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- Institut für Humangenetik (6)
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- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (1)
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Dornelas, Maria ; Antão, Laura H. ; Moyes, Faye ; Bates, Amanda E. ; Magurran, Anne E. ; Adam, Dušan ; Akhmetzhanova, Asem A. ; Appeltans, Ward ; Arcos, José Manuel ; Arnold, Haley ; Ayyappan, Narayanan ; Badihi, Gal ; Baird, Andrew H. ; Barbosa, Miguel ; Barreto, Tiago Egydio ; Bässler, Claus ; Bellgrove, Alecia ; Belmaker, Jonathan ; Benedetti-Cecchi, Lisandro ; Bett, Brian J. ; Bjorkman, Anne D. ; Błażewicz, Magdalena ; Blowes, Shane A. ; Bloch, Christopher P. Bloch ; Bonebrake, Timothy C. ; Boyd, Susan ; Bradford, Matt ; Brooks, Andrew J. ; Brown, James H. ; Bruelheide, Helge ; Budy, Phaedra ; Carvalho, Fernando ; Castañeda-Moya, Edward ; Chen, Chaolun Allen ; Chamblee, John F. ; Chase, Tory J. ; Siegwart Collier, Laura ; Collinge, Sharon K. ; Condit, Richard ; Cooper, Elisabeth J. ; Cornelissen, J. Hans C. ; Cotano, Unai ; Crow, Shannan Kyle ; Damasceno, Gabriella ; Davies, Claire H. ; Davis, Robert A. ; Day, Frank P. ; Degraer, Steven ; Doherty, Tim S. ; Dunn, Timothy E. ; Durigan, Giselda ; Duffy, J. Emmett ; Edelist, Dor ; Edgar, Graham J. ; Elahi, Robin ; Elmendorf, Sarah C. ; Enemar, Anders ; Ernest, S. K. Morgan ; Escribano, Rubén ; Estiarte, Marc ; Evans, Brian S. ; Fan, Tung-Yung ; Turini Farah, Fabiano ; Loureiro Fernandes, Luiz ; Farneda, Fábio Z. ; Fidelis, Alessandra ; Fitt, Robert ; Fosaa, Anna Maria ; Franco, Geraldo Antonio Daher Correa ; Frank, Grace E. ; Fraser, William R. ; García, Hernando ; Cazzolla Gatti, Roberto ; Givan, Or ; Gorgone-Barbosa, Elizabeth ; Gould, William A. ; Gries, Corinna ; Grossman, Gary D. ; Gutierréz, Julio R. ; Hale, Stephen ; Harmon, Mark E. ; Harte, John ; Haskins, Gary ; Henshaw, Donald L. ; Hermanutz, Luise ; Hidalgo, Pamela ; Higuchi, Pedro ; Hoey, Andrew ; Van Hoey, Gert ; Hofgaard, Annika ; Holeck, Kristen ; Hollister, Robert D. ; Holmes, Richard ; Hoogenboom, Mia ; Hsieh, Chih-hao ; Hubbell, Stephen P. ; Huettmann, Falk ; Huffard, Christine L. ; Hurlbert, Allen H. ; Ivanauskas, Natália Macedo ; Janík, David ; Jandt, Ute ; Jażdżewska, Anna ; Johannessen, Tore ; Johnstone, Jill ; Jones, Julia ; Jones, Faith A. M. ; Kang, Jungwon ; Kartawijaya, Tasrif ; Keeley, Erin C. ; Kelt, Douglas A. ; Kinnear, Rebecca ; Klanderud, Kari ; Knutsen, Halvor ; Koenig, Christopher C. ; Kortz, Alessandra R. ; Král, Kamil ; Kuhnz, Linda A. ; Kuo, Chao-Yang ; Kushner, David J. ; Laguionie-Marchais, Claire ; Lancaster, Lesley T. ; Lee, Cheol Min ; Lefcheck, Jonathan S. ; Lévesque, Esther ; Lightfoot, David ; Lloret, Francisco ; Lloyd, John D. ; López-Baucells, Adrià ; Louzao, Maite ; Madin, Joshua S. ; Magnússon, Borgþór ; Malamud, Shahar ; Matthews, Iain ; McFarland, Kent P. ; McGill, Brian ; McKnight, Diane ; McLarney, William O. ; Meador, Jason ; Meserve, Peter L. ; Metcalfe, Daniel J. ; Meyer, Christoph F. J. ; Michelsen, Anders ; Milchakova, Nataliya ; Moens, Tom ; Moland, Even ; Moore, Jon ; Moreira, Carolina Mathias ; Müller, Jörg ; Murphy, Grace ; Myers-Smith, Isla H. ; Myster, Randall W. ; Naumov, Andrew ; Neat, Francis ; Nelson, James A. ; Nelson, Michael Paul ; Newton, Stephen F. ; Norden, Natalia ; Oliver, Jeffrey C. ; Olsen, Esben M. ; Onipchenko, Vladimir G. ; Pabis, Krzysztof ; Pabst, Robert J. ; Paquette, Alain ; Pardede, Sinta ; Paterson, David M. ; Pélissier, Raphaël ; Peñuelas, Josep ; Pérez-Matus, Alejandro ; Pizarro, Oscar ; Pomati, Francesco ; Post, Eric ; Prins, Herbert H. T. ; Priscu, John C. ; Provoost, Pieter ; Prudic, Kathleen L. ; Pulliainen, Erkki ; Ramesh, B. R. ; Ramos, Olivia Mendivil ; Rassweiler, Andrew ; Rebelo, Jose Eduardo ; Reed, Daniel C. ; Reich, Peter B. ; Remillard, Suzanne M. ; Richardson, Anthony J. ; Richardson, J. Paul ; van Rijn, Itai ; Rocha, Ricardo ; Rivera-Monroy, Victor H. ; Rixen, Christian ; Robinson, Kevin P. ; Rodrigues, Ricardo Ribeiro ; de Cerqueira Rossa-Feres, Denise ; Rudstam, Lars ; Ruhl, Henry ; Ruz, Catalina S. ; Sampaio, Erica M. ; Rybicki, Nancy ; Rypel, Andrew ; Sal, Sofia ; Salgado, Beatriz ; Santos, Flavio A. M. ; Savassi-Coutinho, Ana Paula ; Scanga, Sara ; Schmidt, Jochen ; Schooley, Robert ; Setiawan, Fakhrizal ; Shao, Kwang-Tsao ; Shaver, Gaius R. ; Sherman, Sally ; Sherry, Thomas W. ; Siciński, Jacek ; Sievers, Caya ; da Silva, Ana Carolina ; da Silva, Fernando Rodrigues ; Silveira, Fabio L. ; Slingsby, Jasper ; Smart, Tracey ; Snell, Sara J. ; Soudzilovskaia, Nadejda A. ; Souza, Gabriel B. G. ; Souza, Flaviana Maluf ; Souza, Vinícius Castro ; Stallings, Christopher D. ; Stanforth, Rowan ; Stanley, Emily H. ; Sterza, José Mauro ; Stevens, Maarten ; Stuart-Smith, Rick ; Suarez, Yzel Rondon ; Supp, Sarah ; Tamashiro, Jorge Yoshio ; Tarigan, Sukmaraharja ; Thiede, Gary P. ; Thorn, Simon ; Tolvanen, Anne ; Toniato, Maria Teresa Zugliani ; Totland, Ørjan ; Twilley, Robert R. ; Vaitkus, Gediminas ; Valdivia, Nelson ; Vallejo, Martha Isabel ; Valone, Thomas J. ; Van Colen, Carl ; Vanaverbeke, Jan ; Venturoli, Fabio ; Verheye, Hans M. ; Vianna, Marcelo ; Vieira, Rui P. ; Vrška, Tomáš ; Vu, Con Quang ; Vu, Lien Van ; Waide, Robert B. ; Waldock, Conor ; Watts, Dave ; Webb, Sara ; Wesołowski, Tomasz ; White, Ethan P. ; Widdicombe, Claire E. ; Wilgers, Dustin ; Williams, Richard ; Williams, Stefan B. ; Williamson, Mark ; Willig, Michael R. ; Willis, Trevor J. ; Wipf, Sonja ; Woods, Kerry D. ; Woehler, Eric J. ; Zawada, Kyle ; Zettler, Michael L.
Motivation
The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.
Main types of variables included
The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.
Spatial location and grain
BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).
Time period and grain
BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.
Major taxa and level of measurement
BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.
Software format
.csv and .SQL.
Davis, Lea K. ; Yu, Dongmei ; Keenan, Clare L. ; Gamazon, Eric R. ; Konkashbaev, Anuar I. ; Derks, Eske M. ; Neale, Benjamin M. ; Yang, Jian ; Lee, S. Hong ; Evans, Patrick ; Barr, Cathy L. ; Bellodi, Laura ; Benarroch, Fortu ; Berrio, Gabriel Bedoya ; Bienvenu, Oscar J. ; Bloch, Michael H. ; Blom, Rianne M. ; Bruun, Ruth D. ; Budman, Cathy L. ; Camarena, Beatriz ; Campbell, Desmond ; Cappi, Carolina ; Cardona Silgado, Julio C. ; Cath, Danielle C. ; Cavallini, Maria C. ; Chavira, Denise A. ; Chouinard, Sylvian ; Conti, David V. ; Cook, Edwin H. ; Coric, Vladimir ; Cullen, Bernadette A. ; Deforce, Dieter ; Delorme, Richard ; Dion, Yves ; Edlund, Christopher K. ; Egberts, Karin ; Falkai, Peter ; Fernandez, Thomas V. ; Gallagher, Patience J. ; Garrido, Helena ; Geller, Daniel ; Girard, Simon L. ; Grabe, Hans J. ; Grados, Marco A. ; Greenberg, Benjamin D. ; Gross-Tsur, Varda ; Haddad, Stephen ; Heiman, Gary A. ; Hemmings, Sian M. J. ; Hounie, Ana G. ; Illmann, Cornelia ; Jankovic, Joseph ; Jenike, Micheal A. ; Kennedy, James L. ; King, Robert A. ; Kremeyer, Barbara ; Kurlan, Roger ; Lanzagorta, Nuria ; Leboyer, Marion ; Leckman, James F. ; Lennertz, Leonhard ; Liu, Chunyu ; Lochner, Christine ; Lowe, Thomas L. ; Macciardi, Fabio ; McCracken, James T. ; McGrath, Lauren M. ; Restrepo, Sandra C. Mesa ; Moessner, Rainald ; Morgan, Jubel ; Muller, Heike ; Murphy, Dennis L. ; Naarden, Allan L. ; Ochoa, William Cornejo ; Ophoff, Roel A. ; Osiecki, Lisa ; Pakstis, Andrew J. ; Pato, Michele T. ; Pato, Carlos N. ; Piacentini, John ; Pittenger, Christopher ; Pollak, Yehunda ; Rauch, Scott L. ; Renner, Tobias J. ; Reus, Victor I. ; Richter, Margaret A. ; Riddle, Mark A. ; Robertson, Mary M. ; Romero, Roxana ; Rosàrio, Maria C. ; Rosenberg, David ; Rouleau, Guy A. ; Ruhrmann, Stephan ; Ruiz-Linares, Andreas ; Sampaio, Aline S. ; Samuels, Jack ; Sandor, Paul ; Sheppard, Broke ; Singer, Harvey S. ; Smit, Jan H. ; Stein, Dan J. ; Strengman, E. ; Tischfield, Jay A. ; Valencia Duarte, Ana V. ; Vallada, Homero ; Van Nieuwerburgh, Flip ; Veenstra-VanderWeele, Jeremy ; Walitza, Susanne ; Wang, Ying ; Wendland, Jens R. ; Westenberg, Herman G. M. ; Shugart, Yin Yao ; Miguel, Euripedes C. ; McMahon, William ; Wagner, Michael ; Nicolini, Humberto ; Posthuma, Danielle ; Hanna, Gregory L. ; Heutink, Peter ; Denys, Damiaan ; Arnold, Paul D. ; Oostra, Ben A. ; Nestadt, Gerald ; Freimer, Nelson B. ; Pauls, David L. ; Wray, Naomi R. ; Stewart, S. Evelyn ; Mathews, Carol A. ; Knowles, James A. ; Cox, Nancy J. ; Scharf, Jeremiah M.
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Couch, Fergus J. ; Wang, Xianshu ; McGuffog, Lesley ; Lee, Andrew ; Olswold, Curtis ; Kuchenbaecker, Karoline B. ; Soucy, Penny ; Fredericksen, Zachary ; Barrowdale, Daniel ; Dennis, Joe ; Gaudet, Mia M. ; Dicks, Ed ; Kosel, Matthew ; Healey, Sue ; Sinilnikova, Olga M. ; Lee, Adam ; Bacot, Françios ; Vincent, Daniel ; Hogervorst, Frans B. L. ; Peock, Susan ; Stoppa-Lyonnet, Dominique ; Jakubowska, Anna ; Radice, Paolo ; Schmutzler, Rita Katharina ; Domchek, Susan M. ; Piedmonte, Marion ; Singer, Christian F. ; Friedman, Eitan ; Thomassen, Mads ; Hansen, Thomas V. O. ; Neuhausen, Susan L. ; Szabo, Csilla I. ; Blanco, Ingnacio ; Greene, Mark H. ; Karlan, Beth Y. ; Garber, Judy ; Phelan, Catherine M. ; Weitzel, Jeffrey N. ; Montagna, Marco ; Olah, Edith ; Andrulis, Irene L. ; Godwin, Andrew K. ; Yannoukakos, Drakoulis ; Goldgar, David E. ; Caldes, Trinidad ; Nevanlinna, Heli ; Osorio, Ana ; Terry, Mary Beth ; Daly, Mary B. ; van Rensburg, Elisabeth J. ; Hamann, Ute ; Ramus, Susan J. ; Toland, Amanda Ewart ; Caligo, Maria A. ; Olopade, Olufunmilayo I. ; Tung, Nadine ; Claes, Kathleen ; Beattie, Mary S. ; Southey, Melissa C. ; Imyanitov, Evgeny N. ; Tischkowitz, Marc ; Janavicius, Ramunas ; John, Esther M. ; Kwong, Ava ; Diez, Orland ; Kwong, Ava ; Balmaña, Judith ; Barkardottir, Rosa B. ; Arun, Banu K. ; Rennert, Gad ; Teo, Soo-Hwang ; Ganz, Patricia A. ; Campbell, Ian ; van der Hout, Annemarie H. ; van Deurzen, Carolien H. M. ; Seynaeve, Caroline ; Garcia, Encarna B. Gómez ; van Leeuwen, Flora E. ; Meijers-Heijboer, Hanne E. J. ; Gille, Johannes J. P. ; Ausems, Magreet G. E. M. ; Blok, Marinus J. ; Ligtenberg, Marjolinjin J. L. ; Rookus, Matti A. ; Devilee, Peter ; Verhoef, Senno ; van Os, Theo A. M. ; Wijnen, Juul T. ; Frost, Debra ; Ellis, Steve ; Fineberg, Elena ; Platte, Radke ; Evans, D. Gareth ; Izatt, Luise ; Eeles, Rosalind A. ; Adlard, Julian ; Eccles, Diana M. ; Cook, Jackie ; Brewer, Carole ; Douglas, Fiona ; Hodgson, Shirley ; Morrison, Patrick J. ; Side, Lucy E. ; Donaldson, Alan ; Houghton, Catherine ; Rogers, Mark T. ; Dorkins, Huw ; Eason, Jacqueline ; Gregory, Helen ; McCann, Emma ; Murray, Alex ; Calender, Alain ; Hardouin, Agnès ; Berthet, Pascaline ; Delnatte, Capucine ; Nogues, Catherine ; Lasset, Christine ; Houdayer, Claude ; Leroux,, Dominique ; Rouleau, Etienne ; Prieur, Fabienne ; Damiola, Francesca ; Sobol, Hagay ; Coupier, Isabelle ; Venat-Bouvet, Laurence ; Castera, Laurent ; Gauthier-Villars, Marion ; Léoné, Mélanie ; Pujol, Pascal ; Mazoyer, Sylvie ; Bignon, Yves-Jean ; Zlowocka-Perlowska, Elzbieta ; Gronwald, Jacek ; Lubinski,, Jan ; Durda, Katarzyna ; Jaworska, Katarzyna ; Huzarski, Tomasz ; Spurdle, Amanda B. ; Viel, Alessandra ; Peissel, Bernhard ; Bonanni, Bernardo ; Melloni, Guilia ; Ottini, Laura ; Papi, Laura ; Varesco, Liliana ; Tibiletti, Maria Grazia ; Peterlongo, Paolo ; Volorio, Sara ; Manoukian, Siranoush ; Pensotti, Valeria ; Arnold, Norbert ; Engel, Christoph ; Deissler, Helmut ; Gadzicki, Dorothea ; Gehrig, Andrea ; Kast, Karin ; Rhiem, Kerstin ; Meindl, Alfons ; Niederacher, Dieter ; Ditsch, Nina ; Plendl, Hansjoerg ; Preisler-Adams, Sabine ; Engert, Stefanie ; Sutter, Christian ; Varon-Mateeva, Raymenda ; Wappenschmidt, Barbara ; Weber, Bernhard H. F. ; Arver, Brita ; Stenmark-Askmalm, Marie ; Loman, Niklas ; Rosenquist, Richard ; Einbeigi, Zakaria ; Nathanson, Katherine L. ; Rebbeck, Timothy R. ; Blank, Stephanie V. ; Cohn, David E. ; Rodriguez, Gustavo C. ; Small, Laurie ; Friedlander, Michael ; Bae-Jump, Victoria L. ; Fink-Retter, Anneliese ; Rappaport, Christine ; Gschwantler-Kaulich, Daphne ; Pfeiler, Georg ; Tea, Muy-Kheng ; Lindor, Noralane M. ; Kaufman, Bella ; Paluch, Shani Shimon ; Laitman, Yael ; Skytte, Anne-Bine ; Gerdes, Anne-Marie ; Pedersen, Inge Sokilde ; Moeller, Sanne Traasdahl ; Kruse, Torben A. ; Jensen, Uffe Birk ; Vijai, Joseph ; Sarrel, Kara ; Robson, Mark ; Kauff, Noah ; Mulligan, Anna Marie ; Glendon, Gord ; Ozcelik, Hilmi ; Ejlertsen, Bent ; Nielsen, Finn C. ; Jønson, Lars ; Andersen, Mette K. ; Ding, Yuan Chun ; Steele, Linda ; Foretova, Lenka ; Teulé, Alex ; Lazaro, Conxi ; Brunet, Joan ; Pujana, Miquel Angel ; Mai, Phuong L. ; Loud, Jennifer T. ; Walsh, Christine ; Lester, Jenny ; Orsulic, Sandra ; Narod, Steven A. ; Herzog, Josef ; Sand, Sharon R. ; Tognazzo, Silvia ; Agata, Simona ; Vaszko, Tibor ; Weaver, Joellen ; Stravropoulou, Alexandra V. ; Buys, Saundra S. ; Romero, Atocha ; de la Hoya, Miguel ; Aittomäki, Kristiina ; Muranen, Taru A. ; Duran, Mercedes ; Chung, Wendy K. ; Lasa, Adriana ; Dorfling, Cecilia M. ; Miron, Alexander ; Benitez, Javier ; Senter, Leigha ; Huo, Dezheng ; Chan, Salina B. ; Sokolenko, Anna P. ; Chiquette, Jocelyne ; Tihomirova, Laima ; Friebel, Tara M. ; Agnarsson, Bjarne A. ; Lu, Karen H. ; Lejbkowicz, Flavio ; James, Paul A. ; Hall, Per ; Dunning, Alison M. ; Tessier, Daniel ; Cunningham, Julie ; Slager, Susan L. ; Chen, Wang ; Hart, Steven ; Stevens, Kristen ; Simard, Jacques ; Pastinen, Tomi ; Pankratz, Vernon S. ; Offit, Kenneth ; Easton, Douglas F. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C.
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Osorio, Ana ; Milne, Roger L. ; Kuchenbaecker, Karoline ; Vaclová, Tereza ; Pita, Guillermo ; Alonso, Rosario ; Peterlongo, Paolo ; Blanco, Ignacio ; de la Hoya, Miguel ; Duran, Mercedes ; Diez, Orland ; Ramón y Cajal, Teresa ; Konstantopoulou, Irene ; Martínez-Bouzas, Christina ; Conejero, Raquel Andrés ; Soucy, Penny ; McGuffog, Lesley ; Barrowdale, Daniel ; Lee, Andrew ; Arver, Brita ; Rantala, Johanna ; Loman, Niklas ; Ehrencrona, Hans ; Olopade, Olufunmilayo I. ; Beattie, Mary S. ; Domchek, Susan M. ; Nathanson, Katherine ; Rebbeck, Timothy R. ; Arun, Banu K. ; Karlan, Beth Y. ; Walsh, Christine ; Lester, Jenny ; John, Esther M. ; Whittemore, Alice S. ; Daly, Mary B. ; Southey, Melissa ; Hopper, John ; Terry, Mary B. ; Buys, Saundra S. ; Janavicius, Ramunas ; Dorfling, Cecilia M. ; van Rensburg, Elizabeth J. ; Steele, Linda ; Neuhausen, Susan L. ; Ding, Yuan Chun ; Hansen, Thomas V. O. ; Jønson, Lars ; Ejlertsen, Bent ; Gerdes, Anne-Marie ; Infante, Mar ; Herráez, Belén ; Moreno, Leticia Thais ; Weitzel, Jeffrey N. ; Herzog, Josef ; Weeman, Kisa ; Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela ; Scuvera, Guilietta ; Bonanni, Bernardo ; Mariette, Frederique ; Volorio, Sara ; Viel, Alessandra ; Varesco, Liliana ; Papi, Laura ; Ottini, Laura ; Tibiletti, Maria Grazia ; Radice, Paolo ; Yannoukakos, Drakoulis ; Garber, Judy ; Ellis, Steve ; Frost, Debra ; Platte, Radka ; Fineberg, Elena ; Evans, Gareth ; Lalloo, Fiona ; Izatt, Louise ; Eeles, Ros ; Adlard, Julian ; Davidson, Rosemarie ; Cole, Trevor ; Eccles, Diana ; Cook, Jackie ; Hodgson, Shirley ; Brewer, Carole ; Tischkowitz, Marc ; Douglas, Fiona ; Porteous, Mary ; Side, Lucy ; Walker, Lisa ; Morrison, Patrick ; Donaldson, Alan ; Kennedy, John ; Foo, Claire ; Godwin, Andrew K. ; Schmutzler, Rita Katharina ; Wappenschmidt, Barbara ; Rhiem, Kerstin ; Engel, Christoph ; Meindl, Alftons ; Ditsch, Nina ; Arnold, Norbert ; Plendl, Hans Jörg ; Niederacher, Dieter ; Sutter, Christian ; Wang-Gohrke, Shan ; Steinemann, Doris ; Preisler-Adams, Sabine ; Kast, Karin ; Varon-Mateeva, Raymonda ; Gehrig, Andrea ; Stoppa-Lyonnet, Dominique ; Sinilnikova, Olga M. ; Mazoyer, Sylvie ; Damiola, Francesca ; Poppe, Bruce ; Claes, Kathleen ; Piedmonte, Marion ; Tucker, Kathy ; Backes, Floor ; Rodríguez, Gustavo ; Brewster, Wendy ; Wakeley, Katie ; Rutherford, Thomas ; Caldés, Trinidad ; Nevanlinna, Heli ; Aittomäki, Kristiina ; Rookus, Matti A. ; van Os, Theo A. M. ; van der Kolk, Lizet ; de Lange, J. L. ; Meijers-Heijboer, Hanne E. J. ; van der Hout, A. H. ; van Asperen, Christi J. ; Goméz Garcia, Encarna B. ; Encarna, B. ; Hoogerbrugge, Nicoline ; Collée, J. Margriet ; van Deurzen, Carolien H. M. ; van der Luijt, Rob B. ; Devilee, Peter ; Olah, Edith ; Lázaro, Conxi ; Teulé, Alex ; Menéndez, Mireia ; Jakubowska, Anna ; Cybulski, Cezary ; Gronwald, Jecek ; Lubinski, Jan ; Durda, Katarzyna ; Jaworska-Bieniek, Katarzyna ; Johannsson, Oskar Th. ; Maugard, Christine ; Montagna, Marco ; Tognazzo, Silvia ; Teixeira, Manuel R. ; Healey, Sue ; Olswold, Curtis ; Guidugli, Lucia ; Lindor, Noralane ; Slager, Susan ; Szabo, Csilla I. ; Vijai, Joseph ; Robson, Mark ; Kauff, Noah ; Zhang, Liying ; Rau-Murthy, Rohini ; Fink-Retter, Anneliese ; Singer, Christine F. ; Rappaport, Christine ; Kaulich, Daphne Geschwantler ; Pfeiler, Georg ; Tea, Muy-Kheng ; Berger, Andreas ; Phelan, Catherine M. ; Greene, Mark H. ; Mai, Phuong L. ; Lejbkowicz, Flavio ; Andrulis, Irene ; Mulligan, Anna Marie ; Glendon, Gord ; Toland, Amanda Ewart ; Bojesen, Anders ; Pedersen, Inge Sokilde ; Sunde, Lone ; Thomassen, Mads ; Kruse, Torben A. ; Jensen, Uffe Birk ; Friedman, Eitan ; Laitman, Yeal ; Shimon, Shanie Paluch ; Simard, Jaques ; Easton, Douglas F. ; Offit, Kenneth ; Couch, Fergus J. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Benitez, Javier
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7x10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95% CI: 1.03-1.21, p = 4.8x10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Antoniou, Antonis C. ; Kuchenbaecker, Karoline B. ; Soucy, Penny ; Beesley, Jonathan ; Chen, Xiaoqing ; McGuffog, Lesley ; Lee, Andrew ; Barrowdale, Daniel ; Healey, Sue ; Sinilnikova, Olga M. ; Caligo, Maria A. ; Loman, Niklas ; Harbst, Katja ; Lindblom, Annika ; Arver, Brita ; Rosenquist, Richard ; Karlsson, Per ; Nathanson, Kate ; Domchek, Susan ; Rebbeck, Tim ; Jakubowska, Anna ; Lubinski, Jan ; Jaworska, Katarzyna ; Durda, Katarzyna ; Zlowowcka-Perłowska, Elżbieta ; Osorio, Ana ; Durán, Mercedes ; Andrés, Raquel ; Benítez, Javier ; Hamann, Ute ; Hogervorst, Frans B. ; van Os, Theo A. ; Verhoef, Senno ; Meijers-Heijboer, Hanne E. J. ; Wijnen, Juul ; Garcia, Encarna B. Gómez ; Ligtenberg, Marjolijn J. ; Kriege, Mieke ; Collée, Margriet ; Ausems, Margreet G. E. M. ; Oosterwijk, Jan C. ; Peock, Susan ; Frost, Debra ; Ellis, Steve D. ; Platte, Radka ; Fineberg, Elena ; Evans, D. Gareth ; Lalloo, Fiona ; Jacobs, Chris ; Eeles, Ros ; Adlard, Julian ; Davidson, Rosemarie ; Cole, Trevor ; Cook, Jackie ; Paterson, Joan ; Douglas, Fiona ; Brewer, Carole ; Hodgson, Shirley ; Morrison, Patrick J. ; Walker, Lisa ; Rogers, Mark T. ; Donaldson, Alan ; Dorkins, Huw ; Godwin, Andrew K. ; Bove, Betsy ; Stoppa-Lyonnet, Dominique ; Houdayer, Claude ; Buecher, Bruno ; de Pauw, Antoine ; Mazoyer, Sylvie ; Calender, Alain ; Léoné, Mélanie ; Bressac-de Paillerets, Brigitte ; Caron, Olivier ; Sobol, Hagay ; Frenay, Marc ; Prieur, Fabienne ; Ferrer, Sandra Fert ; Mortemousque, Isabelle ; Buys, Saundra ; Daly, Mary ; Miron, Alexander ; Terry, Mary Beth ; Hopper, John L. ; John, Esther M. ; Southey, Melissa ; Goldgar, David ; Singer, Christian F. ; Fink-Retter, Anneliese ; Muy-Kheng, Tea ; Geschwantler Kaulich, Daphne ; Hansen, Thomas V. O. ; Nielsen, Finn C. ; Barkardottir, Rosa B. ; Gaudet, Mia ; Kirchhoff, Tomas ; Joseph, Vijai ; Dutra-Clarke, Ana ; Offit, Kenneth ; Piedmonte, Marion ; Kirk, Judy ; Cohn, David ; Hurteau, Jean ; Byron, John ; Fiorica, James ; Toland, Amanda E. ; Montagna, Marco ; Oliani, Cristina ; Imyanitov, Evgeny ; Isaacs, Claudine ; Tihomirova, Laima ; Blanco, Ignacio ; Lazaro, Conxi ; Teulé, Alex ; Del Valle, J. ; Gayther, Simon A. ; Odunsi, Kunle ; Gross, Jenny ; Karlan, Beth Y. ; Olah, Edith ; Teo, Soo-Hwang ; Ganz, Patricia A. ; Beattie, Mary S. ; Dorfling, Cecelia M. ; Jansen van Rensburg, Elizabeth ; Diez, Orland ; Kwong, Ava ; Schmutzler, Rita K. ; Wappenschmidt, Barbara ; Engel, Christoph ; Meindl, Alfons ; Ditsch, Nina ; Arnold, Norbert ; Heidemann, Simone ; Niederacher, Dieter ; Preisler-Adams, Sabine ; Gadzicki, Dorothea ; Varon-Mateeva, Raymonda ; Deissler, Helmut ; Gehrig, Andrea ; Sutter, Christian ; Kast, Karin ; Fiebig, Britta ; Schäfer, Dieter ; Caldes, Trinidad ; de la Hoya, Miguel ; Nevanlinna, Heli ; Muranen, Taru A. ; Lespérance, Bernard ; Spurdle, Amanda B. ; Neuhausen, Susan L. ; Ding, Yuan C. ; Wang, Xianshu ; Fredericksen, Zachary ; Pankratz, Vernon S. ; Lindor, Noralane M. ; Peterlongo, Paulo ; Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela ; Bonanni, Bernardo ; Bernard, Loris ; Dolcetti, Riccardo ; Papi, Laura ; Ottini, Laura ; Radice, Paolo ; Greene, Mark H. ; Loud, Jennifer T. ; Andrulis, Irene L. ; Ozcelik, Hilmi ; Mulligan, Anna Marie ; Glendon, Gord ; Thomassen, Mads ; Gerdes, Anne-Marie ; Jensen, Uffe B. ; Skytte, Anne-Bine ; Kruse, Torben A. ; Chenevix-Trench, Georgia ; Couch, Fergus J. ; Simard, Jacques ; Easton, Douglas F.
Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
Blein, Sophie ; Bardel, Claire ; Danjean, Vincent ; McGuffog, Lesley ; Healay, Sue ; Barrowdale, Daniel ; Lee, Andrew ; Dennis, Joe ; Kuchenbaecker, Karoline B. ; Soucy, Penny ; Terry, Mary Beth ; Chung, Wendy K. ; Goldgar, David E. ; Buys, Saundra S. ; Janavicius, Ramunas ; Tihomirova, Laima ; Tung, Nadine ; Dorfling, Cecilia M. ; van Rensburg, Elizabeth J. ; Neuhausen, Susan L. ; Ding, Yuan Chun ; Gerdes, Anne-Marie ; Ejlertsen, Bent ; Nielsen, Finn C. ; Hansen, Thomas V. O. ; Osorio, Ana ; Benitez, Javier ; Andreas Conejero, Raquel ; Segota, Ena ; Weitzel, Jeffrey N. ; Thelander, Margo ; Peterlongo, Paolo ; Radice, Paolo ; Pensotti, Valeria ; Dolcetti, Riccardo ; Bonanni, Bernardo ; Peissel, Bernard ; Zaffaroni, Daniela ; Scuvera, Giulietta ; Manoukian, Siranoush ; Varesco, Liliana ; Capone, Gabriele L. ; Papi, Laura ; Ottini, Laura ; Yannoukakos, Drakoulis ; Konstantopoulou, Irene ; Garber, Judy ; Hamann, Ute ; Donaldson, Alan ; Brady, Angela ; Brewer, Carole ; Foo, Claire ; Evans, D. Gareth ; Frost, Debra ; Eccles, Diana ; Douglas, Fiona ; Cook, Jackie ; Adlard, Julian ; Barwell, Julian ; Walker, Lisa ; Izatt, Louise ; Side, Lucy E. ; Kennedy, M. John ; Tischkowitz, Marc ; Rogers, Mark T. ; Porteous, Mary E. ; Morrison, Patrick J. ; Platte, Radka ; Eeles, Ros ; Davidson, Rosemarie ; Hodgson, Shirley ; Cole, Trevor ; Godwin, Andrew K ; Isaacs, Claudine ; Claes, Kathleen ; De Leeneer, Kim ; Meindl, Alfons ; Gehrig, Andrea ; Wappenschmidt, Barbara ; Sutter, Christian ; Engel, Christoph ; Niederacher, Dieter ; Steinemann, Doris ; Plendl, Hansjoerg ; Kast, Karin ; Rhiem, Kerstin ; Ditsch, Nina ; Arnold, Norbert ; Varon-Mateeva, Raymonda ; Schmutzler, Rita K. ; Preisler-Adams, Sabine ; Markov, Nadja Bogdanova ; Wang-Gohrke, Shan ; de Pauw, Antoine ; Lefol, Cedrick ; Lasset, Christine ; Leroux, Dominique ; Rouleau, Etienne ; Damiola, Francesca ; Dreyfus, Helene ; Barjhoux, Laure ; Golmard, Lisa ; Uhrhammer, Nancy ; Bonadona, Valerie ; Sornin, Valerie ; Bignon, Yves-Jean ; Carter, Jonathan ; Van Le, Linda ; Piedmonte, Marion ; DiSilvestro, Paul A. ; de la Hoya, Miguel ; Caldes, Trinidad ; Nevanlinna, Heli ; Aittomäki, Kristiina ; Jager, Agnes ; van den Ouweland, Ans M. W. ; Kets, Carolien M. ; Aalfs, Cora M. ; van Leeuwen, Flora E. ; Hogervorst, Frans B. L. ; Meijers-Heijboer, Hanne E. J. ; Oosterwijk, Jan C. ; van Roozendaal, Kees E. P. ; Rookus, Matti A. ; Devilee, Peter ; van der Luijt, Rob B. ; Olah, Edith ; Diez, Orland ; Teule, Alex ; Lazaro, Conxi ; Blanco, Ignacio ; Del Valle, Jesus ; Jakubowska, Anna ; Sukiennicki, Grzegorz ; Gronwald, Jacek ; Spurdle, Amanda B. ; Foulkes, William ; Olswold, Curtis ; Lindor, Noralene M. ; Pankratz, Vernon S. ; Szabo, Csilla I. ; Lincoln, Anne ; Jacobs, Lauren ; Corines, Marina ; Robson, Mark ; Vijai, Joseph ; Berger, Andreas ; Fink-Retter, Anneliese ; Singer, Christian F. ; Rappaport, Christine ; Geschwantler Kaulich, Daphne ; Pfeiler, Georg ; Tea, Muy-Kheng ; Greene, Mark H. ; Mai, Phuong L. ; Rennert, Gad ; Imyanitov, Evgeny N. ; Mulligan, Anna Marie ; Glendon, Gord ; Andrulis, Irene L. ; Tchatchou, Andrine ; Toland, Amanda Ewart ; Pedersen, Inge Sokilde ; Thomassen, Mads ; Kruse, Torben A. ; Jensen, Uffe Birk ; Caligo, Maria A. ; Friedman, Eitan ; Zidan, Jamal ; Laitman, Yael ; Lindblom, Annika ; Melin, Beatrice ; Arver, Brita ; Loman, Niklas ; Rosenquist, Richard ; Olopade, Olufunmilayo I. ; Nussbaum, Robert L. ; Ramus, Susan J. ; Nathanson, Katherine L. ; Domchek, Susan M. ; Rebbeck, Timothy R. ; Arun, Banu K. ; Mitchell, Gillian ; Karlan, Bethy Y. ; Lester, Jenny ; Orsulic, Sandra ; Stoppa-Lyonnet, Dominique ; Thomas, Gilles ; Simard, Jacques ; Couch, Fergus J. ; Offit, Kenenth ; Easton, Douglas F. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Mazoyer, Sylvie ; Phelan, Catherine M. ; Sinilnikova, Olga M. ; Cox, David G.
Introduction:
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
Methods:
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
Results:
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
Conclusions:
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Blanco, Ignacio ; Kuchenbaecker, Karoline ; Cuadras, Daniel ; Wang, Xianshu ; Barrowdale, Daniel ; Ruiz de Garibay, Gorka ; Librado, Pablo ; Sanchez-Gracia, Alejandro ; Rozas, Julio ; Bonifaci, Núria ; McGuffog, Lesley ; Pankratz, Vernon S. ; Islam, Abul ; Mateo, Francesca ; Berenguer, Antoni ; Petit, Anna ; Català, Isabel ; Brunet, Joan ; Feliubadaló, Lidia ; Tornero, Eva ; Benítez, Javier ; Osorio, Ana ; Ramón y Cajal, Teresa ; Nevanlinna, Heli ; Aittomäki, Kristina ; Arun, Banu K. ; Toland, Amanda E. ; Karlan, Beth Y. ; Walsh, Christine ; Lester, Jenny ; Greene, Mark H. ; Mai, Phuong L. ; Nussbaum, Robert L. ; Andrulis, Irene L. ; Domchek, Susan M. ; Nathanson, Katherine L. ; Rebbeck, Timothy R. ; Barkardottir, Rosa B. ; Jakubowska, Anna ; Lubinski, Jan ; Durda, Katarzyna ; Jaworska-Bieniek, Katarzyna ; Claes, Kathleen ; Van Maerken, Tom ; Díez, Orland ; Hansen, Thomas V. ; Jønson, Lars ; Gerdes, Anne-Marie ; Ejlertsen, Bent ; De la Hoya, Miguel ; Caldés, Trinidad ; Dunning, Alison M. ; Oliver, Clare ; Fineberg, Elena ; Cook, Margaret ; Peock, Susan ; McCann, Emma ; Murray, Alex ; Jacobs, Chris ; Pichert, Gabriella ; Lalloo, Fiona ; Chu, Carol ; Dorkins, Huw ; Paterson, Joan ; Ong, Kai-Ren ; Teixeira, Manuel R. ; Hogervorst, Frans B. L. ; Van der Hout, Annemarie H. ; Seynaeve, Caroline ; Van der Luijt, Rob B. ; Ligtenberg, Marjolijn J. L. ; Devilee, Peter ; Wijnen, Juul T. ; Rookus, Matti A. ; Meijers-Heijboer, Hanne E. J. ; Blok, Marinus J. ; Van den Ouweland, Ans M. W. ; Aalfs, Cora M. ; Rodriguez, Gustavo C. ; Phillips, Kelly-Anne A. ; Piedmonte, Marion ; Nerenstone, Stacy R. ; Bae-Jump, Victoria L. ; O'Malley, David M. ; Schmutzler, Rita K. ; Wappenschmidt, Barbara ; Rhiem, Kerstin ; Engel, Christoph ; Meindl, Alfons ; Ditsch, Nina ; Arnold, Norbert ; Plendl, Hansjoerg J. ; Niederacher, Dieter ; Sutter, Christian ; Wang-Gohrke, Shan ; Steinemann, Doris ; Preisler-Adams, Sabine ; Kast, Karin ; Varon-Mateeva, Raymonda ; Gehrig, Andrea ; Bojesen, Anders ; Pedersen, Inge Sokilde ; Sunde, Lone ; Birk Jensen, Uffe ; Thomassen, Mads ; Kruse, Torben A. ; Foretova, Lenka ; Peterlongo, Paolo ; Bernard, Loris ; Peissel, Bernard ; Scuvera, Giulietta ; Manoukian, Siranoush ; Radice, Paolo ; Ottini, Laura ; Montagna, Marco ; Agata, Simona ; Maugard, Christine ; Simard, Jacques ; Soucy, Penny ; Berger, Andreas ; Fink-Retter, Anneliese ; Singer, Christian F. ; Rappaport, Christine ; Geschwantler-Kaulich, Daphne ; Tea, Muy-Kheng ; Pfeiler, Georg ; John, Esther M. ; Miron, Alex ; Neuhausen, Susan L. ; Terry, Mary Beth ; Chung, Wendy K. ; Daly, Mary B. ; Goldgar, David E. ; Janavicius, Ramunas ; Dorfling, Cecilia M. ; Van Rensburg, Elisabeth J. ; Fostira, Florentia ; Konstantopoulou, Irene ; Garber, Judy ; Godwin, Andrew K. ; Olah, Edith ; Narod, Steven A. ; Rennert, Gad ; Paluch, Shani Shimon ; Laitman, Yael ; Friedman, Eitan ; Liljegren, Annelie ; Rantala, Johanna ; Stenmark-Askmalm, Marie ; Loman, Niklas ; Imyanitov, Evgeny N. ; Hamann, Ute ; Spurdle, Amanda B. ; Healey, Sue ; Weitzel, Jeffrey N. ; Herzog, Josef ; Margileth, David ; Gorrini, Chiara ; Esteller, Manel ; Gómez, Antonio ; Sayols, Sergi ; Vidal, Enrique ; Heyn, Holger ; Stoppa-Lyonnet, Dominique ; Léoné, Melanie ; Barjhoux, Laure ; Fassy-Colcombet, Marion ; Pauw, Antoine de ; Lasset, Christine ; Fert Ferrer, Sandra ; Castera, Laurent ; Berthet, Pascaline ; Cornelis, François ; Bignon, Yves-Jean ; Damiola, Francesca ; Mazoyer, Sylvie ; Sinilnikova, Olga M. ; Maxwell, Christopher A. ; Vijai, Joseph ; Robson, Mark ; Kauff, Noah ; Corines, Marina J. ; Villano, Danylko ; Cunningham, Julie ; Lee, Adam ; Lindor, Noralane ; Lázaro, Conxi ; Easton, Douglas F. ; Offit, Kenneth ; Chenevix-Trench, Georgia ; Couch, Fergus J. ; Antoniou, Antonis C. ; Pujana, Miguel Angel
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10\(^{-4}\) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p\(_{interaction}\) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
Interleukin 4 (IL-4) exerts a decisive role in the coord.ination of proteelive immune responses against parasites, particularly helminths. A disregulation of ll.r4 function is possibly involved in the genesis of allergic disease states. The search for important amino acid residues in human ll.r4 by mutational analysis of charged invariant amino acid positions identified two distinct functional sites in the 4-helix-bundle protein. Site 1 was marked by amino acid substitutions of the glutamic acid at position 9 in helix A and arginine at position 88 in helix C. Exchanges at both positions led to IL-4 variants deficient in binding to the extracellular domain of the ll.r4 receptor (IL-4ReJ. In parallel, up to 1000-fold increased concentrations of this type of variant were required to induce T -cell proliferation and B-eeil CD23 expression. Site 2 was marked by amino acid exchanges in helix D at positions 121, 124 and 125 (arginine, tyrosine and serine respectively in the wild-type).ß.A variants affected at site 2 exhibited partial agonist activity during T -cell proliferation; however, they still bound with high affinity to IL-4Rex. [The generation of an IL-4 antagonist by replacing tyrosine 124 with aspartic acid has been described before by Kruse et al. (1992) (EMBO }., 11, 3237-3244)]. These findings indicate that IL-4 functions by bind.ing IL-4Rex via site 1 which is constituted by residues on helices A and C. They further suggest that the association of a second, still undetined receptor protein with site 2 in helix D activates the receptor system and generates a transmembrane signal.
Neutralizing monoclonal antibodies define two different functional sites in human interleukin-4
(1994)
Human interleukin-4 (IL-4) is a small four-helix-bundle protein which is essential for organizing defense reactions against macroparasites, in particular helminths. Human IL-4 also appears to exert a pathophysiological role during various IgE-mediated allergic diseases. Seven different monoclonal antibodies neutralizing the activity of human IL-4 were studied in order to identify functionally important epitopes. A collection of 41 purified IL-4 variants was used to analyse how defined amino acid replacements affect binding affinity for each individual mAb. Specific amino acid positions could be assigned to four different epitopes. mAbs recognizing epitopes on helix A and/or C interfered with IL-4 receptor binding and thus inhibited IL-4 function. However, other mAbs also inhibiting IL-4 function recognized an epitope on helix D of IL-4 and did not inhibit IL-4 binding to the receptor protein. One mAb, recognizing N-terminal and C-terminal residues, partially competed for binding to the receptor. The results of these mAb epitope analyses confirm and extend previous data on the functional consequences of the amino acid replacements which showed that amino acid residues in helices A and C of IL-4 provide a binding site for the cloned IL-4 receptor and that a signalling site in helix D interacts with a further receptor protein.
Marenholz, Ingo ; Esparza-Gordillo, Jorge ; Rüschendorf, Franz ; Bauerfeind, Anja ; Strachan, David P. ; Spycher, Ben D. ; Baurecht, Hansjörg ; Magaritte-Jeannin, Patricia ; Sääf, Annika ; Kerkhof, Marjan ; Ege, Markus ; Baltic, Svetlana ; Matheson, Melanie C. ; Li, Jin ; Michel, Sven ; Ang, Wei Q. ; McArdle, Wendy ; Arnold, Andreas ; Homuth, Georg ; Demenais, Florence ; Bouzigon, Emmanuelle ; Söderhäll, Cilla ; Pershagen, Göran ; de Jongste, Johan C. ; Postma, Dirkje S. ; Braun-Fahrländer, Charlotte ; Horak, Elisabeth ; Ogorodova, Ludmila M. ; Puzyrev, Valery P. ; Bragina, Elena Yu ; Hudson, Thomas J. ; Morin, Charles ; Duffy, David L. ; Marks, Guy B. ; Robertson, Colin F. ; Montgomery, Grant W. ; Musk, Bill ; Thompson, Philip J. ; Martin, Nicholas G. ; James, Alan ; Sleiman, Patrick ; Toskala, Elina ; Rodriguez, Elke ; Fölster-Holst, Regina ; Franke, Andre ; Lieb, Wolfgang ; Gieger, Christian ; Heinzmann, Andrea ; Rietschel, Ernst ; Keil, Thomas ; Cichon, Sven ; Nöthen, Markus M. ; Pennel, Craig E. ; Sly, Peter D. ; Schmidt, Carsten O. ; Matanovic, Anja ; Schneider, Valentin ; Heinig, Matthias ; Hübner, Norbert ; Holt, Patrick G. ; Lau, Susanne ; Kabesch, Michael ; Weidinger, Stefan ; Hakonarson, Hakon ; Ferreira, Manuel A. R. ; Laprise, Catherine ; Freidin, Maxim B. ; Genuneit, Jon ; Koppelman, Gerard H. ; Melén, Erik ; Dizier, Marie-Hélène ; Henderson, A. John ; Lee, Young Ae
Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.