@article {8881, title = {Genome-wide analysis identifies 12 loci influencing human reproductive behavior.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Dec}, pages = {1462-1472}, abstract = {

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

}, issn = {1546-1718}, doi = {10.1038/ng.3698}, author = {Nicola Barban and Jansen, Rick and de Vlaming, Ronald and Vaez, Ahmad and Mandemakers, Jornt J and Felix C Tropf and Shen, Xia and James F Wilson and Daniel I Chasman and Ilja M Nolte and Tragante, Vinicius and van der Laan, Sander W and Perry, John R B and Kong, Augustine and Ahluwalia, Tarunveer S and Albrecht, Eva and Laura M Yerges-Armstrong and Atzmon, Gil and Auro, Kirsi and Kristin L. Ayers and Bakshi, Andrew and Ben-Avraham, Danny and Klaus Berger and Bergman, Aviv and Bertram, Lars and Bielak, Lawrence F and Bjornsdottir, Gyda and Bonder, Marc Jan and Broer, Linda and Bui, Minh and Barbieri, Caterina and Cavadino, Alana and Chavarro, Jorge E and Turman, Constance and Maria Pina Concas and Cordell, Heather J and Gail Davies and Eibich, Peter and Eriksson, Nicholas and T{\~o}nu Esko and Eriksson, Joel and Falahi, Fahimeh and Felix, Janine F and Mark Alan Fontana and Lude L Franke and Gandin, Ilaria and Gaskins, Audrey J and Gieger, Christian and Gunderson, Erica P and Guo, Xiuqing and Caroline Hayward and He, Chunyan and Edith Hofer and Huang, Hongyan and Joshi, Peter K and Kanoni, Stavroula and Karlsson, Robert and Kiechl, Stefan and Kifley, Annette and Kluttig, Alexander and Kraft, Peter and Lagou, Vasiliki and Lecoeur, Cecile and Lahti, Jari and Li-Gao, Ruifang and Penelope A Lind and Tian Liu and Makalic, Enes and Mamasoula, Crysovalanto and Lindsay K Matteson and Mbarek, Hamdi and McArdle, Patrick F and McMahon, George and Meddens, S Fleur W and Mihailov, Evelin and Michael B Miller and Missmer, Stacey A and Monnereau, Claire and van der Most, Peter J and Myhre, Ronny and Michael A Nalls and Nutile, Teresa and Ioanna Panagiota Kalafati and Porcu, Eleonora and Prokopenko, Inga and Rajan, Kumar B and Rich-Edwards, Janet and Cornelius A Rietveld and Robino, Antonietta and Rose, Lynda M and Rueedi, Rico and Ryan, Kathleen A and Saba, Yasaman and Schmidt, Daniel and Jennifer A Smith and Stolk, Lisette and Streeten, Elizabeth and T{\"o}njes, Anke and Thorleifsson, Gudmar and Ulivi, Sheila and Wedenoja, Juho and J{\"u}rgen Wellmann and Willeit, Peter and Yao, Jie and Yengo, Loic and Jing Hua Zhao and Wei Zhao and Zhernakova, Daria V and Amin, Najaf and Andrews, Howard and Balkau, Beverley and Barzilai, Nir and Bergmann, Sven and Biino, Ginevra and Bisgaard, Hans and B{\o}nnelykke, Klaus and Dorret I Boomsma and Buring, Julie E and Campbell, Harry and Cappellani, Stefania and Ciullo, Marina and Cox, Simon R and Francesco Cucca and Toniolo, Daniela and Davey-Smith, George and Ian J Deary and George Dedoussis and Deloukas, Panos and Cornelia M van Duijn and Eco J. C. de Geus and Johan G Eriksson and Jessica Faul and Cinzia Felicita Sala and Froguel, Philippe and Paolo P. Gasparini and Giorgia G Girotto and Hans-J{\"o}rgen Grabe and Greiser, Karin Halina and Groenen, Patrick J F and de Haan, Hugoline G and Haerting, Johannes and Tamara B Harris and Andrew C Heath and Heikkil{\"a}, Kauko and Hofman, Albert and Homuth, Georg and Holliday, Elizabeth G and John L Hopper and Hypp{\"o}nen, Elina and Jacobsson, Bo and Vincent Jaddoe and Johannesson, Magnus and Jugessur, Astanand and K{\"a}h{\"o}nen, Mika and Kajantie, Eero and Sharon L R Kardia and Keavney, Bernard and Kolcic, Ivana and Koponen, P{\"a}ivikki and Kovacs, Peter and Kronenberg, Florian and Kutalik, Zolt{\'a}n and La Bianca, Martina and Lachance, Genevieve and Iacono, William G and Lai, Sandra and Lehtim{\"a}ki, Terho and David C Liewald and Lindgren, Cecilia M and Yongmei Liu and Luben, Robert and Lucht, Michael and Luoto, Riitta and Magnus, Per and Patrik K E Magnusson and Nicholas G Martin and McGue, Matt and McQuillan, Ruth and Sarah E Medland and Meisinger, Christa and Mellstr{\"o}m, Dan and Andres Metspalu and Traglia, Michela and Lili Milani and Mitchell, Paul and Grant W Montgomery and Dennis O Mook-Kanamori and de Mutsert, Ren{\'e}e and Nohr, Ellen A and Ohlsson, Claes and Olsen, J{\o}rn and Ong, Ken K and Paternoster, Lavinia and Pattie, Alison and Brenda W J H Penninx and Markus Perola and Peyser, Patricia A and Pirastu, Mario and Polasek, Ozren and Power, Chris and Kaprio, Jaakko and Raffel, Leslie J and Katri R{\"a}ikk{\"o}nen and Olli T Raitakari and Ridker, Paul M and Ring, Susan M and Roll, Kathryn and Rudan, Igor and Ruggiero, Daniela and Rujescu, Dan and Veikko Salomaa and Schlessinger, David and Schmidt, Helena and Schmidt, Reinhold and Schupf, Nicole and Johannes H Smit and Sorice, Rossella and Timothy Spector and John M Starr and St{\"o}ckl, Doris and Strauch, Konstantin and Stumvoll, Michael and Swertz, Morris A and Thorsteinsdottir, Unnur and A. Roy Thurik and Nicholas J Timpson and Tung, Joyce Y and Andr{\'e} G Uitterlinden and Vaccargiu, Simona and Viikari, Jorma and Vitart, Veronique and V{\"o}lzke, Henry and Vollenweider, Peter and Vuckovic, Dragana and Waage, Johannes and Wagner, Gert G and Wang, Jie Jin and Wareham, Nicholas J and David R Weir and Gonneke Willemsen and Willeit, Johann and Alan F Wright and Krina T Zondervan and Stefansson, Kari and Krueger, Robert F and Lee, James J and Daniel J. Benjamin and Cesarini, David and Philipp D Koellinger and den Hoed, Marcel and Snieder, Harold and Melinda C Mills} } @article {8889, 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.

}, keywords = {Age Factors, Aging, BRCA1 Protein, Breast Neoplasms, DNA Repair, Female, Genome, Genome-Wide Association Study, Genotype, Humans, Hypothalamus, Menopause, Middle Aged, Models, Genetic, Older Adults, Phenotype, Reproduction, Signal Transduction}, issn = {1546-1718}, doi = {10.1038/ng.3412}, author = {Day, Felix R and Ruth, Katherine S and Thompson, Deborah J and Kathryn L Lunetta and Pervjakova, Natalia and Daniel I Chasman and Stolk, Lisette and Finucane, Hilary K and Sulem, Patrick and Bulik-Sullivan, Brendan and T{\~o}nu Esko and Andrew D Johnson and Elks, Cathy E and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A and Lude L Franke 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 Jennifer A Smith and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Wei Zhao and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Jouke-Jan Hottenga and Mangino, Massimo and Albert Vernon Smith and Toshiko Tanaka and Gon{\c c}alo R Abecasis and Andrulis, Irene L and Anton-Culver, Hoda and Antoniou, Antonis C and Arndt, Volker and Alice M. Arnold 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 Manjeet K. Bolla 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 Yii-Der I Chen 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 Ellen W Demerath and Joe G Dennis and Devilee, Peter and D{\"o}rk, Thilo and Dos-Santos-Silva, Isabel and Dunning, Alison M and John D Eicher and Fasching, Peter A and Jessica Faul and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Melissa E Garcia and Garc{\'\i}a-Closas, Montserrat and Giles, Graham G and Giorgia G Girotto and Goldberg, Mark S and Gonz{\'a}lez-Neira, Anna and Goodarzi, Mark O and Grove, Megan L and Gudbjartsson, Daniel F and Gu{\'e}nel, Pascal and Guo, Xiuqing and Christopher A Haiman and Hall, Per and Hamann, Ute and Henderson, Brian E and Lynne J Hocking and Hofman, Albert and Homuth, Georg and Hooning, Maartje J and John L Hopper 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 Charles Kooperberg 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 Yongmei Liu 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 Nicholas G Martin and Masciullo, Corrado and Meindl, Alfons and Michailidou, Kyriaki and Mihailov, Evelin and Lili Milani and Milne, Roger L and M{\"u}ller-Nurasyid, Martina and Michael A Nalls and Neale, Benjamin M and Nevanlinna, Heli and Neven, Patrick and Anne B Newman and B{\o}rge G Nordestgaard 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 Nicola Pirastu and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and David J Porteous and Psaty, Bruce M and Pylk{\"a}s, Katri and Radice, Paolo and Raffel, Leslie J and Fernando Rivadeneira and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Cinzia Felicita Sala 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 Kent D Taylor and Thorsteinsdottir, Unnur and Toland, Amanda E and Tomlinson, Ian and Truong, Th{\'e}r{\`e}se and Tryggvadottir, Laufey and Stephen T Turner and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Gonneke Willemsen and James F Wilson and Winqvist, Robert and Wolffenbuttel, Bruce B H R and Alan F Wright and Yannoukakos, Drakoulis and Zemunik, Tatijana and Wei Zhang and Zygmunt, Marek and Bergmann, Sven and Dorret I Boomsma and Buring, Julie E and Luigi Ferrucci and Grant W Montgomery and Gudnason, Vilmundur and Timothy Spector and Cornelia M van Duijn and Alizadeh, Behrooz Z and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F and Paolo P. Gasparini and Gieger, Christian and Tamara B Harris and Caroline Hayward and Sharon L R Kardia and Kraft, Peter and McKnight, Barbara and Andres Metspalu and Alanna C Morrison and Reiner, Alex P and Ridker, Paul M and Rotter, Jerome I and Toniolo, Daniela and Andr{\'e} G Uitterlinden and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and David R Weir and Laura M Yerges-Armstrong and Price, Alkes L and Stefansson, Kari and Visser, Jenny A and Ong, Ken K and Chang-Claude, Jenny and Joanne M Murabito and Perry, John R B and Murray, Anna} }