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

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

doi:10.1038/s41588-024-01798-4

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

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

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Original language	English
Journal	Nature Genetics
DOIs	https://doi.org/10.1038/s41588-024-01798-4 https://doi.org/10.1038/s41588-024-01798-4
Publication status	Published - 1 Jul 2024

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s41588-024-01798-4-1
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Cite this

Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., Mendes de oliveira, E., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santoni, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., ... Ong, K. K. (2024). Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nature Genetics. https://doi.org/10.1038/s41588-024-01798-4, https://doi.org/10.1038/s41588-024-01798-4

@article{aed9ba154a4c43eebf66d95bd0c09a2f,

title = "Understanding the genetic complexity of puberty timing across the allele frequency spectrum",

abstract = "Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also 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 {Mendes de oliveira}, Edson and Andrea Messina and Walters, {Robin g.} and Xiaoxi Liu and Busch, {Alexander s.} and Hannes Helgason and Thompson, {Deborah j.} and Federico Santoni 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 Jia, {Raina y.} and Chikashi Terao and Riggan, {Marjorie j.} and Bolla, {Manjeet k.} and Mojgan Yazdanpanah and Nahid Yazdanpanah and Bradfield, {Jonathan 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{\textquoteright}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 l. k.} and Beckmann, {Matthias w.} and {Berrington de gonzalez}, Amy 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 {De vivo}, Immaculata 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 Huebner 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 k. e.} 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{\textquoteright}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 Schmidt, {Marjanka k.} 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 f. a.} 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 John, {Esther m.} and Per Hall and Robert Winqvis and Pharoah, {Paul d. p.} and Liming Li and Easton, {Douglas f.} and Nj{\o}lstad, {P{\aa}l r.} 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 r. b.} and Ong, {Ken k.}",

year = "2024",

month = jul,

day = "1",

doi = "10.1038/s41588-024-01798-4",

language = "English",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, Mendes de oliveira, E, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santoni, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, RY, Terao, C, Riggan, MJ, 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, CLK, Beckmann, MW, Berrington de gonzalez, 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, De vivo, I, 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, Huebner, H, Hunter, DJ, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PKE, 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, Schmidt, MK, 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, SFA, 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, John, EM, Hall, P, Winqvis, R, Pharoah, PDP, Li, L, Easton, DF, Njølstad, PR, 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, JRB & Ong, KK 2024, 'Understanding the genetic complexity of puberty timing across the allele frequency spectrum', Nature Genetics. https://doi.org/10.1038/s41588-024-01798-4, https://doi.org/10.1038/s41588-024-01798-4

TY - JOUR

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 - Mendes de oliveira, Edson

AU - Messina, Andrea

AU - Walters, Robin g.

AU - Liu, Xiaoxi

AU - Busch, Alexander s.

AU - Helgason, Hannes

AU - Thompson, Deborah j.

AU - Santoni, 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 y.

AU - Terao, Chikashi

AU - Riggan, Marjorie j.

AU - Bolla, Manjeet k.

AU - Yazdanpanah, Mojgan

AU - Yazdanpanah, Nahid

AU - Bradfield, Jonathan 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 l. k.

AU - Beckmann, Matthias w.

AU - Berrington de gonzalez, 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 - De vivo, Immaculata

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 - Huebner, 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 k. e.

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 - Schmidt, Marjanka k.

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 f. a.

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 - John, Esther m.

AU - Hall, Per

AU - Winqvis, Robert

AU - Pharoah, Paul d. p.

AU - Li, Liming

AU - Easton, Douglas f.

AU - Njølstad, Pål r.

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 r. b.

AU - Ong, Ken k.

PY - 2024/7/1

Y1 - 2024/7/1

N2 - Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

AB - Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

U2 - 10.1038/s41588-024-01798-4

DO - 10.1038/s41588-024-01798-4

M3 - Article

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

ER -

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

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