TY - JOUR
T1 - Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty
AU - The ReproGen Consortium
AU - The Early Growth Genetics (EGG) Consortium
AU - The GIANT Consortium
AU - Cousminer, Diana L.
AU - Stergiakouli, Evangelia
AU - Berry, Diane J.
AU - Ang, Wei
AU - Groen-Blokhuis, Maria M.
AU - Körner, Antje
AU - Siitonen, Niina
AU - Ntalla, Ioanna
AU - Marinelli, Marcella
AU - Perry, John R.B.
AU - Kettunen, Johannes
AU - Jansen, Rick
AU - Surakka, Ida
AU - Timpson, Nicholas J.
AU - Ring, Susan
AU - McMahon, George
AU - Power, Chris
AU - Wang, Carol
AU - Kähönen, Mika
AU - Viikari, Jorma
AU - Lehtimäki, Terho
AU - Middeldorp, Christel M.
AU - Hulshoff Pol, Hilleke E.
AU - Neef, Madlen
AU - Weise, Sebastian
AU - Pahkala, Katja
AU - Niinikoski, Harri
AU - Zeggini, Eleftheria
AU - Panoutsopoulou, Kalliope
AU - Bustamante, Mariona
AU - Penninx, Brenda W.J.H.
AU - Murabito, Joanne M.
AU - Torrent, Maties
AU - Dedoussis, George V.
AU - Kiess, Wieland
AU - Boomsma, Dorret I.
AU - Pennell, Craig E.
AU - Raitakari, Olli T.
AU - Hyppönen, Elina
AU - Smith, George Davey
AU - Ripatti, Samuli
AU - McCarthy, Mark I.
AU - Widén, Elisabeth
AU - Adair, Linda S.
AU - Atalay, Mustafa
AU - van Beijsterveldt, Toos
AU - Bergen, Nienke
AU - Benke, Kelly
AU - Bradfield, Jonathan P.
AU - Charoen, Pimphen
AU - Coin, Lachlan
AU - Cooper, Cyrus
AU - Das, Shikta
AU - Davis, Oliver S.P.
AU - Elliott, Paul
AU - Estivill, Xavier
AU - Evans, David M.
AU - Feenstra, Bjarke
AU - Flexeder, Claudia
AU - Frayling, Tim
AU - Freathy, Rachel M.
AU - Gaillard, Romy
AU - Geller, Frank
AU - Gillman, Matthew
AU - Grant, Struan F.A.
AU - Goh, Liang Kee
AU - Guxens, Mònica
AU - Hakonarson, Hakon
AU - Hattersley, Andrew T.
AU - Haworth, Claire M.A.
AU - Hadley, Dexter
AU - Hedebrand, Johannes
AU - Heinrich, Joachim
AU - Hinney, Anke
AU - Hirschhorn, Joel N.
AU - Hocher, Berthold
AU - Holloway, John W.
AU - Holst, Claus
AU - Hottenga, Jouke Jan
AU - Horikoshi, Momoko
AU - Huikari, Ville
AU - Iñiguez, Carmen
AU - Jaddoe, Vincent W.V.
AU - Jarvelin, Marjo Riitta
AU - Kaakinen, Marika
AU - Kilpeläinen, Tuomas O.
AU - Kirin, Mirna
AU - Kowgier, Matthew
AU - Lakka, Hanna Maaria
AU - Lakka, Timo A.
AU - Lange, Leslie A.
AU - Lawlor, Debbie A.
AU - Lewin, Alex
AU - Lindgren, Cecilia
AU - Lindi, Virpi
AU - Maggi, Reedik
AU - Marsh, Julie
AU - Melbye, Mads
AU - Millwood, Iona
AU - Mohlke, Karen L.
AU - Mook-Kanamori, Dennis O.
AU - Murray, Jeffrey C.
AU - Nivard, Michel
AU - Nohr, Ellen Aagaard
AU - Oken, Emily
AU - Ong, Ken K.
AU - O’reilly, Paul F.
AU - Palmer, Lyle J.
AU - Pararajasingham, Jennifer
AU - Pearson, Ewan R.
AU - Price, Thomas S.
AU - Prokopenko, Inga
AU - Rodriguez, Alina
AU - Salem, Rany M.
AU - Saw, Seang Mei
AU - Scherag, Andre
AU - Sebert, Sylvain
AU - Simell, Olli
AU - Sørensen, Thorkild I.A.
AU - Sovio, Ulla
AU - St Pourcain, Beate
AU - Strachan, David P.
AU - Sunyer, Jordi
AU - Rob Taal, H.
AU - Teo, Yik Ying
AU - Thiering, Elisabeth
AU - Tiesler, Carla
AU - Uitterlinden, Andre G.
AU - Valcárcel, Beatriz
AU - Warrington, Nicole M.
AU - White, Scott
AU - Willemsen, Gonneke
AU - Wilson, James F.
AU - Yaghootkar, Hanieh
AU - Elks, Cathy E.
AU - Sulem, Patrick
AU - Chasman, Daniel I.
AU - Franceschini, Nora
AU - He, Chunyan
AU - Lunetta, Kathryn L.
AU - Visser, Jenny A.
AU - Byrne, Enda M.
AU - Gudbjartsson, Daniel F.
AU - Esko, Tõnu
AU - Hottenga, Jouke Jan
AU - Koller, Daniel L.
AU - Kutalik, Zoltán
AU - Lin, Peng
AU - Mangino, Massimo
AU - Marongiu, Mara
AU - McArdle, Patrick F.
AU - Smith, Albert V.
AU - Stolk, Lisette
AU - van Wingerden, Sophie H.
AU - Zhao, Jing Hua
AU - Albrecht, Eva
AU - Corre, Tanguy
AU - Ingelsson, Erik
AU - Hayward, Caroline
AU - Magnusson, Patrik K.E.
AU - Smith, Erin N.
AU - Ulivi, Shelia
AU - Zgaga, Lina
AU - Alavere, Helen
AU - Amin, Najaf
AU - Aspelund, Thor
AU - Bandinelli, Stefania
AU - Barroso, Inês
AU - Berenson, Gerald S.
AU - Bergmann, Sven
AU - Blackburn, Hannah
AU - Boerwinkle, Eric
AU - Buring, Julie E.
AU - Busonero, Fabio
AU - Campbell, Harry
AU - Chanock, Stephen J.
AU - Chen, Wei
AU - Cornelis, Marilyn C.
AU - Couper, David
AU - Coviello, Andrea D.
AU - D'adamo, Pio
AU - de Faire, Ulf
AU - de Geus, Eco J.C.
AU - Deloukas, Panos
AU - Döring, Angela
AU - Easton, Douglas F.
AU - Eiriksdottir, Gudny
AU - Emilsson, Valur
AU - Eriksson, Johan
AU - Ferrucci, Luigi
AU - Folsom, Aaron R.
AU - Foroud, Tatiana
AU - Garcia, Melissa
AU - Gasparini, Paolo
AU - Gieger, Christian
AU - Gudnason, Vilmundur
AU - Hall, Per
AU - Heath, Andrew C.
AU - Rice, John P.
AU - Bierut, Laura J.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Little is known about genes regulating male puberty. Further, while many identified pubertal timing 1variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9×10-9), amenarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6×10-5) and short adult stature (p = 7.5×10-6) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
AB - Little is known about genes regulating male puberty. Further, while many identified pubertal timing 1variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9×10-9), amenarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6×10-5) and short adult stature (p = 7.5×10-6) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
UR - http://www.scopus.com/inward/record.url?scp=84904751759&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu150
DO - 10.1093/hmg/ddu150
M3 - Article
C2 - 24770850
AN - SCOPUS:84904751759
SN - 0964-6906
VL - 23
SP - 4452
EP - 4464
JO - Human molecular genetics
JF - Human molecular genetics
IS - 16
ER -