%0 Journal Article %J Nat Genet %D 2015 %T Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. %A Day, Felix R %A Ruth, Katherine S %A Thompson, Deborah J %A Lunetta, Kathryn L %A Pervjakova, Natalia %A Chasman, Daniel I %A Stolk, Lisette %A Finucane, Hilary K %A Sulem, Patrick %A Bulik-Sullivan, Brendan %A Esko, Tõnu %A Johnson, Andrew D %A Elks, Cathy E %A Franceschini, Nora %A He, Chunyan %A Altmaier, Elisabeth %A Brody, Jennifer A %A Franke, Lude L %A Huffman, Jennifer E %A Keller, Margaux F %A McArdle, Patrick F %A Nutile, Teresa %A Porcu, Eleonora %A Robino, Antonietta %A Rose, Lynda M %A Schick, Ursula M %A Smith, Jennifer A %A Teumer, Alexander %A Traglia, Michela %A Vuckovic, Dragana %A Yao, Jie %A Zhao, Wei %A Albrecht, Eva %A Amin, Najaf %A Corre, Tanguy %A Hottenga, Jouke-Jan %A Mangino, Massimo %A Smith, Albert V %A Tanaka, Toshiko %A Abecasis, Goncalo %A Andrulis, Irene L %A Anton-Culver, Hoda %A Antoniou, Antonis C %A Arndt, Volker %A Arnold, Alice M %A Barbieri, Caterina %A Beckmann, Matthias W %A Beeghly-Fadiel, Alicia %A Benitez, Javier %A Bernstein, Leslie %A Bielinski, Suzette J %A Blomqvist, Carl %A Eric Boerwinkle %A Bogdanova, Natalia V %A Bojesen, Stig E %A Bolla, Manjeet K %A Borresen-Dale, Anne-Lise %A Boutin, Thibaud S %A Brauch, Hiltrud %A Brenner, Hermann %A Brüning, Thomas %A Burwinkel, Barbara %A Campbell, Archie %A Campbell, Harry %A Chanock, Stephen J %A Chapman, J Ross %A Chen, Yii-Der Ida %A Chenevix-Trench, Georgia %A Couch, Fergus J %A Coviello, Andrea D %A Cox, Angela %A Czene, Kamila %A Darabi, Hatef %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Devilee, Peter %A Dörk, Thilo %A Dos-Santos-Silva, Isabel %A Dunning, Alison M %A Eicher, John D %A Fasching, Peter A %A Faul, Jessica D %A Figueroa, Jonine %A Flesch-Janys, Dieter %A Gandin, Ilaria %A Garcia, Melissa E %A García-Closas, Montserrat %A Giles, Graham G %A Girotto, Giorgia G %A Goldberg, Mark S %A González-Neira, Anna %A Goodarzi, Mark O %A Grove, Megan L %A Gudbjartsson, Daniel F %A Guénel, Pascal %A Guo, Xiuqing %A Haiman, Christopher A %A Hall, Per %A Hamann, Ute %A Henderson, Brian E %A Hocking, Lynne J %A Hofman, Albert %A Homuth, Georg %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank B %A Huang, Jinyan %A Humphreys, Keith %A Hunter, David J %A Jakubowska, Anna %A Jones, Samuel E %A Kabisch, Maria %A Karasik, David %A Knight, Julia A %A Kolcic, Ivana %A Kooperberg, Charles %A Kosma, Veli-Matti %A Kriebel, Jennifer %A Kristensen, Vessela %A Lambrechts, Diether %A Langenberg, Claudia %A Li, Jingmei %A Li, Xin %A Lindström, Sara %A Liu, Yongmei %A Luan, Jian'an %A Lubinski, Jan %A Mägi, Reedik %A Mannermaa, Arto %A Manz, Judith %A Margolin, Sara %A Marten, Jonathan %A Martin, Nicholas G %A Masciullo, Corrado %A Meindl, Alfons %A Michailidou, Kyriaki %A Mihailov, Evelin %A Milani, Lili %A Milne, Roger L %A Müller-Nurasyid, Martina %A Nalls, Michael %A Neale, Ben M %A Nevanlinna, Heli %A Neven, Patrick %A Newman, Anne B %A Nordestgaard, Børge G %A Olson, Janet E %A Padmanabhan, Sandosh %A Peterlongo, Paolo %A Peters, Ulrike %A Petersmann, Astrid %A Peto, Julian %A Pharoah, Paul D P %A Pirastu, Nicola N %A Pirie, Ailith %A Pistis, Giorgio %A Polasek, Ozren %A Porteous, David %A Psaty, Bruce M %A Pylkäs, Katri %A Radice, Paolo %A Raffel, Leslie J %A Rivadeneira, Fernando %A Rudan, Igor %A Rudolph, Anja %A Ruggiero, Daniela %A Sala, Cinzia F %A Sanna, Serena %A Sawyer, Elinor J %A Schlessinger, David %A Schmidt, Marjanka K %A Schmidt, Frank %A Schmutzler, Rita K %A Schoemaker, Minouk J %A Scott, Robert A %A Seynaeve, Caroline M %A Simard, Jacques %A Sorice, Rossella %A Southey, Melissa C %A Stöckl, Doris %A Strauch, Konstantin %A Swerdlow, Anthony %A Taylor, Kent D %A Thorsteinsdottir, Unnur %A Toland, Amanda E %A Tomlinson, Ian %A Truong, Thérèse %A Tryggvadottir, Laufey %A Turner, Stephen T %A Vozzi, Diego %A Wang, Qin %A Wellons, Melissa %A Willemsen, Gonneke %A Wilson, James F %A Winqvist, Robert %A Wolffenbuttel, Bruce B H R %A Wright, Alan F %A Yannoukakos, Drakoulis %A Zemunik, Tatijana %A Zheng, Wei %A Zygmunt, Marek %A Bergmann, Sven %A Boomsma, Dorret I %A Buring, Julie E %A Ferrucci, Luigi %A Montgomery, Grant W %A Gudnason, Vilmundur %A Spector, Tim D %A van Duijn, Cornelia M %A Alizadeh, Behrooz Z %A Ciullo, Marina %A Crisponi, Laura %A Easton, Douglas F %A Gasparini, Paolo P %A Gieger, Christian %A Harris, Tamara B %A Hayward, Caroline %A Kardia, Sharon L R %A Kraft, Peter %A McKnight, Barbara %A Metspalu, Andres %A Morrison, Alanna C %A Reiner, Alex P %A Ridker, Paul M %A Rotter, Jerome I %A Toniolo, Daniela %A Uitterlinden, André G %A Ulivi, Sheila %A Völzke, Henry %A Wareham, Nicholas J %A Weir, David R %A Yerges-Armstrong, Laura M %A Price, Alkes L %A Stefansson, Kari %A Visser, Jenny A %A Ong, Ken K %A Chang-Claude, Jenny %A Murabito, Joanne M %A Perry, John R B %A Murray, Anna %K Adult %K Age Factors %K Aging %K BRCA1 Protein %K Breast Neoplasms %K DNA Repair %K Female %K Gene Regulatory Networks %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Genotype %K Humans %K Hypothalamus %K Menopause %K Middle Aged %K Models, Genetic %K Phenotype %K Reproduction %K Signal Transduction %X

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 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

%B Nat Genet %V 47 %P 1294-1303 %8 2015 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract %R 10.1038/ng.3412 %0 Journal Article %J Nat Genet %D 2013 %T A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. %A Shah, Sohela %A Schrader, Kasmintan A %A Waanders, Esmé %A Timms, Andrew E %A Vijai, Joseph %A Miething, Cornelius %A Wechsler, Jeremy %A Yang, Jun %A Hayes, James %A Klein, Robert J %A Zhang, Jinghui %A Wei, Lei %A Wu, Gang %A Rusch, Michael %A Nagahawatte, Panduka %A Ma, Jing %A Chen, Shann-Ching %A Song, Guangchun %A Cheng, Jinjun %A Meyers, Paul %A Bhojwani, Deepa %A Jhanwar, Suresh %A Maslak, Peter %A Fleisher, Martin %A Littman, Jason %A Offit, Lily %A Rau-Murthy, Rohini %A Fleischut, Megan Harlan %A Corines, Marina %A Murali, Rajmohan %A Gao, Xiaoni %A Manschreck, Christopher %A Kitzing, Thomas %A Murty, Vundavalli V %A Raimondi, Susana %A Kuiper, Roland P %A Simons, Annet %A Schiffman, Joshua D %A Onel, Kenan %A Plon, Sharon E %A Wheeler, David %A Ritter, Deborah %A Ziegler, David S %A Tucker, Kathy %A Sutton, Rosemary %A Chenevix-Trench, Georgia %A Li, Jun %A Huntsman, David G %A Hansford, Samantha %A Senz, Janine %A Walsh, Thomas %A Lee, Ming %A Hahn, Christopher N %A Roberts, Kathryn %A King, Mary-Claire %A Lo, Sarah M %A Levine, Ross L %A Viale, Agnes %A Socci, Nicholas D %A Nathanson, Katherine L %A Scott, Hamish S %A Daly, Mark %A Lipkin, Steven M %A Lowe, Scott W %A Downing, James R %A Altshuler, David %A Sandlund, John T %A Horwitz, Marshall S %A Mullighan, Charles G %A Offit, Kenneth %K Genetic Predisposition to Disease %K Germ-Line Mutation %K Humans %K PAX5 Transcription Factor %K Polymorphism, Single Nucleotide %K Precursor B-Cell Lymphoblastic Leukemia-Lymphoma %X

Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.

%B Nat Genet %V 45 %P 1226-1231 %8 2013 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/24013638?dopt=Abstract %R 10.1038/ng.2754