Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

JRB Perry; F Day; CE Elks; P Sulem; DJ Thompson; T Ferreira; CY He; DI Chasman; T Esko; G Thorleifsson; E Albrecht; WQ Ang; T Corre; DL Cousminer; B Feenstra; N Franceschini; A Ganna; AD Johnson; S Kjellqvist; KL Lunetta; G McMahon; IM (Ilja) Nolte; L Paternoster; E Porcu; AV Smith; Lisette Stolk; A Teumer; N Tsernikova; E Tikkanen; S Ulivi; EK Wagner; Najaf Amin; LJ Bierut; EM Byrne; JJ (Jouke Jan) Hottenga; DL Koller; M Mangino; TH Pers; LM Yerges-Armstrong; JH Zhao; IL Andrulis; H Anton-Culver; F Atsma; S Bandinelli; MW Beckmann; J Benitez; C Blomqvist; SE Bojesen; MK Bolla; B Bonanni; H Brauch; H Brenner; JE Buring; J Chang-Claude; S Chanock; JH Chen; G Chenevix-Trench; Margriet Collee; FJ Couch; D Couper; AD Coviello; A Cox; K Czene; AP d'Adamo; GD Smith; I de Vivo; EW Demerath; J Dennis; P Devilee; AK Dieffenbach; AM Dunning; G Eiriksdottir; JG Eriksson; PA Fasching; L Ferrucci; D Flesch-Janys; H Flyger; T Foroud; L Franke; ME Garcia; M Garcia-Closas; F Geller; EEJ de Geus; GG Giles; DF Gudbjartsson; V Gudnason; P Guenel; SQ Guo; P Hall; U Hamann; R Haring; CA Hartman; A Heath; Bert Hofman; Maartje Hooning; JL Hopper; FB Hu; DJ Hunter; D Karasik; DP Kiel; JA Knight; VM Kosma; Z Kutalik; S Lai; D Lambrechts; A Lindblom; R Magi; PK Magnusson; A Mannermaa; NG Martin; G Masson; PF McArdle; WL McArdle; M Melbye; K Michailidou; E Mihailov; L Milani; RL Milne; H Nevanlinna; P Neven; EA Nohr; AJ (A.) Oldehinkel; Ben Oostra; A Palotie; M Peacock; NL Pedersen; P Peterlongo; J Peto; PDP Pharoah; DS Postma; A Pouta; K Pylkas; P Radice; S Ring; Fernando Rivadeneira; A Robino; LM Rose; A Rudolph; V Salomaa; S Sanna; D Schlessinger; MK (Marjanka) Schmidt; MC Southey; U Sovio; MJ Stampfer; D Stockl; AM Storniolo; NJ Timpson; J Tyrer; Jenny Visser; P Vollenweider; H Volzke; G Waeber; M Waldenberger; H Wallaschofski; Q (Qing) Wang; G Willemsen; R Winqvist; BHR Wolffenbuttel; MJ Wright; DI Boomsma; MJ Econs; KT Khaw; RJF Loos; MI McCarthy; GW Montgomery; JP Rice; EA Streeten; U Thorsteinsdottir; Cornelia Duijn; BZ Alizadeh; S Bergmann; E Boerwinkle; HA Boyd; L Crisponi; P Gasparini; C Gieger; TB Harris; E Ingelsson; MR Jarvelin; P Kraft; D Lawlor; A Metspalu; CE Pennell; PM Ridker; H Snieder; TIA Sorensen; TD Spector; DP Strachan; André Uitterlinden; NJ Wareham; E Widen; M Zygmunt; A Murray; DF Easton; K Stefansson; JM Murabito; KK Ong

doi:10.1038/nature13545

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

JRB Perry, F Day, CE Elks, P Sulem, DJ Thompson, T Ferreira, CY He, DI Chasman, T Esko, G Thorleifsson, E Albrecht, WQ Ang, T Corre, DL Cousminer, B Feenstra, N Franceschini, A Ganna, AD Johnson, S Kjellqvist, KL LunettaG McMahon, IM (Ilja) Nolte, L Paternoster, E Porcu, AV Smith, Lisette Stolk, A Teumer, N Tsernikova, E Tikkanen, S Ulivi, EK Wagner, Najaf Amin, LJ Bierut, EM Byrne, JJ (Jouke Jan) Hottenga, DL Koller, M Mangino, TH Pers, LM Yerges-Armstrong, JH Zhao, IL Andrulis, H Anton-Culver, F Atsma, S Bandinelli, MW Beckmann, J Benitez, C Blomqvist, SE Bojesen, MK Bolla, B Bonanni, H Brauch, H Brenner, JE Buring, J Chang-Claude, S Chanock, JH Chen, G Chenevix-Trench, Margriet Collee, FJ Couch, D Couper, AD Coviello, A Cox, K Czene, AP d'Adamo, GD Smith, I de Vivo, EW Demerath, J Dennis, P Devilee, AK Dieffenbach, AM Dunning, G Eiriksdottir, JG Eriksson, PA Fasching, L Ferrucci, D Flesch-Janys, H Flyger, T Foroud, L Franke, ME Garcia, M Garcia-Closas, F Geller, EEJ de Geus, GG Giles, DF Gudbjartsson, V Gudnason, P Guenel, SQ Guo, P Hall, U Hamann, R Haring, CA Hartman, A Heath, Bert Hofman, Maartje Hooning, JL Hopper, FB Hu, DJ Hunter, D Karasik, DP Kiel, JA Knight, VM Kosma, Z Kutalik, S Lai, D Lambrechts, A Lindblom, R Magi, PK Magnusson, A Mannermaa, NG Martin, G Masson, PF McArdle, WL McArdle, M Melbye, K Michailidou, E Mihailov, L Milani, RL Milne, H Nevanlinna, P Neven, EA Nohr, AJ (A.) Oldehinkel, Ben Oostra, A Palotie, M Peacock, NL Pedersen, P Peterlongo, J Peto, PDP Pharoah, DS Postma, A Pouta, K Pylkas, P Radice, S Ring, Fernando Rivadeneira, A Robino, LM Rose, A Rudolph, V Salomaa, S Sanna, D Schlessinger, MK (Marjanka) Schmidt, MC Southey, U Sovio, MJ Stampfer, D Stockl, AM Storniolo, NJ Timpson, J Tyrer, Jenny Visser, P Vollenweider, H Volzke, G Waeber, M Waldenberger, H Wallaschofski, Q (Qing) Wang, G Willemsen, R Winqvist, BHR Wolffenbuttel, MJ Wright, DI Boomsma, MJ Econs, KT Khaw, RJF Loos, MI McCarthy, GW Montgomery, JP Rice, EA Streeten, U Thorsteinsdottir, Cornelia Duijn, BZ Alizadeh, S Bergmann, E Boerwinkle, HA Boyd, L Crisponi, P Gasparini, C Gieger, TB Harris, E Ingelsson, MR Jarvelin, P Kraft, D Lawlor, A Metspalu, CE Pennell, PM Ridker, H Snieder, TIA Sorensen, TD Spector, DP Strachan, André Uitterlinden, NJ Wareham, E Widen, M Zygmunt, A Murray, DF Easton, K Stefansson, JM Murabito, KK Ong

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

458 Citations (Scopus)

Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Original language	Undefined/Unknown
Pages (from-to)	92-+
Journal	Nature
Volume	514
Issue number	7520
DOIs	https://doi.org/10.1038/nature13545
Publication status	Published - 2014

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EMC MM-01-39-04
EMC MM-01-39-09-A
EMC MM-03-86-01
EMC NIHES-01-64-02

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

Access to Document

10.1038/nature13545

Cite this

Perry, JRB., Day, F., Elks, CE., Sulem, P., Thompson, DJ., Ferreira, T., He, CY., Chasman, DI., Esko, T., Thorleifsson, G., Albrecht, E., Ang, WQ., Corre, T., Cousminer, DL., Feenstra, B., Franceschini, N., Ganna, A., Johnson, AD., Kjellqvist, S., ... Ong, KK. (2014). Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature, 514(7520), 92-+. https://doi.org/10.1038/nature13545

@article{940733f391da4ee38246e1956987f07f,

title = "Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche",

abstract = "Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.",

author = "JRB Perry and F Day and CE Elks and P Sulem and DJ Thompson and T Ferreira and CY He and DI Chasman and T Esko and G Thorleifsson and E Albrecht and WQ Ang and T Corre and DL Cousminer and B Feenstra and N Franceschini and A Ganna and AD Johnson and S Kjellqvist and KL Lunetta and G McMahon and Nolte, {IM (Ilja)} and L Paternoster and E Porcu and AV Smith and Lisette Stolk and A Teumer and N Tsernikova and E Tikkanen and S Ulivi and EK Wagner and Najaf Amin and LJ Bierut and EM Byrne and Hottenga, {JJ (Jouke Jan)} and DL Koller and M Mangino and TH Pers and LM Yerges-Armstrong and JH Zhao and IL Andrulis and H Anton-Culver and F Atsma and S Bandinelli and MW Beckmann and J Benitez and C Blomqvist and SE Bojesen and MK Bolla and B Bonanni and H Brauch and H Brenner and JE Buring and J Chang-Claude and S Chanock and JH Chen and G Chenevix-Trench and Margriet Collee and FJ Couch and D Couper and AD Coviello and A Cox and K Czene and AP d'Adamo and GD Smith and {de Vivo}, I and EW Demerath and J Dennis and P Devilee and AK Dieffenbach and AM Dunning and G Eiriksdottir and JG Eriksson and PA Fasching and L Ferrucci and D Flesch-Janys and H Flyger and T Foroud and L Franke and ME Garcia and M Garcia-Closas and F Geller and {de Geus}, EEJ and GG Giles and DF Gudbjartsson and V Gudnason and P Guenel and SQ Guo and P Hall and U Hamann and R Haring and CA Hartman and A Heath and Bert Hofman and Maartje Hooning and JL Hopper and FB Hu and DJ Hunter and D Karasik and DP Kiel and JA Knight and VM Kosma and Z Kutalik and S Lai and D Lambrechts and A Lindblom and R Magi and PK Magnusson and A Mannermaa and NG Martin and G Masson and PF McArdle and WL McArdle and M Melbye and K Michailidou and E Mihailov and L Milani and RL Milne and H Nevanlinna and P Neven and EA Nohr and Oldehinkel, {AJ (A.)} and Ben Oostra and A Palotie and M Peacock and NL Pedersen and P Peterlongo and J Peto and PDP Pharoah and DS Postma and A Pouta and K Pylkas and P Radice and S Ring and Fernando Rivadeneira and A Robino and LM Rose and A Rudolph and V Salomaa and S Sanna and D Schlessinger and Schmidt, {MK (Marjanka)} and MC Southey and U Sovio and MJ Stampfer and D Stockl and AM Storniolo and NJ Timpson and J Tyrer and Jenny Visser and P Vollenweider and H Volzke and G Waeber and M Waldenberger and H Wallaschofski and Wang, {Q (Qing)} and G Willemsen and R Winqvist and BHR Wolffenbuttel and MJ Wright and DI Boomsma and MJ Econs and KT Khaw and RJF Loos and MI McCarthy and GW Montgomery and JP Rice and EA Streeten and U Thorsteinsdottir and Cornelia Duijn and BZ Alizadeh and S Bergmann and E Boerwinkle and HA Boyd and L Crisponi and P Gasparini and C Gieger and TB Harris and E Ingelsson and MR Jarvelin and P Kraft and D Lawlor and A Metspalu and CE Pennell and PM Ridker and H Snieder and TIA Sorensen and TD Spector and DP Strachan and Andr{\'e} Uitterlinden and NJ Wareham and E Widen and M Zygmunt and A Murray and DF Easton and K Stefansson and JM Murabito and KK Ong",

year = "2014",

doi = "10.1038/nature13545",

language = "Undefined/Unknown",

volume = "514",

pages = "92--+",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7520",

}

Perry, JRB, Day, F, Elks, CE, Sulem, P, Thompson, DJ, Ferreira, T, He, CY, Chasman, DI, Esko, T, Thorleifsson, G, Albrecht, E, Ang, WQ, Corre, T, Cousminer, DL, Feenstra, B, Franceschini, N, Ganna, A, Johnson, AD, Kjellqvist, S, Lunetta, KL, McMahon, G, Nolte, IM, Paternoster, L, Porcu, E, Smith, AV, Stolk, L, Teumer, A, Tsernikova, N, Tikkanen, E, Ulivi, S, Wagner, EK, Amin, N, Bierut, LJ, Byrne, EM, Hottenga, JJ, Koller, DL, Mangino, M, Pers, TH, Yerges-Armstrong, LM, Zhao, JH, Andrulis, IL, Anton-Culver, H, Atsma, F, Bandinelli, S, Beckmann, MW, Benitez, J, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Buring, JE, Chang-Claude, J, Chanock, S, Chen, JH, Chenevix-Trench, G, Collee, M, Couch, FJ, Couper, D, Coviello, AD, Cox, A, Czene, K, d'Adamo, AP, Smith, GD, de Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Dieffenbach, AK, Dunning, AM, Eiriksdottir, G, Eriksson, JG, Fasching, PA, Ferrucci, L, Flesch-Janys, D, Flyger, H, Foroud, T, Franke, L, Garcia, ME, Garcia-Closas, M, Geller, F, de Geus, EEJ, Giles, GG, Gudbjartsson, DF, Gudnason, V, Guenel, P, Guo, SQ, Hall, P, Hamann, U, Haring, R, Hartman, CA, Heath, A, Hofman, B , Hooning, M, Hopper, JL, Hu, FB, Hunter, DJ, Karasik, D, Kiel, DP, Knight, JA, Kosma, VM, Kutalik, Z, Lai, S, Lambrechts, D, Lindblom, A, Magi, R, Magnusson, PK, Mannermaa, A, Martin, NG, Masson, G, McArdle, PF, McArdle, WL, Melbye, M, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Nevanlinna, H, Neven, P, Nohr, EA, Oldehinkel, AJ, Oostra, B, Palotie, A, Peacock, M, Pedersen, NL, Peterlongo, P, Peto, J, Pharoah, PDP, Postma, DS, Pouta, A, Pylkas, K, Radice, P, Ring, S, Rivadeneira, F, Robino, A, Rose, LM, Rudolph, A, Salomaa, V, Sanna, S, Schlessinger, D, Schmidt, MK, Southey, MC, Sovio, U, Stampfer, MJ, Stockl, D, Storniolo, AM, Timpson, NJ, Tyrer, J, Visser, J, Vollenweider, P, Volzke, H, Waeber, G, Waldenberger, M, Wallaschofski, H, Wang, Q, Willemsen, G, Winqvist, R, Wolffenbuttel, BHR, Wright, MJ, Boomsma, DI, Econs, MJ, Khaw, KT, Loos, RJF, McCarthy, MI, Montgomery, GW, Rice, JP, Streeten, EA, Thorsteinsdottir, U, Duijn, C, Alizadeh, BZ, Bergmann, S, Boerwinkle, E, Boyd, HA, Crisponi, L, Gasparini, P, Gieger, C, Harris, TB, Ingelsson, E, Jarvelin, MR, Kraft, P, Lawlor, D, Metspalu, A, Pennell, CE, Ridker, PM, Snieder, H, Sorensen, TIA, Spector, TD, Strachan, DP, Uitterlinden, A, Wareham, NJ, Widen, E, Zygmunt, M, Murray, A, Easton, DF, Stefansson, K, Murabito, JM & Ong, KK 2014, 'Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche', Nature, vol. 514, no. 7520, pp. 92-+. https://doi.org/10.1038/nature13545

TY - JOUR

T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

AU - Perry, JRB

AU - Day, F

AU - Elks, CE

AU - Sulem, P

AU - Thompson, DJ

AU - Ferreira, T

AU - He, CY

AU - Chasman, DI

AU - Esko, T

AU - Thorleifsson, G

AU - Albrecht, E

AU - Ang, WQ

AU - Corre, T

AU - Cousminer, DL

AU - Feenstra, B

AU - Franceschini, N

AU - Ganna, A

AU - Johnson, AD

AU - Kjellqvist, S

AU - Lunetta, KL

AU - McMahon, G

AU - Nolte, IM (Ilja)

AU - Paternoster, L

AU - Porcu, E

AU - Smith, AV

AU - Stolk, Lisette

AU - Teumer, A

AU - Tsernikova, N

AU - Tikkanen, E

AU - Ulivi, S

AU - Wagner, EK

AU - Amin, Najaf

AU - Bierut, LJ

AU - Byrne, EM

AU - Hottenga, JJ (Jouke Jan)

AU - Koller, DL

AU - Mangino, M

AU - Pers, TH

AU - Yerges-Armstrong, LM

AU - Zhao, JH

AU - Andrulis, IL

AU - Anton-Culver, H

AU - Atsma, F

AU - Bandinelli, S

AU - Beckmann, MW

AU - Benitez, J

AU - Blomqvist, C

AU - Bojesen, SE

AU - Bolla, MK

AU - Bonanni, B

AU - Brauch, H

AU - Brenner, H

AU - Buring, JE

AU - Chang-Claude, J

AU - Chanock, S

AU - Chen, JH

AU - Chenevix-Trench, G

AU - Collee, Margriet

AU - Couch, FJ

AU - Couper, D

AU - Coviello, AD

AU - Cox, A

AU - Czene, K

AU - d'Adamo, AP

AU - Smith, GD

AU - de Vivo, I

AU - Demerath, EW

AU - Dennis, J

AU - Devilee, P

AU - Dieffenbach, AK

AU - Dunning, AM

AU - Eiriksdottir, G

AU - Eriksson, JG

AU - Fasching, PA

AU - Ferrucci, L

AU - Flesch-Janys, D

AU - Flyger, H

AU - Foroud, T

AU - Franke, L

AU - Garcia, ME

AU - Garcia-Closas, M

AU - Geller, F

AU - de Geus, EEJ

AU - Giles, GG

AU - Gudbjartsson, DF

AU - Gudnason, V

AU - Guenel, P

AU - Guo, SQ

AU - Hall, P

AU - Hamann, U

AU - Haring, R

AU - Hartman, CA

AU - Heath, A

AU - Hofman, Bert

AU - Hooning, Maartje

AU - Hopper, JL

AU - Hu, FB

AU - Hunter, DJ

AU - Karasik, D

AU - Kiel, DP

AU - Knight, JA

AU - Kosma, VM

AU - Kutalik, Z

AU - Lai, S

AU - Lambrechts, D

AU - Lindblom, A

AU - Magi, R

AU - Magnusson, PK

AU - Mannermaa, A

AU - Martin, NG

AU - Masson, G

AU - McArdle, PF

AU - McArdle, WL

AU - Melbye, M

AU - Michailidou, K

AU - Mihailov, E

AU - Milani, L

AU - Milne, RL

AU - Nevanlinna, H

AU - Neven, P

AU - Nohr, EA

AU - Oldehinkel, AJ (A.)

AU - Oostra, Ben

AU - Palotie, A

AU - Peacock, M

AU - Pedersen, NL

AU - Peterlongo, P

AU - Peto, J

AU - Pharoah, PDP

AU - Postma, DS

AU - Pouta, A

AU - Pylkas, K

AU - Radice, P

AU - Ring, S

AU - Rivadeneira, Fernando

AU - Robino, A

AU - Rose, LM

AU - Rudolph, A

AU - Salomaa, V

AU - Sanna, S

AU - Schlessinger, D

AU - Schmidt, MK (Marjanka)

AU - Southey, MC

AU - Sovio, U

AU - Stampfer, MJ

AU - Stockl, D

AU - Storniolo, AM

AU - Timpson, NJ

AU - Tyrer, J

AU - Visser, Jenny

AU - Vollenweider, P

AU - Volzke, H

AU - Waeber, G

AU - Waldenberger, M

AU - Wallaschofski, H

AU - Wang, Q (Qing)

AU - Willemsen, G

AU - Winqvist, R

AU - Wolffenbuttel, BHR

AU - Wright, MJ

AU - Boomsma, DI

AU - Econs, MJ

AU - Khaw, KT

AU - Loos, RJF

AU - McCarthy, MI

AU - Montgomery, GW

AU - Rice, JP

AU - Streeten, EA

AU - Thorsteinsdottir, U

AU - Duijn, Cornelia

AU - Alizadeh, BZ

AU - Bergmann, S

AU - Boerwinkle, E

AU - Boyd, HA

AU - Crisponi, L

AU - Gasparini, P

AU - Gieger, C

AU - Harris, TB

AU - Ingelsson, E

AU - Jarvelin, MR

AU - Kraft, P

AU - Lawlor, D

AU - Metspalu, A

AU - Pennell, CE

AU - Ridker, PM

AU - Snieder, H

AU - Sorensen, TIA

AU - Spector, TD

AU - Strachan, DP

AU - Uitterlinden, André

AU - Wareham, NJ

AU - Widen, E

AU - Zygmunt, M

AU - Murray, A

AU - Easton, DF

AU - Stefansson, K

AU - Murabito, JM

AU - Ong, KK

PY - 2014

Y1 - 2014

N2 - Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

AB - Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

U2 - 10.1038/nature13545

DO - 10.1038/nature13545

M3 - Article

C2 - 25231870

SN - 0028-0836

VL - 514

SP - 92-+

JO - Nature

JF - Nature

IS - 7520

ER -