@article {10556, title = {Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {834-841}, abstract = {

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to \~{}370,000 women, we identify 389 independent signals (P < 5 {\texttimes} 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain \~{}7.4\% of the population variance in age at menarche, corresponding to \~{}25\% of the estimated heritability. We implicate \~{}250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

}, keywords = {Adolescent, Age Factors, Body Mass Index, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomic Imprinting, Humans, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Neoplasms, Polymorphism, Single Nucleotide, Puberty, Quantitative Trait Loci, Ribonucleoproteins, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3841}, author = {Day, Felix R and Thompson, Deborah J and Helgason, Hannes and Chasman, Daniel I and Finucane, Hilary and Sulem, Patrick and Ruth, Katherine S and Whalen, Sean and Sarkar, Abhishek K and Albrecht, Eva and Altmaier, Elisabeth and Amini, Marzyeh and Barbieri, Caterina M and Boutin, Thibaud and Campbell, Archie and Demerath, Ellen and Giri, Ayush and He, Chunyan and Hottenga, Jouke J and Karlsson, Robert and Kolcic, Ivana and Loh, Po-Ru and Lunetta, Kathryn L and Mangino, Massimo and Marco, Brumat and McMahon, George and Medland, Sarah E and Nolte, Ilja M and Noordam, Raymond and Nutile, Teresa and Paternoster, Lavinia and Perjakova, Natalia and Porcu, Eleonora and Rose, Lynda M and Schraut, Katharina E and Segr{\`e}, Ayellet V and Smith, Albert V and Stolk, Lisette and Teumer, Alexander and Andrulis, Irene L and Bandinelli, Stefania and Beckmann, Matthias W and Benitez, Javier and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Brand, Judith S and Brauch, Hiltrud and Brenner, Hermann and Broer, Linda and Br{\"u}ning, Thomas and Buring, Julie E and Campbell, Harry and Catamo, Eulalia and Chanock, Stephen and Chenevix-Trench, Georgia and Corre, Tanguy and Couch, Fergus J and Cousminer, Diana L and Cox, Angela and Crisponi, Laura and Czene, Kamila and Davey Smith, George and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Dennis, Joe and Devilee, Peter and Dos-Santos-Silva, Isabel and Dunning, Alison M and Eriksson, Johan G and Fasching, Peter A and Fern{\'a}ndez-Rhodes, Lindsay and Ferrucci, Luigi and Flesch-Janys, Dieter and Franke, Lude and Gabrielson, Marike and Gandin, Ilaria and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Guenel, Pascal and Hall, Per and Hallberg, Emily and Hamann, Ute and Harris, Tamara B and Hartman, Catharina A and Heiss, Gerardo and Hooning, Maartje J and Hopper, John L and Hu, Frank and Hunter, David J and Ikram, M Arfan and Im, Hae Kyung and J{\"a}rvelin, Marjo-Riitta and Joshi, Peter K and Karasik, David and Kellis, Manolis and Kutalik, Zolt{\'a}n and LaChance, Genevieve and Lambrechts, Diether and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lenarduzzi, Stefania and Li, Jingmei and Lind, Penelope A and Lindstr{\"o}m, Sara and Liu, Yongmei and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mannermaa, Arto and Mbarek, Hamdi and McCarthy, Mark I and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Michailidou, Kyriaki and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mulligan, Anna M and Nalls, Mike A and Navarro, Pau and Nevanlinna, Heli and Nyholt, Dale R and Oldehinkel, Albertine J and O{\textquoteright}Mara, Tracy A and Padmanabhan, Sandosh and Palotie, Aarno and Pedersen, Nancy and Peters, Annette and Peto, Julian and Pharoah, Paul D P and Pouta, Anneli and Radice, Paolo and Rahman, Iffat and Ring, Susan M and Robino, Antonietta and Rosendaal, Frits R and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Schmidt, Marjanka K and Scott, Robert A and Shah, Mitul and Sorice, Rossella and Southey, Melissa C and Sovio, Ulla and Stampfer, Meir and Steri, Maristella and Strauch, Konstantin and Tanaka, Toshiko and Tikkanen, Emmi and Timpson, Nicholas J and Traglia, Michela and Truong, Therese and Tyrer, Jonathan P and Uitterlinden, Andr{\'e} G and Edwards, Digna R Velez and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Qin and Widen, Elisabeth and van Dijk, Ko Willems and Willemsen, Gonneke and Winqvist, Robert and Wolffenbuttel, Bruce H R and Zhao, Jing Hua and Zoledziewska, Magdalena and Zygmunt, Marek and Alizadeh, Behrooz Z and Boomsma, Dorret I and Ciullo, Marina and Cucca, Francesco and Esko, T{\~o}nu and Franceschini, Nora and Gieger, Christian and Gudnason, Vilmundur and Hayward, Caroline and Kraft, Peter and Lawlor, Debbie A and Magnusson, Patrik K E and Martin, Nicholas G and Mook-Kanamori, Dennis O and Nohr, Ellen A and Polasek, Ozren and Porteous, David and Price, Alkes L and Ridker, Paul M and Snieder, Harold and Spector, Tim D and St{\"o}ckl, Doris and Toniolo, Daniela and Ulivi, Sheila and Visser, Jenny A and V{\"o}lzke, Henry and Wareham, Nicholas J and Wilson, James F and Spurdle, Amanda B and Thorsteindottir, Unnur and Pollard, Katherine S and Easton, Douglas F and Tung, Joyce Y and Chang-Claude, Jenny and Hinds, David and Murray, Anna and Murabito, Joanne M and Stefansson, Kari and Ong, Ken K and Perry, John R B} } @article {8066, title = {Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1294-303}, abstract = {

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in \~{}70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (\~{}6\% increase in risk per year; P = 3 {\texttimes} 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

}, issn = {1546-1718}, doi = {10.1038/ng.3412}, author = {Day, Felix R and Ruth, Katherine S and Thompson, Deborah J and Lunetta, Kathryn L and Pervjakova, Natalia and Chasman, Daniel I and Stolk, Lisette and Finucane, Hilary K and Sulem, Patrick and Bulik-Sullivan, Brendan and Esko, T{\~o}nu and Johnson, Andrew D and Elks, Cathy E and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A and Franke, Lude L and Huffman, Jennifer E and Keller, Margaux F and McArdle, Patrick F and Nutile, Teresa and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Smith, Jennifer A and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Zhao, Wei and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Hottenga, Jouke-Jan and Mangino, Massimo and Smith, Albert V and Tanaka, Toshiko and Abecasis, Goncalo R and Andrulis, Irene L and Anton-Culver, Hoda and Antoniou, Antonis C and Arndt, Volker and Arnold, Alice M and Barbieri, Caterina and Beckmann, Matthias W and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Bielinski, Suzette J and Blomqvist, Carl and Boerwinkle, Eric and Bogdanova, Natalia V and Bojesen, Stig E and Bolla, Manjeet K and Borresen-Dale, Anne-Lise and Boutin, Thibaud S and Brauch, Hiltrud and Brenner, Hermann and Br{\"u}ning, Thomas and Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Chanock, Stephen J and Chapman, J Ross and Chen, Yii-Der Ida and Chenevix-Trench, Georgia and Couch, Fergus J and Coviello, Andrea D and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Devilee, Peter and D{\"o}rk, Thilo and Dos-Santos-Silva, Isabel and Dunning, Alison M and Eicher, John D and Fasching, Peter A and Faul, Jessica D and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Garcia, Melissa E and Garc{\'\i}a-Closas, Montserrat and Giles, Graham G and Girotto, Giorgia G and Goldberg, Mark S and Gonz{\'a}lez-Neira, Anna and Goodarzi, Mark O and Grove, Megan L and Gudbjartsson, Daniel F and Guenel, Pascal and Guo, Xiuqing and Haiman, Christopher A and Hall, Per and Hamann, Ute and Henderson, Brian E and Hocking, Lynne J and Hofman, Albert and Homuth, Georg and Hooning, Maartje J and Hopper, John L and Hu, Frank B and Huang, Jinyan and Humphreys, Keith and Hunter, David J and Jakubowska, Anna and Jones, Samuel E and Kabisch, Maria and Karasik, David and Knight, Julia A and Kolcic, Ivana and Kooperberg, Charles and Kosma, Veli-Matti and Kriebel, Jennifer and Kristensen, Vessela and Lambrechts, Diether and Langenberg, Claudia and Li, Jingmei and Li, Xin and Lindstr{\"o}m, Sara and Liu, Yongmei and Luan, Jian{\textquoteright}an and Lubinski, Jan and M{\"a}gi, Reedik and Mannermaa, Arto and Manz, Judith and Margolin, Sara and Marten, Jonathan and Martin, Nicholas G and Masciullo, Corrado and Meindl, Alfons and Michailidou, Kyriaki and Mihailov, Evelin and Milani, Lili and Milne, Roger L and M{\"u}ller-Nurasyid, Martina and Nalls, Michael and Neale, Benjamin M and Nevanlinna, Heli and Neven, Patrick and Newman, Anne B and Nordestgaard, B{\o}rge G and Olson, Janet E and Padmanabhan, Sandosh and Peterlongo, Paolo and Peters, Ulrike and Petersmann, Astrid and Peto, Julian and Pharoah, Paul D P and Pirastu, Nicola N and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and Porteous, David and Psaty, Bruce M and Pylk{\"a}s, Katri and Radice, Paolo and Raffel, Leslie J and Rivadeneira, Fernando and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Sala, Cinzia F and Sanna, Serena and Sawyer, Elinor J and Schlessinger, David and Schmidt, Marjanka K and Schmidt, Frank and Schmutzler, Rita K and Schoemaker, Minouk J and Scott, Robert A and Seynaeve, Caroline M and Simard, Jacques and Sorice, Rossella and Southey, Melissa C and St{\"o}ckl, Doris and Strauch, Konstantin and Swerdlow, Anthony and Taylor, Kent D and Thorsteinsdottir, Unnur and Toland, Amanda E and Tomlinson, Ian and Truong, Therese and Tryggvadottir, Laufey and Turner, Stephen T and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Willemsen, Gonneke and Wilson, James F and Winqvist, Robert and Wolffenbuttel, Bruce B H R and Wright, Alan F and Yannoukakos, Drakoulis and Zemunik, Tatijana and Zheng, Wei and Zygmunt, Marek and Bergmann, Sven and Boomsma, Dorret I and Buring, Julie E and Ferrucci, Luigi and Montgomery, Grant W and Gudnason, Vilmundur and Spector, Tim D and van Duijn, Cornelia M and Alizadeh, Behrooz Z and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F and Gasparini, Paolo P and Gieger, Christian and Harris, Tamara B and Hayward, Caroline and Kardia, Sharon L R and Kraft, Peter and McKnight, Barbara and Metspalu, Andres and Morrison, Alanna C and Reiner, Alex P and Ridker, Paul M and Rotter, Jerome I and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and Weir, David R and Yerges-Armstrong, Laura M and Price, Alkes L and Stefansson, Kari and Visser, Jenny A and Ong, Ken K and Chang-Claude, Jenny and Murabito, Joanne M and Perry, John R B and Murray, Anna} } @article {3593, title = {Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.}, journal = {Nature}, volume = {514}, year = {2014}, month = {2014 Oct 2}, pages = {92-7}, 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 {\texttimes} 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.

}, keywords = {Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins}, issn = {1476-4687}, doi = {10.1038/nature13545}, author = {Perry, John R B and Day, Felix and Elks, Cathy E and Sulem, Patrick and Thompson, Deborah J and Ferreira, Teresa and He, Chunyan and Chasman, Daniel I and Esko, T{\~o}nu and Thorleifsson, Gudmar and Albrecht, Eva and Ang, Wei Q and Corre, Tanguy and Cousminer, Diana L and Feenstra, Bjarke and Franceschini, Nora and Ganna, Andrea and Johnson, Andrew D and Kjellqvist, Sanela and Lunetta, Kathryn L and McMahon, George and Nolte, Ilja M and Paternoster, Lavinia and Porcu, Eleonora and Smith, Albert V and Stolk, Lisette and Teumer, Alexander and T{\v s}ernikova, Natalia and Tikkanen, Emmi and Ulivi, Sheila and Wagner, Erin K and Amin, Najaf and Bierut, Laura J and Byrne, Enda M and Hottenga, Jouke-Jan and Koller, Daniel L and Mangino, Massimo and Pers, Tune H and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Andrulis, Irene L and Anton-Culver, Hoda and Atsma, Femke and Bandinelli, Stefania and Beckmann, Matthias W and Benitez, Javier and Blomqvist, Carl and Bojesen, Stig E and Bolla, Manjeet K and Bonanni, Bernardo and Brauch, Hiltrud and Brenner, Hermann and Buring, Julie E and Chang-Claude, Jenny and Chanock, Stephen and Chen, Jinhui and Chenevix-Trench, Georgia and Coll{\'e}e, J Margriet and Couch, Fergus J and Couper, David and Coviello, Andrea D and Cox, Angela and Czene, Kamila and d{\textquoteright}Adamo, Adamo Pio and Davey Smith, George and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Devilee, Peter and Dieffenbach, Aida K and Dunning, Alison M and Eiriksdottir, Gudny and Eriksson, Johan G and Fasching, Peter A and Ferrucci, Luigi and Flesch-Janys, Dieter and Flyger, Henrik and Foroud, Tatiana and Franke, Lude and Garcia, Melissa E and Garc{\'\i}a-Closas, Montserrat and Geller, Frank and de Geus, Eco E J and Giles, Graham G and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Guenel, Pascal and Guo, Suiqun and Hall, Per and Hamann, Ute and Haring, Robin and Hartman, Catharina A and Heath, Andrew C and Hofman, Albert and Hooning, Maartje J and Hopper, John L and Hu, Frank B and Hunter, David J and Karasik, David and Kiel, Douglas P and Knight, Julia A and Kosma, Veli-Matti and Kutalik, Zolt{\'a}n and Lai, Sandra and Lambrechts, Diether and Lindblom, Annika and M{\"a}gi, Reedik and Magnusson, Patrik K and Mannermaa, Arto and Martin, Nicholas G and Masson, Gisli and McArdle, Patrick F and McArdle, Wendy L and Melbye, Mads and Michailidou, Kyriaki and Mihailov, Evelin and Milani, Lili and Milne, Roger L and Nevanlinna, Heli and Neven, Patrick and Nohr, Ellen A and Oldehinkel, Albertine J and Oostra, Ben A and Palotie, Aarno and Peacock, Munro and Pedersen, Nancy L and Peterlongo, Paolo and Peto, Julian and Pharoah, Paul D P and Postma, Dirkje S and Pouta, Anneli and Pylk{\"a}s, Katri and Radice, Paolo and Ring, Susan and Rivadeneira, Fernando and Robino, Antonietta and Rose, Lynda M and Rudolph, Anja and Salomaa, Veikko and Sanna, Serena and Schlessinger, David and Schmidt, Marjanka K and Southey, Mellissa C and Sovio, Ulla and Stampfer, Meir J and St{\"o}ckl, Doris and Storniolo, Anna M and Timpson, Nicholas J and Tyrer, Jonathan and Visser, Jenny A and Vollenweider, Peter and V{\"o}lzke, Henry and Waeber, Gerard and Waldenberger, Melanie and Wallaschofski, Henri and Wang, Qin and Willemsen, Gonneke and Winqvist, Robert and Wolffenbuttel, Bruce H R and Wright, Margaret J and Boomsma, Dorret I and Econs, Michael J and Khaw, Kay-Tee and Loos, Ruth J F and McCarthy, Mark I and Montgomery, Grant W and Rice, John P and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Alizadeh, Behrooz Z and Bergmann, Sven and Boerwinkle, Eric and Boyd, Heather A and Crisponi, Laura and Gasparini, Paolo and Gieger, Christian and Harris, Tamara B and Ingelsson, Erik and J{\"a}rvelin, Marjo-Riitta and Kraft, Peter and Lawlor, Debbie and Metspalu, Andres and Pennell, Craig E and Ridker, Paul M and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Tim D and Strachan, David P and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Widen, Elisabeth and Zygmunt, Marek and Murray, Anna and Easton, Douglas F and Stefansson, Kari and Murabito, Joanne M and Ong, Ken K} }