Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
: Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, He C, 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, Tšernikova N, Tikkanen E, Ulivi S, Wagner EK, Amin N, Bierut LJ, Byrne EM, Hottenga JJ, Koller DL, Mangino M, Pers TH, Yerges-Armstrong LM, Hua Zhao J, 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 J, Chenevix-Trench G, Collée JM, Couch FJ, Couper D, Coviello AD, Cox A, Czene K, D'adamo AP, Davey Smith G, 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, García-Closas M, Geller F, de Geus EE, Giles GG, Gudbjartsson DF, Gudnason V, Guénel P, Guo S, Hall P, Hamann U, Haring R, Hartman CA, Heath AC, Hofman A, Hooning MJ, Hopper JL, Hu FB, Hunter DJ, Karasik D, Kiel DP, Knight JA, Kosma VM, Kutalik Z, Lai S, Lambrechts D, Lindblom A, Mägi 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 BA, Palotie A, Peacock M, Pedersen NL, Peterlongo P, Peto J, Pharoah PD, Postma DS, Pouta A, Pylkäs 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, Stöckl D, Storniolo AM, Timpson NJ, Tyrer J, Visser JA, Vollenweider P, Völzke H, Waeber G, Waldenberger M, Wallaschofski H, Wang Q, Willemsen G, Winqvist R, Wolffenbuttel BH, Wright MJ; Australian Ovarian Cancer Study; GENICA Network; kConFab; LifeLines Cohort Study; InterAct Consortium; Early Growth Genetics (EGG) Consortium, Boomsma DI, Econs MJ, Khaw KT, Loos RJ, McCarthy MI, Montgomery GW, Rice JP, Streeten EA, Thorsteinsdottir U, van Duijn CM, Alizadeh BZ, Bergmann S, Boerwinkle E, Boyd HA, Crisponi L, Gasparini P, Gieger C, Harris TB, Ingelsson E, Järvelin MR, Kraft P, Lawlor D, Metspalu A, Pennell CE, Ridker PM, Snieder H, Sørensen TI, Spector TD, Strachan DP, Uitterlinden AG, Wareham NJ, Widen E, Zygmunt M, Murray A, Easton DF, Stefansson K, Murabito JM, Ong KK, Cousminer DL, Stergiakouli E, Berry DJ, Ang W, Groen-Blokhuis MM, Körner A, Siitonen N, Ntalla I, Marinelli M, Perry JR, Kettunen J, Jansen R, Surakka I, Timpson NJ, Ring S, McMahon G, Power C, Wang C, Kähönen M, Viikari J, Lehtimäki T, Middeldorp CM, Hulshoff Pol HE, Neef M, Weise S, Pahkala K, Niinikoski H, Zeggini E, Panoutsopoulou K, Bustamante M, Penninx BW, Murabito J, Torrent M, Dedoussis GV, Kiess W, Boomsma DI, Pennell CE, Raitakari OT, Hyppönen E, Davey Smith G, Ripatti S, McCarthy MI, Widén E, Alizadeh BZ, de Boer RA, Boezen HM, Bruinenberg M, Franke L, van der Harst P, Hillege HL, van der Klauw MM, Navis G, Ormel J, Postma D, Rosmalen JG, Slaets JP, Snieder H, Stolk RP, Wolffenbuttel BH, Wijmenga C, Forouhi N, Kerrison ND, Langenberg C, Scott RA, Sharp SJ, Sims M, Barroso I, Deloukas P, McCarthy MI, Arriola L, Balkau B, Barricarte A, Boeing H, Franks PW, Gonzalez C, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quirós J, Rolandsson O, Sacerdote C, Sánchez MJ, Slimani N, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, Riboli E, Wareham NJ, Bowtell DD, Green A, Chenevix-Trench G, deFazio A, Gertig D, Webb PM, Brauch H, Justenhoven C, Hamann U, Ko YD, Baisch C, Fischer HP, Pesch B, Rabstein S, Spickenheuer A, Harth V, Aghmesheh M, Amor D, Andrews L, Antill Y, Armitage S, Arnold L, Balleine R, Bankier A, Bastick P, Beesley J, Beilby J, Bennett I, Bennett B, Berry G, Blackburn A, Bogwitz M, Brennan M, Brown M, Buckley M, Burgess M, Burke J, Butow P, Byron K, Callen D, Campbell I, Chauhan D, Chenevix-Trench G, Christian A, Clarke C, Colley A, Cotton D, Crook A, Cui J, Culling B, Cummings M, Dawson SJ, deFazio A, Delatycki M, Dickson R, Dixon J, Dobrovic A, Dudding T, Edkins T, Edwards S, Eisenbruch M, Farshid G, Fawcett S, Fellows A, Fenton G, Field M, Firgaira F, Flanagan J, Fleming J, Fong P, Forbes J, Fox S, French J, Friedlander M, Gaff C, Gardner M, Gattas M, George P, Giles G, Gill G, Goldblatt J, Greening S, Grist S, Eric H, Hardie K, Harris M, Hart S, Hayward N, Healey S, Heiniger L, Hopper J, Humphrey E, Hunt C, James P, Jenkins M, Jones A, Kefford R, Kidd A, Kiely B, Kirk J, Koehler J, Kollias J, Kovalenko S, Lakhani S, Leaming A, Leary J, Lim J, Lindeman G, Lipton L, Lobb L, Mann G, Marsh D, McLachlan SA, Meiser B, Meldrum C, Milne R, Mitchell G, Newman B, O'Connell S, O'Loughlin I, Osborne R, Pachter N, Patterson B, Peters L, Phillips K, Price M, Purser L, Reeve J, Reeve T, Richards R, Rickard E, Robinson B, Rudzki B, Saleh M, Salisbury E, Sambrook J, Saunders C, Saunus J, Sayer R, Scott E, Scott R, Scott C, Seshadri R, Sexton A, Sharma R, Shelling A, Simpson P, Southey M, Spurdle A, Suthers G, Sykes P, Taylor D, Taylor J, Thierry B, Thompson E, Thorne H, Townshend S, Trainer A, Tran L, Tucker K, Tyler J, Visvader J, Walker L, Walpole I, Waring P, Warner B, Warren G, Williams R, Wilson J, Winship I, Wu K, Young MA
: 2014
: Nature
: 514
: 7520
: 92
: 97
: 17
: 0028-0836
DOI: https://doi.org/10.1038/nature13545
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-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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 × 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 γ-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.