%0 Journal Article %J Nat Genet %D 2012 %T Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. %A Stolk, Lisette %A Perry, John R B %A Chasman, Daniel I %A He, Chunyan %A Mangino, Massimo %A Sulem, Patrick %A Barbalic, Maja %A Broer, Linda %A Byrne, Enda M %A Ernst, Florian %A Esko, Tõnu %A Franceschini, Nora %A Gudbjartsson, Daniel F %A Hottenga, Jouke-Jan %A Kraft, Peter %A McArdle, Patrick F %A Porcu, Eleonora %A Shin, So-Youn %A Smith, Albert V %A van Wingerden, Sophie %A Zhai, Guangju %A Zhuang, Wei V %A Albrecht, Eva %A Alizadeh, Behrooz Z %A Aspelund, Thor %A Bandinelli, Stefania %A Lauc, Lovorka Barac %A Beckmann, Jacques S %A Boban, Mladen %A Boerwinkle, Eric %A Broekmans, Frank J %A Burri, Andrea %A Campbell, Harry %A Chanock, Stephen J %A Chen, Constance %A Cornelis, Marilyn C %A Corre, Tanguy %A Coviello, Andrea D %A d'Adamo, Pio %A Davies, Gail %A de Faire, Ulf %A de Geus, Eco J C %A Deary, Ian J %A Dedoussis, George V Z %A Deloukas, Panagiotis %A Ebrahim, Shah %A Eiriksdottir, Gudny %A Emilsson, Valur %A Eriksson, Johan G %A Fauser, Bart C J M %A Ferreli, Liana %A Ferrucci, Luigi %A Fischer, Krista %A Folsom, Aaron R %A Garcia, Melissa E %A Gasparini, Paolo %A Gieger, Christian %A Glazer, Nicole %A Grobbee, Diederick E %A Hall, Per %A Haller, Toomas %A Hankinson, Susan E %A Hass, Merli %A Hayward, Caroline %A Heath, Andrew C %A Hofman, Albert %A Ingelsson, Erik %A Janssens, A Cecile J W %A Johnson, Andrew D %A Karasik, David %A Kardia, Sharon L R %A Keyzer, Jules %A Kiel, Douglas P %A Kolcic, Ivana %A Kutalik, Zoltán %A Lahti, Jari %A Lai, Sandra %A Laisk, Triin %A Laven, Joop S E %A Lawlor, Debbie A %A Liu, Jianjun %A Lopez, Lorna M %A Louwers, Yvonne V %A Magnusson, Patrik K E %A Marongiu, Mara %A Martin, Nicholas G %A Klaric, Irena Martinovic %A Masciullo, Corrado %A McKnight, Barbara %A Medland, Sarah E %A Melzer, David %A Mooser, Vincent %A Navarro, Pau %A Newman, Anne B %A Nyholt, Dale R %A Onland-Moret, N Charlotte %A Palotie, Aarno %A Paré, Guillaume %A Parker, Alex N %A Pedersen, Nancy L %A Peeters, Petra H M %A Pistis, Giorgio %A Plump, Andrew S %A Polasek, Ozren %A Pop, Victor J M %A Psaty, Bruce M %A Räikkönen, Katri %A Rehnberg, Emil %A Rotter, Jerome I %A Rudan, Igor %A Sala, Cinzia %A Salumets, Andres %A Scuteri, Angelo %A Singleton, Andrew %A Smith, Jennifer A %A Snieder, Harold %A Soranzo, Nicole %A Stacey, Simon N %A Starr, John M %A Stathopoulou, Maria G %A Stirrups, Kathleen %A Stolk, Ronald P %A Styrkarsdottir, Unnur %A Sun, Yan V %A Tenesa, Albert %A Thorand, Barbara %A Toniolo, Daniela %A Tryggvadottir, Laufey %A Tsui, Kim %A Ulivi, Sheila %A van Dam, Rob M %A van der Schouw, Yvonne T %A van Gils, Carla H %A van Nierop, Peter %A Vink, Jacqueline M %A Visscher, Peter M %A Voorhuis, Marlies %A Waeber, Gerard %A Wallaschofski, Henri %A Wichmann, H Erich %A Widen, Elisabeth %A Wijnands-van Gent, Colette J M %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Zemunik, Tatijana %A Zgaga, Lina %A Zillikens, M Carola %A Zygmunt, Marek %A Arnold, Alice M %A Boomsma, Dorret I %A Buring, Julie E %A Crisponi, Laura %A Demerath, Ellen W %A Gudnason, Vilmundur %A Harris, Tamara B %A Hu, Frank B %A Hunter, David J %A Launer, Lenore J %A Metspalu, Andres %A Montgomery, Grant W %A Oostra, Ben A %A Ridker, Paul M %A Sanna, Serena %A Schlessinger, David %A Spector, Tim D %A Stefansson, Kari %A Streeten, Elizabeth A %A Thorsteinsdottir, Unnur %A Uda, Manuela %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Murray, Anna %A Murabito, Joanne M %A Visser, Jenny A %A Lunetta, Kathryn L %K Age Factors %K DNA Helicases %K DNA Primase %K DNA Repair %K DNA Repair Enzymes %K DNA-Directed DNA Polymerase %K European Continental Ancestry Group %K Exodeoxyribonucleases %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Immunity %K Menopause %K Polymorphism, Single Nucleotide %K Proteins %X

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

%B Nat Genet %V 44 %P 260-8 %8 2012 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract %R 10.1038/ng.1051 %0 Journal Article %J PLoS Genet %D 2011 %T Multiple loci are associated with white blood cell phenotypes. %A Nalls, Michael A %A Couper, David J %A Tanaka, Toshiko %A van Rooij, Frank J A %A Chen, Ming-Huei %A Smith, Albert V %A Toniolo, Daniela %A Zakai, Neil A %A Yang, Qiong %A Greinacher, Andreas %A Wood, Andrew R %A Garcia, Melissa %A Gasparini, Paolo %A Liu, Yongmei %A Lumley, Thomas %A Folsom, Aaron R %A Reiner, Alex P %A Gieger, Christian %A Lagou, Vasiliki %A Felix, Janine F %A Völzke, Henry %A Gouskova, Natalia A %A Biffi, Alessandro %A Döring, Angela %A Völker, Uwe %A Chong, Sean %A Wiggins, Kerri L %A Rendon, Augusto %A Dehghan, Abbas %A Moore, Matt %A Taylor, Kent %A Wilson, James G %A Lettre, Guillaume %A Hofman, Albert %A Bis, Joshua C %A Pirastu, Nicola %A Fox, Caroline S %A Meisinger, Christa %A Sambrook, Jennifer %A Arepalli, Sampath %A Nauck, Matthias %A Prokisch, Holger %A Stephens, Jonathan %A Glazer, Nicole L %A Cupples, L Adrienne %A Okada, Yukinori %A Takahashi, Atsushi %A Kamatani, Yoichiro %A Matsuda, Koichi %A Tsunoda, Tatsuhiko %A Tanaka, Toshihiro %A Kubo, Michiaki %A Nakamura, Yusuke %A Yamamoto, Kazuhiko %A Kamatani, Naoyuki %A Stumvoll, Michael %A Tönjes, Anke %A Prokopenko, Inga %A Illig, Thomas %A Patel, Kushang V %A Garner, Stephen F %A Kuhnel, Brigitte %A Mangino, Massimo %A Oostra, Ben A %A Thein, Swee Lay %A Coresh, Josef %A Wichmann, H-Erich %A Menzel, Stephan %A Lin, JingPing %A Pistis, Giorgio %A Uitterlinden, André G %A Spector, Tim D %A Teumer, Alexander %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Bandinelli, Stefania %A Frayling, Timothy M %A Chakravarti, Aravinda %A van Duijn, Cornelia M %A Melzer, David %A Ouwehand, Willem H %A Levy, Daniel %A Boerwinkle, Eric %A Singleton, Andrew B %A Hernandez, Dena G %A Longo, Dan L %A Soranzo, Nicole %A Witteman, Jacqueline C M %A Psaty, Bruce M %A Ferrucci, Luigi %A Harris, Tamara B %A O'Donnell, Christopher J %A Ganesh, Santhi K %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Leukocyte Count %K Leukocytes %K Molecular Epidemiology %K Multigene Family %K Phenotype %K Polymorphism, Single Nucleotide %K Ubiquitin-Protein Ligases %X

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

%B PLoS Genet %V 7 %P e1002113 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21738480?dopt=Abstract %R 10.1371/journal.pgen.1002113 %0 Journal Article %J Nat Genet %D 2010 %T Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. %A Elks, Cathy E %A Perry, John R B %A Sulem, Patrick %A Chasman, Daniel I %A Franceschini, Nora %A He, Chunyan %A Lunetta, Kathryn L %A Visser, Jenny A %A Byrne, Enda M %A Cousminer, Diana L %A Gudbjartsson, Daniel F %A Esko, Tõnu %A Feenstra, Bjarke %A Hottenga, Jouke-Jan %A Koller, Daniel L %A Kutalik, Zoltán %A Lin, Peng %A Mangino, Massimo %A Marongiu, Mara %A McArdle, Patrick F %A Smith, Albert V %A Stolk, Lisette %A van Wingerden, Sophie H %A Zhao, Jing Hua %A Albrecht, Eva %A Corre, Tanguy %A Ingelsson, Erik %A Hayward, Caroline %A Magnusson, Patrik K E %A Smith, Erin N %A Ulivi, Shelia %A Warrington, Nicole M %A Zgaga, Lina %A Alavere, Helen %A Amin, Najaf %A Aspelund, Thor %A Bandinelli, Stefania %A Barroso, Inês %A Berenson, Gerald S %A Bergmann, Sven %A Blackburn, Hannah %A Boerwinkle, Eric %A Buring, Julie E %A Busonero, Fabio %A Campbell, Harry %A Chanock, Stephen J %A Chen, Wei %A Cornelis, Marilyn C %A Couper, David %A Coviello, Andrea D %A d'Adamo, Pio %A de Faire, Ulf %A de Geus, Eco J C %A Deloukas, Panos %A Döring, Angela %A Smith, George Davey %A Easton, Douglas F %A Eiriksdottir, Gudny %A Emilsson, Valur %A Eriksson, Johan %A Ferrucci, Luigi %A Folsom, Aaron R %A Foroud, Tatiana %A Garcia, Melissa %A Gasparini, Paolo %A Geller, Frank %A Gieger, Christian %A Gudnason, Vilmundur %A Hall, Per %A Hankinson, Susan E %A Ferreli, Liana %A Heath, Andrew C %A Hernandez, Dena G %A Hofman, Albert %A Hu, Frank B %A Illig, Thomas %A Järvelin, Marjo-Riitta %A Johnson, Andrew D %A Karasik, David %A Khaw, Kay-Tee %A Kiel, Douglas P %A Kilpeläinen, Tuomas O %A Kolcic, Ivana %A Kraft, Peter %A Launer, Lenore J %A Laven, Joop S E %A Li, Shengxu %A Liu, Jianjun %A Levy, Daniel %A Martin, Nicholas G %A McArdle, Wendy L %A Melbye, Mads %A Mooser, Vincent %A Murray, Jeffrey C %A Murray, Sarah S %A Nalls, Michael A %A Navarro, Pau %A Nelis, Mari %A Ness, Andrew R %A Northstone, Kate %A Oostra, Ben A %A Peacock, Munro %A Palmer, Lyle J %A Palotie, Aarno %A Paré, Guillaume %A Parker, Alex N %A Pedersen, Nancy L %A Peltonen, Leena %A Pennell, Craig E %A Pharoah, Paul %A Polasek, Ozren %A Plump, Andrew S %A Pouta, Anneli %A Porcu, Eleonora %A Rafnar, Thorunn %A Rice, John P %A Ring, Susan M %A Rivadeneira, Fernando %A Rudan, Igor %A Sala, Cinzia %A Salomaa, Veikko %A Sanna, Serena %A Schlessinger, David %A Schork, Nicholas J %A Scuteri, Angelo %A Segrè, Ayellet V %A Shuldiner, Alan R %A Soranzo, Nicole %A Sovio, Ulla %A Srinivasan, Sathanur R %A Strachan, David P %A Tammesoo, Mar-Liis %A Tikkanen, Emmi %A Toniolo, Daniela %A Tsui, Kim %A Tryggvadottir, Laufey %A Tyrer, Jonathon %A Uda, Manuela %A van Dam, Rob M %A van Meurs, Joyce B J %A Vollenweider, Peter %A Waeber, Gerard %A Wareham, Nicholas J %A Waterworth, Dawn M %A Weedon, Michael N %A Wichmann, H Erich %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Young, Lauren %A Zhai, Guangju %A Zhuang, Wei Vivian %A Bierut, Laura J %A Boomsma, Dorret I %A Boyd, Heather A %A Crisponi, Laura %A Demerath, Ellen W %A van Duijn, Cornelia M %A Econs, Michael J %A Harris, Tamara B %A Hunter, David J %A Loos, Ruth J F %A Metspalu, Andres %A Montgomery, Grant W %A Ridker, Paul M %A Spector, Tim D %A Streeten, Elizabeth A %A Stefansson, Kari %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Widen, Elisabeth %A Murabito, Joanne M %A Ong, Ken K %A Murray, Anna %K Adolescent %K Aging %K Body Height %K Body Size %K Child %K DNA Copy Number Variations %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Inheritance Patterns %K Menarche %K Obesity %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %K Time Factors %X

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

%B Nat Genet %V 42 %P 1077-85 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21102462?dopt=Abstract %R 10.1038/ng.714