horikoshi and Zhengming Chen and Farooqi, {I Sadaf} and Nelly Pitteloud and Stefan Johansson and Day, {Felix R} and Perry, {John Rb} and Ong, {Ken K} and {ABCTB Investigators}",
year = "2023",
month = jun,
day = "20",
doi = "10.1101/2023.06.14.23291322",
language = "English",
publisher = "medRxiv",
type = "WorkingPaper",
institution = "medRxiv",

}

RIS

TY - UNPB

T1 - Understanding the genetic complexity of puberty timing across the allele frequency spectrum

AU - Kentistou, Katherine A

AU - Kaisinger, Lena R

AU - Stankovic, Stasa

AU - Vaudel, Marc

AU - de Oliveira, Edson M

AU - Messina, Andrea

AU - Walters, Robin G

AU - Liu, Xiaoxi

AU - Busch, Alexander S

AU - Helgason, Hannes

AU - Thompson, Deborah J

AU - Santon, Federico

AU - Petricek, Konstantin M

AU - Zouaghi, Yassine

AU - Huang-Doran, Isabel

AU - Gudbjartsson, Daniel F

AU - Bratland, Eirik

AU - Lin, Kuang

AU - Gardner, Eugene J

AU - Zhao, Yajie

AU - Jia, Raina

AU - Terao, Chikashi

AU - Riggan, Margie

AU - Bolla, Manjeet K

AU - Yazdanpanah, Mojgan

AU - Yazdanpanah, Nahid

AU - Bradfield, Jonath P

AU - Broer, Linda

AU - Campbell, Archie

AU - Chasman, Daniel I

AU - Cousminer, Diana L

AU - Franceschini, Nora

AU - Franke, Lude H

AU - Girotto, Giorgia

AU - He, Chunyan

AU - Järvelin, Marjo-Riitta

AU - Joshi, Peter K

AU - Kamatani, Yoichiro

AU - Karlsson, Robert

AU - Luan, Jian'an

AU - Lunetta, Kathryn L

AU - Mägi, Reedik

AU - Mangino, Massimo

AU - Medland, Sarah E

AU - Meisinger, Christa

AU - Noordam, Raymond

AU - Nutile, Teresa

AU - Concas, Maria Pina

AU - Polašek, Ozren

AU - Porcu, Eleonora

AU - Ring, Susan M

AU - Sala, Cinzia

AU - Smith, Albert V

AU - Tanaka, Toshiko

AU - van der Most, Peter J

AU - Vitart, Veronique

AU - Wang, Carol A

AU - Willemsen, Gonneke

AU - Zygmunt, Marek

AU - Ahearn, Thomas U

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Antoniou, Antonis C

AU - Auer, Paul L

AU - Barnes, Catriona Lk

AU - Beckmann, Matthias W

AU - Berrington, Amy

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Brenner, Hermann

AU - Buring, Julie E

AU - Canzian, Federico

AU - Chang-Claude, Jenny

AU - Couch, Fergus J

AU - Cox, Angela

AU - Crisponi, Laura

AU - Czene, Kamila

AU - Daly, Mary B

AU - Demerath, Ellen W

AU - Dennis, Joe

AU - Devilee, Peter

AU - Vivo, Immaculata De

AU - Dörk, Thilo

AU - Dunning, Alison M

AU - Dwek, Miriam

AU - Eriksson, Johan G

AU - Fasching, Peter A

AU - Fernandez-Rhodes, Lindsay

AU - Ferreli, Liana

AU - Fletcher, Olivia

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - García-Sáenz, José A

AU - González-Neira, Anna

AU - Grallert, Harald

AU - Guénel, Pascal

AU - Haiman, Christopher A

AU - Hall, Per

AU - Hamann, Ute

AU - Hakonarson, Hakon

AU - Hart, Roger J

AU - Hickey, Martha

AU - Hooning, Maartje J

AU - Hoppe, Reiner

AU - Hopper, John L

AU - Hottenga, Jouke-Jan

AU - Hu, Frank B

AU - Hübner, Hanna

AU - Hunter, David J

AU - Jernström, Helena

AU - John, Esther M

AU - Karasik, David

AU - Khusnutdinova, Elza K

AU - Kristensen, Vessela N

AU - Lacey, James V

AU - Lambrechts, Diether

AU - Launer, Lenore J

AU - Lind, Penelope A

AU - Lindblom, Annika

AU - Magnusson, Patrik Ke

AU - Mannermaa, Arto

AU - McCarthy, Mark I

AU - Meitinger, Thomas

AU - Menni, Cristina

AU - Michailidou, Kyriaki

AU - Millwood, Iona Y

AU - Milne, Roger L

AU - Montgomery, Grant W

AU - Nevanlinna, Heli

AU - Nolte, Ilja M

AU - Nyholt, Dale R

AU - Obi, Nadia

AU - O'Brien, Katie M

AU - Offit, Kenneth

AU - Oldehinkel, Albertine J

AU - Ostrowski, Sisse R

AU - Palotie, Aarno

AU - Pedersen, Ole B

AU - Peters, Annette

AU - Pianigiani, Giulia

AU - Plaseska-Karanfilska, Dijana

AU - Pouta, Anneli

AU - Pozarickij, Alfred

AU - Radice, Paolo

AU - Rennert, Gad

AU - Rosendaal, Frits R

AU - Ruggiero, Daniela

AU - Saloustros, Emmanouil

AU - Sandler, Dale P

AU - Schipf, Sabine

AU - Schmidt, Carsten O

AU - Small, Kerrin

AU - Spedicati, Beatrice

AU - Stampfer, Meir

AU - Stone, Jennifer

AU - Tamimi, Rulla M

AU - Teras, Lauren R

AU - Tikkanen, Emmi

AU - Turman, Constance

AU - Vachon, Celine M

AU - Wang, Qin

AU - Winqvist, Robert

AU - Wolk, Alicja

AU - Zemel, Babette S

AU - Zheng, Wei

AU - van Dijk, Ko W

AU - Alizadeh, Behrooz Z

AU - Bandinelli, Stefania

AU - Boerwinkle, Eric

AU - Boomsma, Dorret I

AU - Ciullo, Marina

AU - Chenevix-Trench, Georgia

AU - Cucca, Francesco

AU - Esko, Tõnu

AU - Gieger, Christian

AU - Grant, Struan Fa

AU - Gudnason, Vilmundur

AU - Hayward, Caroline

AU - Kolčić, Ivana

AU - Kraft, Peter

AU - Lawlor, Deborah A

AU - Martin, Nicholas G

AU - Nøhr, Ellen A

AU - Pedersen, Nancy L

AU - Pennell, Craig E

AU - Ridker, Paul M

AU - Robino, Antonietta

AU - Snieder, Harold

AU - Sovio, Ulla

AU - Spector, Tim D

AU - Stöckl, Doris

AU - Sudlow, Cathie

AU - Timpson, Nic J

AU - Toniolo, Daniela

AU - Uitterlinden, André

AU - Ulivi, Sheila

AU - Völzke, Henry

AU - Wareham, Nicholas J

AU - Widen, Elisabeth

AU - Wilson, James F

AU - Pharoah, Paul Dp

AU - Li, Liming

AU - Easton, Douglas F

AU - Njølstad, Pål

AU - Sulem, Patrick

AU - Murabito, Joanne M

AU - Murray, Anna

AU - Manousaki, Despoina

AU - Juul, Anders

AU - Erikstrup, Christian

AU - Stefansson, Kari

AU - Horikoshi, Momoko

AU - Chen, Zhengming

AU - Farooqi, I Sadaf

AU - Pitteloud, Nelly

AU - Johansson, Stefan

AU - Day, Felix R

AU - Perry, John Rb

AU - Ong, Ken K

AU - ABCTB Investigators

PY - 2023/6/20

Y1 - 2023/6/20

N2 - Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

AB - Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

U2 - 10.1101/2023.06.14.23291322

DO - 10.1101/2023.06.14.23291322

M3 - Preprint

C2 - 37503126

BT - Understanding the genetic complexity of puberty timing across the allele frequency spectrum

PB - medRxiv

ER -