%0 Journal Article %J Hum Mol Genet %D 2014 %T Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. %A Cousminer, Diana L %A Stergiakouli, Evangelia %A Berry, Diane J %A Ang, Wei %A Groen-Blokhuis, Maria M %A Körner, Antje %A Siitonen, Niina %A Ntalla, Ioanna %A Marinelli, Marcella %A Perry, John R B %A Kettunen, Johannes %A Jansen, Rick %A Surakka, Ida %A Timpson, Nicholas J %A Ring, Susan %A McMahon, George %A Power, Chris %A Wang, Carol %A Kähönen, Mika %A Viikari, Jorma %A Lehtimäki, Terho %A Middeldorp, Christel M %A Hulshoff Pol, Hilleke E %A Neef, Madlen %A Weise, Sebastian %A Pahkala, Katja %A Niinikoski, Harri %A Zeggini, Eleftheria %A Panoutsopoulou, Kalliope %A Bustamante, Mariona %A Penninx, Brenda W J H %A Murabito, Joanne %A Torrent, Maties %A Dedoussis, George V %A Kiess, Wieland %A Boomsma, Dorret I %A Pennell, Craig E %A Raitakari, Olli T %A Hyppönen, Elina %A Davey Smith, George %A Ripatti, Samuli %A McCarthy, Mark I %A Widen, Elisabeth %X

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants 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)), a menarche 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.

%B Hum Mol Genet %V 23 %P 4452-64 %8 2014 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/24770850?dopt=Abstract %R 10.1093/hmg/ddu150 %0 Journal Article %J Nature %D 2014 %T Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. %A Perry, John R B %A Day, Felix %A Elks, Cathy E %A Sulem, Patrick %A Thompson, Deborah J %A Ferreira, Teresa %A He, Chunyan %A Chasman, Daniel I %A Esko, Tõnu %A Thorleifsson, Gudmar %A Albrecht, Eva %A Ang, Wei Q %A Corre, Tanguy %A Cousminer, Diana L %A Feenstra, Bjarke %A Franceschini, Nora %A Ganna, Andrea %A Johnson, Andrew D %A Kjellqvist, Sanela %A Lunetta, Kathryn L %A McMahon, George %A Nolte, Ilja M %A Paternoster, Lavinia %A Porcu, Eleonora %A Smith, Albert V %A Stolk, Lisette %A Teumer, Alexander %A Tšernikova, Natalia %A Tikkanen, Emmi %A Ulivi, Sheila %A Wagner, Erin K %A Amin, Najaf %A Bierut, Laura J %A Byrne, Enda M %A Hottenga, Jouke-Jan %A Koller, Daniel L %A Mangino, Massimo %A Pers, Tune H %A Yerges-Armstrong, Laura M %A Hua Zhao, Jing %A Andrulis, Irene L %A Anton-Culver, Hoda %A Atsma, Femke %A Bandinelli, Stefania %A Beckmann, Matthias W %A Benitez, Javier %A Blomqvist, Carl %A Bojesen, Stig E %A Bolla, Manjeet K %A Bonanni, Bernardo %A Brauch, Hiltrud %A Brenner, Hermann %A Buring, Julie E %A Chang-Claude, Jenny %A Chanock, Stephen %A Chen, Jinhui %A Chenevix-Trench, Georgia %A Collée, J Margriet %A Couch, Fergus J %A Couper, David %A Coviello, Andrea D %A Cox, Angela %A Czene, Kamila %A d'Adamo, Adamo Pio %A Davey Smith, George %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Devilee, Peter %A Dieffenbach, Aida K %A Dunning, Alison M %A Eiriksdottir, Gudny %A Eriksson, Johan G %A Fasching, Peter A %A Ferrucci, Luigi %A Flesch-Janys, Dieter %A Flyger, Henrik %A Foroud, Tatiana %A Franke, Lude %A Garcia, Melissa E %A García-Closas, Montserrat %A Geller, Frank %A de Geus, Eco E J %A Giles, Graham G %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Guenel, Pascal %A Guo, Suiqun %A Hall, Per %A Hamann, Ute %A Haring, Robin %A Hartman, Catharina A %A Heath, Andrew C %A Hofman, Albert %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank B %A Hunter, David J %A Karasik, David %A Kiel, Douglas P %A Knight, Julia A %A Kosma, Veli-Matti %A Kutalik, Zoltán %A Lai, Sandra %A Lambrechts, Diether %A Lindblom, Annika %A Mägi, Reedik %A Magnusson, Patrik K %A Mannermaa, Arto %A Martin, Nicholas G %A Masson, Gisli %A McArdle, Patrick F %A McArdle, Wendy L %A Melbye, Mads %A Michailidou, Kyriaki %A Mihailov, Evelin %A Milani, Lili %A Milne, Roger L %A Nevanlinna, Heli %A Neven, Patrick %A Nohr, Ellen A %A Oldehinkel, Albertine J %A Oostra, Ben A %A Palotie, Aarno %A Peacock, Munro %A Pedersen, Nancy L %A Peterlongo, Paolo %A Peto, Julian %A Pharoah, Paul D P %A Postma, Dirkje S %A Pouta, Anneli %A Pylkäs, Katri %A Radice, Paolo %A Ring, Susan %A Rivadeneira, Fernando %A Robino, Antonietta %A Rose, Lynda M %A Rudolph, Anja %A Salomaa, Veikko %A Sanna, Serena %A Schlessinger, David %A Schmidt, Marjanka K %A Southey, Mellissa C %A Sovio, Ulla %A Stampfer, Meir J %A Stöckl, Doris %A Storniolo, Anna M %A Timpson, Nicholas J %A Tyrer, Jonathan %A Visser, Jenny A %A Vollenweider, Peter %A Völzke, Henry %A Waeber, Gerard %A Waldenberger, Melanie %A Wallaschofski, Henri %A Wang, Qin %A Willemsen, Gonneke %A Winqvist, Robert %A Wolffenbuttel, Bruce H R %A Wright, Margaret J %A Boomsma, Dorret I %A Econs, Michael J %A Khaw, Kay-Tee %A Loos, Ruth J F %A McCarthy, Mark I %A Montgomery, Grant W %A Rice, John P %A Streeten, Elizabeth A %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Alizadeh, Behrooz Z %A Bergmann, Sven %A Boerwinkle, Eric %A Boyd, Heather A %A Crisponi, Laura %A Gasparini, Paolo %A Gieger, Christian %A Harris, Tamara B %A Ingelsson, Erik %A Järvelin, Marjo-Riitta %A Kraft, Peter %A Lawlor, Debbie %A Metspalu, Andres %A Pennell, Craig E %A Ridker, Paul M %A Snieder, Harold %A Sørensen, Thorkild I A %A Spector, Tim D %A Strachan, David P %A Uitterlinden, André G %A Wareham, Nicholas J %A Widen, Elisabeth %A Zygmunt, Marek %A Murray, Anna %A Easton, Douglas F %A Stefansson, Kari %A Murabito, Joanne M %A Ong, Ken K %K Adolescent %K Age Factors %K Alleles %K Body Mass Index %K Breast Neoplasms %K Cardiovascular Diseases %K Child %K Diabetes Mellitus, Type 2 %K Europe %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genomic Imprinting %K Humans %K Hypothalamo-Hypophyseal System %K Intercellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Menarche %K Obesity %K Ovary %K Parents %K Polymorphism, Single Nucleotide %K Potassium Channels, Tandem Pore Domain %K Proteins %K Quantitative Trait Loci %K Receptors, GABA-B %K Receptors, Retinoic Acid %K Ribonucleoproteins %X

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.

%B Nature %V 514 %P 92-7 %8 2014 Oct 2 %G eng %N 7520 %1 http://www.ncbi.nlm.nih.gov/pubmed/25231870?dopt=Abstract %R 10.1038/nature13545