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. JF - Hum Mol Genet Y1 - 2014 A1 - Cousminer, Diana L A1 - Stergiakouli, Evangelia A1 - Berry, Diane J A1 - Ang, Wei A1 - Groen-Blokhuis, Maria M A1 - Körner, Antje A1 - Siitonen, Niina A1 - Ntalla, Ioanna A1 - Marinelli, Marcella A1 - Perry, John R B A1 - Kettunen, Johannes A1 - Jansen, Rick A1 - Surakka, Ida A1 - Timpson, Nicholas J A1 - Ring, Susan A1 - McMahon, George A1 - Power, Chris A1 - Wang, Carol A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Lehtimäki, Terho A1 - Middeldorp, Christel M A1 - Hulshoff Pol, Hilleke E A1 - Neef, Madlen A1 - Weise, Sebastian A1 - Pahkala, Katja A1 - Niinikoski, Harri A1 - Zeggini, Eleftheria A1 - Panoutsopoulou, Kalliope A1 - Bustamante, Mariona A1 - Penninx, Brenda W J H A1 - Murabito, Joanne A1 - Torrent, Maties A1 - Dedoussis, George V A1 - Kiess, Wieland A1 - Boomsma, Dorret I A1 - Pennell, Craig E A1 - Raitakari, Olli T A1 - Hyppönen, Elina A1 - Davey Smith, George A1 - Ripatti, Samuli A1 - McCarthy, Mark I A1 - Widen, Elisabeth AB -

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.

VL - 23 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24770850?dopt=Abstract ER - TY - JOUR T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. JF - Nature Y1 - 2014 A1 - Perry, John R B A1 - Day, Felix A1 - Elks, Cathy E A1 - Sulem, Patrick A1 - Thompson, Deborah J A1 - Ferreira, Teresa A1 - He, Chunyan A1 - Chasman, Daniel I A1 - Esko, Tõnu A1 - Thorleifsson, Gudmar A1 - Albrecht, Eva A1 - Ang, Wei Q A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Feenstra, Bjarke A1 - Franceschini, Nora A1 - Ganna, Andrea A1 - Johnson, Andrew D A1 - Kjellqvist, Sanela A1 - Lunetta, Kathryn L A1 - McMahon, George A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Porcu, Eleonora A1 - Smith, Albert V A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Tšernikova, Natalia A1 - Tikkanen, Emmi A1 - Ulivi, Sheila A1 - Wagner, Erin K A1 - Amin, Najaf A1 - Bierut, Laura J A1 - Byrne, Enda M A1 - Hottenga, Jouke-Jan A1 - Koller, Daniel L A1 - Mangino, Massimo A1 - Pers, Tune H A1 - Yerges-Armstrong, Laura M A1 - Hua Zhao, Jing A1 - Andrulis, Irene L A1 - Anton-Culver, Hoda A1 - Atsma, Femke A1 - Bandinelli, Stefania A1 - Beckmann, Matthias W A1 - Benitez, Javier A1 - Blomqvist, Carl A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Bonanni, Bernardo A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Buring, Julie E A1 - Chang-Claude, Jenny A1 - Chanock, Stephen A1 - Chen, Jinhui A1 - Chenevix-Trench, Georgia A1 - Collée, J Margriet A1 - Couch, Fergus J A1 - Couper, David A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - d'Adamo, Adamo Pio A1 - Davey Smith, George A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dieffenbach, Aida K A1 - Dunning, Alison M A1 - Eiriksdottir, Gudny A1 - Eriksson, Johan G A1 - Fasching, Peter A A1 - Ferrucci, Luigi A1 - Flesch-Janys, Dieter A1 - Flyger, Henrik A1 - Foroud, Tatiana A1 - Franke, Lude A1 - Garcia, Melissa E A1 - García-Closas, Montserrat A1 - Geller, Frank A1 - de Geus, Eco E J A1 - Giles, Graham G A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guenel, Pascal A1 - Guo, Suiqun A1 - Hall, Per A1 - Hamann, Ute A1 - Haring, Robin A1 - Hartman, Catharina A A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank B A1 - Hunter, David J A1 - Karasik, David A1 - Kiel, Douglas P A1 - Knight, Julia A A1 - Kosma, Veli-Matti A1 - Kutalik, Zoltán A1 - Lai, Sandra A1 - Lambrechts, Diether A1 - Lindblom, Annika A1 - Mägi, Reedik A1 - Magnusson, Patrik K A1 - Mannermaa, Arto A1 - Martin, Nicholas G A1 - Masson, Gisli A1 - McArdle, Patrick F A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Milne, Roger L A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Nohr, Ellen A A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Pedersen, Nancy L A1 - Peterlongo, Paolo A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Postma, Dirkje S A1 - Pouta, Anneli A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Ring, Susan A1 - Rivadeneira, Fernando A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rudolph, Anja A1 - Salomaa, Veikko A1 - Sanna, Serena A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Southey, Mellissa C A1 - Sovio, Ulla A1 - Stampfer, Meir J A1 - Stöckl, Doris A1 - Storniolo, Anna M A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan A1 - Visser, Jenny A A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Waeber, Gerard A1 - Waldenberger, Melanie A1 - Wallaschofski, Henri A1 - Wang, Qin A1 - Willemsen, Gonneke A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce H R A1 - Wright, Margaret J A1 - Boomsma, Dorret I A1 - Econs, Michael J A1 - Khaw, Kay-Tee A1 - Loos, Ruth J F A1 - McCarthy, Mark I A1 - Montgomery, Grant W A1 - Rice, John P A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Alizadeh, Behrooz Z A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boyd, Heather A A1 - Crisponi, Laura A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Ingelsson, Erik A1 - Järvelin, Marjo-Riitta A1 - Kraft, Peter A1 - Lawlor, Debbie A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Tim D A1 - Strachan, David P A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Widen, Elisabeth A1 - Zygmunt, Marek A1 - Murray, Anna A1 - Easton, Douglas F A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K KW - Adolescent KW - Age Factors KW - Alleles KW - Body Mass Index KW - Breast Neoplasms KW - Cardiovascular Diseases KW - Child KW - Diabetes Mellitus, Type 2 KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomic Imprinting KW - Humans KW - Hypothalamo-Hypophyseal System KW - Intercellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Menarche KW - Obesity KW - Ovary KW - Parents KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Tandem Pore Domain KW - Proteins KW - Quantitative Trait Loci KW - Receptors, GABA-B KW - Receptors, Retinoic Acid KW - Ribonucleoproteins 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-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.

VL - 514 IS - 7520 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25231870?dopt=Abstract ER -