TY  - JOUR
A1  - Ferreira, Manuel A.
A1  - Gamazon, Eric R.
A1  - Al-Ejeh, Fares
A1  - Aittomäki, Kristiina
A1  - Andrulis, Irene L.
A1  - Anton-Culver, Hoda
A1  - Arason, Adalgeir
A1  - Arndt, Volker
A1  - Aronson, Kristan J.
A1  - Arun, Banu K.
A1  - Asseryanis, Ella
A1  - Azzollini, Jacopo
A1  - Balmaña, Judith
A1  - Barnes, Daniel R.
A1  - Barrowdale, Daniel
A1  - Beckmann, Matthias W.
A1  - Behrens, Sabine
A1  - Benitez, Javier
A1  - Bermisheva, Marina
A1  - Bialkowska, Katarzyna
A1  - Blomqvist, Carl
A1  - Bogdanova, Natalia V.
A1  - Bojesen, Stig E.
A1  - Bolla, Manjeet K.
A1  - Borg, Ake
A1  - Brauch, Hiltrud
A1  - Brenner, Hermann
A1  - Broeks, Annegien
A1  - Burwinkel, Barbara
A1  - Caldés, Trinidad
A1  - Caligo, Maria A.
A1  - Campa, Daniele
A1  - Campbell, Ian
A1  - Canzian, Federico
A1  - Carter, Jonathan
A1  - Carter, Brian D.
A1  - Castelao, Jose E.
A1  - Chang-Claude, Jenny
A1  - Chanock, Stephen J.
A1  - Christiansen, Hans
A1  - Chung, Wendy K.
A1  - Claes, Kathleen B. M.
A1  - Clarke, Christine L.
A1  - Couch, Fergus J.
A1  - Cox, Angela
A1  - Cross, Simon S.
A1  - Czene, Kamila
A1  - Daly, Mary B.
A1  - de la Hoya, Miguel
A1  - Dennis, Joe
A1  - Devilee, Peter
A1  - Diez, Orland
A1  - Dörk, Thilo
A1  - Dunning, Alison M.
A1  - Dwek, Miriam
A1  - Eccles, Diana M.
A1  - Ejlertsen, Bent
A1  - Ellberg, Carolina
A1  - Engel, Christoph
A1  - Eriksson, Mikael
A1  - Fasching, Peter A.
A1  - Fletcher, Olivia
A1  - Flyger, Henrik
A1  - Friedman, Eitan
A1  - Frost, Debra
A1  - Gabrielson, Marike
A1  - Gago-Dominguez, Manuela
A1  - Ganz, Patricia A.
A1  - Gapstur, Susan M.
A1  - Garber, Judy
A1  - García-Closas, Montserrat
A1  - García-Sáenz, José A.
A1  - Gaudet, Mia M.
A1  - Giles, Graham G.
A1  - Glendon, Gord
A1  - Godwin, Andrew K.
A1  - Goldberg, Mark S.
A1  - Goldgar, David E.
A1  - González-Neira, Anna
A1  - Greene, Mark H.
A1  - Gronwald, Jacek
A1  - Guenél, Pascal
A1  - Haimann, Christopher A.
A1  - Hall, Per
A1  - Hamann, Ute
A1  - He, Wei
A1  - Heyworth, Jane
A1  - Hogervorst, Frans B. L.
A1  - Hollestelle, Antoinette
A1  - Hoover, Robert N.
A1  - Hopper, John L.
A1  - Hulick, Peter J.
A1  - Humphreys, Keith
A1  - Imyanitov, Evgeny N.
A1  - Isaacs, Claudine
A1  - Jakimovska, Milena
A1  - Jakubowska, Anna
A1  - James, Paul A.
A1  - Janavicius, Ramunas
A1  - Jankowitz, Rachel C.
A1  - John, Esther M.
A1  - Johnson, Nichola
A1  - Joseph, Vijai
A1  - Karlan, Beth Y.
A1  - Khusnutdinova, Elza
A1  - Kiiski, Johanna I.
A1  - Ko, Yon-Dschun
A1  - Jones, Michael E.
A1  - Konstantopoulou, Irene
A1  - Kristensen, Vessela N.
A1  - Laitman, Yael
A1  - Lambrechts, Diether
A1  - Lazaro, Conxi
A1  - Leslie, Goska
A1  - Lester, Jenny
A1  - Lesueur, Fabienne
A1  - Lindström, Sara
A1  - Long, Jirong
A1  - Loud, Jennifer T.
A1  - Lubiński, Jan
A1  - Makalic, Enes
A1  - Mannermaa, Arto
A1  - Manoochehri, Mehdi
A1  - Margolin, Sara
A1  - Maurer, Tabea
A1  - Mavroudis, Dimitrios
A1  - McGuffog, Lesley
A1  - Meindl, Alfons
A1  - Menon, Usha
A1  - Michailidou, Kyriaki
A1  - Miller, Austin
A1  - Montagna, Marco
A1  - Moreno, Fernando
A1  - Moserle, Lidia
A1  - Mulligan, Anna Marie
A1  - Nathanson, Katherine L.
A1  - Neuhausen, Susan L.
A1  - Nevanlinna, Heli
A1  - Nevelsteen, Ines
A1  - Nielsen, Finn C.
A1  - Nikitina-Zake, Liene
A1  - Nussbaum, Robert L.
A1  - Offit, Kenneth
A1  - Olah, Edith
A1  - Olopade, Olufunmilayo I.
A1  - Olsson, Håkan
A1  - Osorio, Ana
A1  - Papp, Janos
A1  - Park-Simon, Tjoung-Won
A1  - Parsons, Michael T.
A1  - Pedersen, Inge Sokilde
A1  - Peixoto, Ana
A1  - Peterlongo, Paolo
A1  - Pharaoh, Paul D. P.
A1  - Plaseska-Karanfilska, Dijana
A1  - Poppe, Bruce
A1  - Presneau, Nadege
A1  - Radice, Paolo
A1  - Rantala, Johanna
A1  - Rennert, Gad
A1  - Risch, Harvey A.
A1  - Saloustros, Emmanouil
A1  - Sanden, Kristin
A1  - Sawyer, Elinor J.
A1  - Schmidt, Marjanka K.
A1  - Schmutzler, Rita K.
A1  - Sharma, Priyanka
A1  - Shu, Xiao-Ou
A1  - Simard, Jaques
A1  - Singer, Christian F.
A1  - Soucy, Penny
A1  - Southey, Melissa C.
A1  - Spinelli, John J.
A1  - Spurdle, Amanda B.
A1  - Stone, Jennifer
A1  - Swerdlow, Anthony J.
A1  - Tapper, William J.
A1  - Taylor, Jack A.
A1  - Teixeira, Manuel R.
A1  - Terry, Mary Beth
A1  - Teulé, Alex
A1  - Thomassen, Mads
A1  - Thöne, Kathrin
A1  - Thull, Darcy L.
A1  - Tischkowitz, Marc
A1  - Toland, Amanda E.
A1  - Torres, Diana
A1  - Truong, Thérèse
A1  - Tung, Nadine
A1  - Vachon, Celine M.
A1  - van Asperen, Christi J.
A1  - van den Ouweland, Ans M. W.
A1  - van Rensburg, Elizabeth J.
A1  - Vega, Ana
A1  - Viel, Alexandra
A1  - Wang, Qin
A1  - Wappenschmidt, Barbara
A1  - Weitzel, Jeffrey N.
A1  - Wendt, Camilla
A1  - Winqvist, Robert
A1  - Yang, Xiaohong R.
A1  - Yannoukakos, Drakoulis
A1  - Ziogas, Argyrios
A1  - Kraft, Peter
A1  - Antoniou, Antonis C.
A1  - Zheng, Wei
A1  - Easton, Douglas F.
A1  - Milne, Roger L.
A1  - Beesley, Jonathan
A1  - Chenevix-Trench, Georgia
T1  - Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
JF  - Nature Communications
N2  - Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
KW  - cancer
KW  - genetics
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228024
VL  - 10
ER  - 
TY  - JOUR
A1  - Iyengar, Sudha K.
A1  - Sedor, John R.
A1  - Freedman, Barry I.
A1  - Kao, W. H. Linda
A1  - Kretzler, Matthias
A1  - Keller, Benjamin J.
A1  - Abboud, Hanna E.
A1  - Adler, Sharon G.
A1  - Best, Lyle G.
A1  - Bowden, Donald W.
A1  - Burlock, Allison
A1  - Chen, Yii-Der Ida
A1  - Cole, Shelley A.
A1  - Comeau, Mary E.
A1  - Curtis, Jeffrey M.
A1  - Divers, Jasmin
A1  - Drechsler, Christiane
A1  - Duggirala, Ravi
A1  - Elston, Robert C.
A1  - Guo, Xiuqing
A1  - Huang, Huateng
A1  - Hoffmann, Michael Marcus
A1  - Howard, Barbara V.
A1  - Ipp, Eli
A1  - Kimmel, Paul L.
A1  - Klag, Michael J.
A1  - Knowler, William C.
A1  - Kohn, Orly F.
A1  - Leak, Tennille S.
A1  - Leehey, David J.
A1  - Li, Man
A1  - Malhotra, Alka
A1  - März, Winfried
A1  - Nair, Viji
A1  - Nelson, Robert G.
A1  - Nicholas, Susanne B.
A1  - O’Brien, Stephen J.
A1  - Pahl, Madeleine V.
A1  - Parekh, Rulan S.
A1  - Pezzolesi, Marcus G.
A1  - Rasooly, Rebekah S.
A1  - Rotimi, Charles N.
A1  - Rotter, Jerome I.
A1  - Schelling, Jeffrey R.
A1  - Seldin, Michael F.
A1  - Shah, Vallabh O.
A1  - Smiles, Adam M.
A1  - Smith, Michael W.
A1  - Taylor, Kent D.
A1  - Thameem, Farook
A1  - Thornley-Brown, Denyse P.
A1  - Truitt, Barbara J.
A1  - Wanner, Christoph
A1  - Weil, E. Jennifer
A1  - Winkler, Cheryl A.
A1  - Zager, Philip G.
A1  - Igo, Jr, Robert P.
A1  - Hanson, Robert L.
A1  - Langefeld, Carl D.
T1  - Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: Family Investigation of Nephropathy and Diabetes (FIND)
JF  - PLoS Genetics
N2  - Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10\(^{−9}\)). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10\(^{−8}\)), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
KW  - diabetic kidney disease
KW  - genome-wide association study
KW  - Family Investigation of Nephropathy and Diabetes
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180545
VL  - 11
IS  - 8
ER  - 
TY  - JOUR
A1  - Gröbner, Susanne N.
A1  - Worst, Barbara C.
A1  - Weischenfeldt, Joachim
A1  - Buchhalter, Ivo
A1  - Kleinheinz, Kortine
A1  - Rudneva, Vasilisa A.
A1  - Johann, Pascal D.
A1  - Balasubramanian, Gnana Prakash
A1  - Segura-Wang, Maia
A1  - Brabetz, Sebastian
A1  - Bender, Sebastian
A1  - Hutter, Barbara
A1  - Sturm, Dominik
A1  - Pfaff, Elke
A1  - Hübschmann, Daniel
A1  - Zipprich, Gideon
A1  - Heinold, Michael
A1  - Eils, Jürgen
A1  - Lawerenz, Christian
A1  - Erkek, Serap
A1  - Lambo, Sander
A1  - Waszak, Sebastian
A1  - Blattmann, Claudia
A1  - Borkhardt, Arndt
A1  - Kuhlen, Michaela
A1  - Eggert, Angelika
A1  - Fulda, Simone
A1  - Gessler, Manfred
A1  - Wegert, Jenny
A1  - Kappler, Roland
A1  - Baumhoer, Daniel
A1  - Stefan, Burdach
A1  - Kirschner-Schwabe, Renate
A1  - Kontny, Udo
A1  - Kulozik, Andreas E.
A1  - Lohmann, Dietmar
A1  - Hettmer, Simone
A1  - Eckert, Cornelia
A1  - Bielack, Stefan
A1  - Nathrath, Michaela
A1  - Niemeyer, Charlotte
A1  - Richter, Günther H.
A1  - Schulte, Johannes
A1  - Siebert, Reiner
A1  - Westermann, Frank
A1  - Molenaar, Jan J.
A1  - Vassal, Gilles
A1  - Witt, Hendrik
A1  - Burkhardt, Birgit
A1  - Kratz, Christian P.
A1  - Witt, Olaf
A1  - van Tilburg, Cornelis M.
A1  - Kramm, Christof M.
A1  - Fleischhack, Gudrun
A1  - Dirksen, Uta
A1  - Rutkowski, Stefan
A1  - Frühwald, Michael
A1  - Hoff, Katja von
A1  - Wolf, Stephan
A1  - Klingebeil, Thomas
A1  - Koscielniak, Ewa
A1  - Landgraf, Pablo
A1  - Koster, Jan
A1  - Resnick, Adam C.
A1  - Zhang, Jinghui
A1  - Liu, Yanling
A1  - Zhou, Xin
A1  - Waanders, Angela J.
A1  - Zwijnenburg, Danny A.
A1  - Raman, Pichai
A1  - Brors, Benedikt
A1  - Weber, Ursula D.
A1  - Northcott, Paul A.
A1  - Pajtler, Kristian W.
A1  - Kool, Marcel
A1  - Piro, Rosario M.
A1  - Korbel, Jan O.
A1  - Schlesner, Matthias
A1  - Eils, Roland
A1  - Jones, David T. W.
A1  - Lichter, Peter
A1  - Chavez, Lukas
A1  - Zapatka, Marc
A1  - Pfister, Stefan M.
T1  - The landscape of genomic alterations across childhood cancers
JF  - Nature
N2  - Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
KW  - cancer genomics
KW  - oncogenesis
KW  - paediatric cancer
KW  - predictive markers
KW  - translational research
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229579
VL  - 555
ER  - 
TY  - JOUR
A1  - Bousquet, J.
A1  - Farrell, J.
A1  - Crooks, G.
A1  - Hellings, P.
A1  - Bel, E. H.
A1  - Bewick, M.
A1  - Chavannes, N. H.
A1  - Correia de Sousa, J.
A1  - Cruz, A. A.
A1  - Haahtela, T.
A1  - Joos, G.
A1  - Khaltaev, N.
A1  - Malva, J.
A1  - Muraro, A.
A1  - Nogues, M.
A1  - Palkonen, S.
A1  - Pedersen, S.
A1  - Robalo-Cordeiro, C.
A1  - Samolinski, B.
A1  - Strandberg, T.
A1  - Valiulis, A.
A1  - Yorgancioglu, A.
A1  - Zuberbier, T.
A1  - Bedbrook, A.
A1  - Aberer, W.
A1  - Adachi, M.
A1  - Agusti, A.
A1  - Akdis, C. A.
A1  - Akdis, M.
A1  - Ankri, J.
A1  - Alonso, A.
A1  - Annesi-Maesano, I.
A1  - Ansotegui, I. J.
A1  - Anto, J. M.
A1  - Arnavielhe, S.
A1  - Arshad, H.
A1  - Bai, C.
A1  - Baiardini, I.
A1  - Bachert, C.
A1  - Baigenzhin, A. K.
A1  - Barbara, C.
A1  - Bateman, E. D.
A1  - Beghé, B.
A1  - Ben Kheder, A.
A1  - Bennoor, K. S.
A1  - Benson, M.
A1  - Bergmann, K. C.
A1  - Bieber, T.
A1  - Bindslev-Jensen, C.
A1  - Bjermer, L.
A1  - Blain, H.
A1  - Blasi, F.
A1  - Boner, A. L.
A1  - Bonini, M.
A1  - Bonini, S.
A1  - Bosnic-Anticevitch, S.
A1  - Boulet, L. P.
A1  - Bourret, R.
A1  - Bousquet, P. J.
A1  - Braido, F.
A1  - Briggs, A. H.
A1  - Brightling, C. E.
A1  - Brozek, J.
A1  - Buhl, R.
A1  - Burney, P. G.
A1  - Bush, A.
A1  - Caballero-Fonseca, F.
A1  - Caimmi, D.
A1  - Calderon, M. A.
A1  - Calverley, P. M.
A1  - Camargos, P. A. M.
A1  - Canonica, G. W.
A1  - Camuzat, T.
A1  - Carlsen, K. H.
A1  - Carr, W.
A1  - Carriazo, A.
A1  - Casale, T.
A1  - Cepeda Sarabia, A. M.
A1  - Chatzi, L.
A1  - Chen, Y. Z.
A1  - Chiron, R.
A1  - Chkhartishvili, E.
A1  - Chuchalin, A. G.
A1  - Chung, K. F.
A1  - Ciprandi, G.
A1  - Cirule, I.
A1  - Cox, L.
A1  - Costa, D. J.
A1  - Custovic, A.
A1  - Dahl, R.
A1  - Dahlen, S. E.
A1  - Darsow, U.
A1  - De Carlo, G.
A1  - De Blay, F.
A1  - Dedeu, T.
A1  - Deleanu, D.
A1  - De Manuel Keenoy, E.
A1  - Demoly, P.
A1  - Denburg, J. A.
A1  - Devillier, P.
A1  - Didier, A.
A1  - Dinh-Xuan, A. T.
A1  - Djukanovic, R.
A1  - Dokic, D.
A1  - Douagui, H.
A1  - Dray, G.
A1  - Dubakiene, R.
A1  - Durham, S. R.
A1  - Dykewicz, M. S.
A1  - El-Gamal, Y.
A1  - Emuzyte, R.
A1  - Fabbri, L. M.
A1  - Fletcher, M.
A1  - Fiocchi, A.
A1  - Fink Wagner, A.
A1  - Fonseca, J.
A1  - Fokkens, W. J.
A1  - Forastiere, F.
A1  - Frith, P.
A1  - Gaga, M.
A1  - Gamkrelidze, A.
A1  - Garces, J.
A1  - Garcia-Aymerich, J.
A1  - Gemicioğlu, B.
A1  - Gereda, J. E.
A1  - González Diaz, S.
A1  - Gotua, M.
A1  - Grisle, I.
A1  - Grouse, L.
A1  - Gutter, Z.
A1  - Guzmán, M. A.
A1  - Heaney, L. G.
A1  - Hellquist-Dahl, B.
A1  - Henderson, D.
A1  - Hendry, A.
A1  - Heinrich, J.
A1  - Heve, D.
A1  - Horak, F.
A1  - Hourihane, J. O’. B.
A1  - Howarth, P.
A1  - Humbert, M.
A1  - Hyland, M. E.
A1  - Illario, M.
A1  - Ivancevich, J. C.
A1  - Jardim, J. R.
A1  - Jares, E. J.
A1  - Jeandel, C.
A1  - Jenkins, C.
A1  - Johnston, S. L.
A1  - Jonquet, O.
A1  - Julge, K.
A1  - Jung, K. S.
A1  - Just, J.
A1  - Kaidashev, I.
A1  - Kaitov, M. R.
A1  - Kalayci, O.
A1  - Kalyoncu, A. F.
A1  - Keil, T.
A1  - Keith, P. K.
A1  - Klimek, L.
A1  - Koffi N’Goran, B.
A1  - Kolek, V.
A1  - Koppelman, G. H.
A1  - Kowalski, M. L.
A1  - Kull, I.
A1  - Kuna, P.
A1  - Kvedariene, V.
A1  - Lambrecht, B.
A1  - Lau, S.
A1  - Larenas‑Linnemann, D.
A1  - Laune, D.
A1  - Le, L. T. T.
A1  - Lieberman, P.
A1  - Lipworth, B.
A1  - Li, J.
A1  - Lodrup Carlsen, K.
A1  - Louis, R.
A1  - MacNee, W.
A1  - Magard, Y.
A1  - Magnan, A.
A1  - Mahboub, B.
A1  - Mair, A.
A1  - Majer, I.
A1  - Makela, M. J.
A1  - Manning, P.
A1  - Mara, S.
A1  - Marshall, G. D.
A1  - Masjedi, M. R.
A1  - Matignon, P.
A1  - Maurer, M.
A1  - Mavale‑Manuel, S.
A1  - Melén, E.
A1  - Melo‑Gomes, E.
A1  - Meltzer, E. O.
A1  - Menzies‑Gow, A.
A1  - Merk, H.
A1  - Michel, J. P.
A1  - Miculinic, N.
A1  - Mihaltan, F.
A1  - Milenkovic, B.
A1  - Mohammad, G. M. Y.
A1  - Molimard, M.
A1  - Momas, I.
A1  - Montilla‑Santana, A.
A1  - Morais‑Almeida, M.
A1  - Morgan, M.
A1  - Mösges, R.
A1  - Mullol, J.
A1  - Nafti, S.
A1  - Namazova‑Baranova, L.
A1  - Naclerio, R.
A1  - Neou, A.
A1  - Neffen, H.
A1  - Nekam, K.
A1  - Niggemann, B.
A1  - Ninot, G.
A1  - Nyembue, T. D.
A1  - O’Hehir, R. E.
A1  - Ohta, K.
A1  - Okamoto, Y.
A1  - Okubo, K.
A1  - Ouedraogo, S.
A1  - Paggiaro, P.
A1  - Pali‑Schöll, I.
A1  - Panzner, P.
A1  - Papadopoulos, N.
A1  - Papi, A.
A1  - Park, H. S.
A1  - Passalacqua, G.
A1  - Pavord, I.
A1  - Pawankar, R.
A1  - Pengelly, R.
A1  - Pfaar, O.
A1  - Picard, R.
A1  - Pigearias, B.
A1  - Pin, I.
A1  - Plavec, D.
A1  - Poethig, D.
A1  - Pohl, W.
A1  - Popov, T. A.
A1  - Portejoie, F.
A1  - Potter, P.
A1  - Postma, D.
A1  - Price, D.
A1  - Rabe, K. F.
A1  - Raciborski, F.
A1  - Radier Pontal, F.
A1  - Repka‑Ramirez, S.
A1  - Reitamo, S.
A1  - Rennard, S.
A1  - Rodenas, F.
A1  - Roberts, J.
A1  - Roca, J.
A1  - Rodriguez Mañas, L.
A1  - et al, 
T1  - Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5)
JF  - Clinical and Translational Allergy
N2  - Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.
KW  - EIP on AHA
KW  - European Innovation Partnership on Active and Healthy Ageing
KW  - AIRWAYS ICPs
KW  - MACVIA
KW  - Scaling up
KW  - Chronic respiratory diseases
KW  - ARIA
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166874
VL  - 6
IS  - 29
ER  - 
TY  - JOUR
A1  - Postema, Merel C.
A1  - Hoogman, Martine
A1  - Ambrosino, Sara
A1  - Asherson, Philip
A1  - Banaschewski, Tobias
A1  - Bandeira, Cibele E.
A1  - Baranov, Alexandr
A1  - Bau, Claiton H.D.
A1  - Baumeister, Sarah
A1  - Baur‐Streubel, Ramona
A1  - Bellgrove, Mark A.
A1  - Biederman, Joseph
A1  - Bralten, Janita
A1  - Brandeis, Daniel
A1  - Brem, Silvia
A1  - Buitelaar, Jan K.
A1  - Busatto, Geraldo F.
A1  - Castellanos, Francisco X.
A1  - Cercignani, Mara
A1  - Chaim‐Avancini, Tiffany M.
A1  - Chantiluke, Kaylita C.
A1  - Christakou, Anastasia
A1  - Coghill, David
A1  - Conzelmann, Annette
A1  - Cubillo, Ana I.
A1  - Cupertino, Renata B.
A1  - de Zeeuw, Patrick
A1  - Doyle, Alysa E.
A1  - Durston, Sarah
A1  - Earl, Eric A.
A1  - Epstein, Jeffery N.
A1  - Ethofer, Thomas
A1  - Fair, Damien A.
A1  - Fallgatter, Andreas J.
A1  - Faraone, Stephen V.
A1  - Frodl, Thomas
A1  - Gabel, Matt C.
A1  - Gogberashvili, Tinatin
A1  - Grevet, Eugenio H.
A1  - Haavik, Jan
A1  - Harrison, Neil A.
A1  - Hartman, Catharina A.
A1  - Heslenfeld, Dirk J.
A1  - Hoekstra, Pieter J.
A1  - Hohmann, Sarah
A1  - Høvik, Marie F.
A1  - Jernigan, Terry L.
A1  - Kardatzki, Bernd
A1  - Karkashadze, Georgii
A1  - Kelly, Clare
A1  - Kohls, Gregor
A1  - Konrad, Kerstin
A1  - Kuntsi, Jonna
A1  - Lazaro, Luisa
A1  - Lera‐Miguel, Sara
A1  - Lesch, Klaus‐Peter
A1  - Louza, Mario R.
A1  - Lundervold, Astri J.
A1  - Malpas, Charles B
A1  - Mattos, Paulo
A1  - McCarthy, Hazel
A1  - Namazova‐Baranova, Leyla
A1  - Nicolau, Rosa
A1  - Nigg, Joel T.
A1  - Novotny, Stephanie E.
A1  - Oberwelland Weiss, Eileen
A1  - O'Gorman Tuura, Ruth L.
A1  - Oosterlaan, Jaap
A1  - Oranje, Bob
A1  - Paloyelis, Yannis
A1  - Pauli, Paul
A1  - Picon, Felipe A.
A1  - Plessen, Kerstin J.
A1  - Ramos‐Quiroga, J. Antoni
A1  - Reif, Andreas
A1  - Reneman, Liesbeth
A1  - Rosa, Pedro G.P.
A1  - Rubia, Katya
A1  - Schrantee, Anouk
A1  - Schweren, Lizanne J.S.
A1  - Seitz, Jochen
A1  - Shaw, Philip
A1  - Silk, Tim J.
A1  - Skokauskas, Norbert
A1  - Soliva Vila, Juan C.
A1  - Stevens, Michael C.
A1  - Sudre, Gustavo
A1  - Tamm, Leanne
A1  - Tovar‐Moll, Fernanda
A1  - van Erp, Theo G.M.
A1  - Vance, Alasdair
A1  - Vilarroya, Oscar
A1  - Vives‐Gilabert, Yolanda
A1  - von Polier, Georg G.
A1  - Walitza, Susanne
A1  - Yoncheva, Yuliya N.
A1  - Zanetti, Marcus V.
A1  - Ziegler, Georg C.
A1  - Glahn, David C.
A1  - Jahanshad, Neda
A1  - Medland, Sarah E.
A1  - Thompson, Paul M.
A1  - Fisher, Simon E.
A1  - Franke, Barbara
A1  - Francks, Clyde
T1  - Analysis of structural brain asymmetries in attention‐deficit/hyperactivity disorder in 39 datasets
JF  - Journal of Child Psychology and Psychiatry
N2  - Objective
Some studies have suggested alterations of structural brain asymmetry in attention‐deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left‐right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods
We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results
There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study‐wide correction for multiple testing.

Conclusion
Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
KW  - attention‐deficit
KW  - hyperactivity disorder
KW  - brain asymmetry
KW  - brain laterality
KW  - structural MRI
KW  - large‐scale data
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239968
VL  - 62
IS  - 10
SP  - 1202
EP  - 1219
ER  - 
TY  - JOUR
A1  - Sonnenschein-van der Voort, Agnes M. M.
A1  - Arends, Lidia R.
A1  - de Jongste, Johan C.
A1  - Annesi-Maesano, Isabella
A1  - Arshad, S. Hasan
A1  - Barros, Henrique
A1  - Basterrechea, Mikel
A1  - Bisgaard, Hans
A1  - Chatzi, Leda
A1  - Corpeleijn, Eva
A1  - Correia, Sofia
A1  - Craig, Leone C.
A1  - Devereux, Graham
A1  - Dogaru, Cristian
A1  - Dostal, Miroslav
A1  - Duchen, Karel
A1  - Eggesbø, Merete
A1  - van der Ent, C. Kors
A1  - Fantini, Maria P.
A1  - Forastiere, Francesco
A1  - Frey, Urs
A1  - Gehring, Ulrike
A1  - Gori, Davide
A1  - van der Gugten, Anne C.
A1  - Hanke, Wojciech
A1  - Henderson, A. John
A1  - Heude, Barbara
A1  - Iñiguez, Carmen
A1  - Inskip, Hazel M.
A1  - Keil, Thomas
A1  - Kelleher, Cecily C.
A1  - Kogevinas, Manolis
A1  - Kreiner-Møller, Eskil
A1  - Kuehni, Claudia E.
A1  - Küpers, Leanne K.
A1  - Lancz, Kinga
A1  - Larsen, Pernille S.
A1  - Lau, Susanne
A1  - Ludvigsson, Johnny
A1  - Mommers, Monique
A1  - Andersen, Anne-Marie Nybo
A1  - Palkovicova, Lubica
A1  - Pike, Katherine C.
A1  - Pizzi, Constanza
A1  - Polanska, Kinga
A1  - Porta, Daniela
A1  - Richiardi, Lorenzo
A1  - Roberts, Graham
A1  - Schmidt, Anne
A1  - Sram, Radim J.
A1  - Sunyer, Jordi
A1  - Thijs, Carel
A1  - Torrent, Maties
A1  - Viljoen, Karien
A1  - Wijga, Alet H.
A1  - Vrijheid, Martine
A1  - Jaddoe, Vincent W. V.
A1  - Duijts, Liesbeth
T1  - Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children
JF  - The Journal of Allergy and Clinical Immunology
N2  - Background
Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.

Objectives
We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).

Methods
First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.

Results
Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).

Conclusion
Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth."
KW  - gestational age
KW  - low birth weight
KW  - infant growth
KW  - wheezing
KW  - asthma
KW  - epidemiology
KW  - cohort studies
KW  - children
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120714
VL  - 133
IS  - 5
ER  - 
TY  - JOUR
A1  - Davis, Lea K.
A1  - Yu, Dongmei
A1  - Keenan, Clare L.
A1  - Gamazon, Eric R.
A1  - Konkashbaev, Anuar I.
A1  - Derks, Eske M.
A1  - Neale, Benjamin M.
A1  - Yang, Jian
A1  - Lee, S. Hong
A1  - Evans, Patrick
A1  - Barr, Cathy L.
A1  - Bellodi, Laura
A1  - Benarroch, Fortu
A1  - Berrio, Gabriel Bedoya
A1  - Bienvenu, Oscar J.
A1  - Bloch, Michael H.
A1  - Blom, Rianne M.
A1  - Bruun, Ruth D.
A1  - Budman, Cathy L.
A1  - Camarena, Beatriz
A1  - Campbell, Desmond
A1  - Cappi, Carolina
A1  - Cardona Silgado, Julio C.
A1  - Cath, Danielle C.
A1  - Cavallini, Maria C.
A1  - Chavira, Denise A.
A1  - Chouinard, Sylvian
A1  - Conti, David V.
A1  - Cook, Edwin H.
A1  - Coric, Vladimir
A1  - Cullen, Bernadette A.
A1  - Deforce, Dieter
A1  - Delorme, Richard
A1  - Dion, Yves
A1  - Edlund, Christopher K.
A1  - Egberts, Karin
A1  - Falkai, Peter
A1  - Fernandez, Thomas V.
A1  - Gallagher, Patience J.
A1  - Garrido, Helena
A1  - Geller, Daniel
A1  - Girard, Simon L.
A1  - Grabe, Hans J.
A1  - Grados, Marco A.
A1  - Greenberg, Benjamin D.
A1  - Gross-Tsur, Varda
A1  - Haddad, Stephen
A1  - Heiman, Gary A.
A1  - Hemmings, Sian M. J.
A1  - Hounie, Ana G.
A1  - Illmann, Cornelia
A1  - Jankovic, Joseph
A1  - Jenike, Micheal A.
A1  - Kennedy, James L.
A1  - King, Robert A.
A1  - Kremeyer, Barbara
A1  - Kurlan, Roger
A1  - Lanzagorta, Nuria
A1  - Leboyer, Marion
A1  - Leckman, James F.
A1  - Lennertz, Leonhard
A1  - Liu, Chunyu
A1  - Lochner, Christine
A1  - Lowe, Thomas L.
A1  - Macciardi, Fabio
A1  - McCracken, James T.
A1  - McGrath, Lauren M.
A1  - Restrepo, Sandra C. Mesa
A1  - Moessner, Rainald
A1  - Morgan, Jubel
A1  - Muller, Heike
A1  - Murphy, Dennis L.
A1  - Naarden, Allan L.
A1  - Ochoa, William Cornejo
A1  - Ophoff, Roel A.
A1  - Osiecki, Lisa
A1  - Pakstis, Andrew J.
A1  - Pato, Michele T.
A1  - Pato, Carlos N.
A1  - Piacentini, John
A1  - Pittenger, Christopher
A1  - Pollak, Yehunda
A1  - Rauch, Scott L.
A1  - Renner, Tobias J.
A1  - Reus, Victor I.
A1  - Richter, Margaret A.
A1  - Riddle, Mark A.
A1  - Robertson, Mary M.
A1  - Romero, Roxana
A1  - Rosàrio, Maria C.
A1  - Rosenberg, David
A1  - Rouleau, Guy A.
A1  - Ruhrmann, Stephan
A1  - Ruiz-Linares, Andreas
A1  - Sampaio, Aline S.
A1  - Samuels, Jack
A1  - Sandor, Paul
A1  - Sheppard, Broke
A1  - Singer, Harvey S.
A1  - Smit, Jan H.
A1  - Stein, Dan J.
A1  - Strengman, E.
A1  - Tischfield, Jay A.
A1  - Valencia Duarte, Ana V.
A1  - Vallada, Homero
A1  - Van Nieuwerburgh, Flip
A1  - Veenstra-VanderWeele, Jeremy
A1  - Walitza, Susanne
A1  - Wang, Ying
A1  - Wendland, Jens R.
A1  - Westenberg, Herman G. M.
A1  - Shugart, Yin Yao
A1  - Miguel, Euripedes C.
A1  - McMahon, William
A1  - Wagner, Michael
A1  - Nicolini, Humberto
A1  - Posthuma, Danielle
A1  - Hanna, Gregory L.
A1  - Heutink, Peter
A1  - Denys, Damiaan
A1  - Arnold, Paul D.
A1  - Oostra, Ben A.
A1  - Nestadt, Gerald
A1  - Freimer, Nelson B.
A1  - Pauls, David L.
A1  - Wray, Naomi R.
A1  - Stewart, S. Evelyn
A1  - Mathews, Carol A.
A1  - Knowles, James A.
A1  - Cox, Nancy J.
A1  - Scharf, Jeremiah M.
T1  - Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture
JF  - PLoS Genetics
N2  - 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.
KW  - TIC disorders
KW  - missing heritability
KW  - complex diseases
KW  - neuropsychiatric disorders
KW  - common SNPS
KW  - gilles
KW  - family
KW  - brain
KW  - expression
KW  - autism
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127377
SN  - 1553-7390
VL  - 9
IS  - 10
ER  - 
TY  - JOUR
A1  - Hudson, Lawrence N.
A1  - Newbold, Tim
A1  - Contu, Sara
A1  - Hill, Samantha L. L.
A1  - Lysenko, Igor
A1  - De Palma, Adriana
A1  - Phillips, Helen R. P.
A1  - Senior, Rebecca A.
A1  - Bennett, Dominic J.
A1  - Booth, Hollie
A1  - Choimes, Argyrios
A1  - Correia, David L. P.
A1  - Day, Julie
A1  - Echeverria-Londono, Susy
A1  - Garon, Morgan
A1  - Harrison, Michelle L. K.
A1  - Ingram, Daniel J.
A1  - Jung, Martin
A1  - Kemp, Victoria
A1  - Kirkpatrick, Lucinda
A1  - Martin, Callum D.
A1  - Pan, Yuan
A1  - White, Hannah J.
A1  - Aben, Job
A1  - Abrahamczyk, Stefan
A1  - Adum, Gilbert B.
A1  - Aguilar-Barquero, Virginia
A1  - Aizen, Marcelo
A1  - Ancrenaz, Marc
A1  - Arbelaez-Cortes, Enrique
A1  - Armbrecht, Inge
A1  - Azhar, Badrul
A1  - Azpiroz, Adrian B.
A1  - Baeten, Lander
A1  - Báldi, András
A1  - Banks, John E.
A1  - Barlow, Jos
A1  - Batáry, Péter
A1  - Bates, Adam J.
A1  - Bayne, Erin M.
A1  - Beja, Pedro
A1  - Berg, Ake
A1  - Berry, Nicholas J.
A1  - Bicknell, Jake E.
A1  - Bihn, Jochen H.
A1  - Böhning-Gaese, Katrin
A1  - Boekhout, Teun
A1  - Boutin, Celine
A1  - Bouyer, Jeremy
A1  - Brearley, Francis Q.
A1  - Brito, Isabel
A1  - Brunet, Jörg
A1  - Buczkowski, Grzegorz
A1  - Buscardo, Erika
A1  - Cabra-Garcia, Jimmy
A1  - Calvino-Cancela, Maria
A1  - Cameron, Sydney A.
A1  - Cancello, Eliana M.
A1  - Carrijo, Tiago F.
A1  - Carvalho, Anelena L.
A1  - Castro, Helena
A1  - Castro-Luna, Alejandro A.
A1  - Cerda, Rolando
A1  - Cerezo, Alexis
A1  - Chauvat, Matthieu
A1  - Clarke, Frank M.
A1  - Cleary, Daniel F. R.
A1  - Connop, Stuart P.
A1  - D'Aniello, Biagio
A1  - da Silva, Pedro Giovani
A1  - Darvill, Ben
A1  - Dauber, Jens
A1  - Dejean, Alain
A1  - Diekötter, Tim
A1  - Dominguez-Haydar, Yamileth
A1  - Dormann, Carsten F.
A1  - Dumont, Bertrand
A1  - Dures, Simon G.
A1  - Dynesius, Mats
A1  - Edenius, Lars
A1  - Elek, Zoltán
A1  - Entling, Martin H.
A1  - Farwig, Nina
A1  - Fayle, Tom M.
A1  - Felicioli, Antonio
A1  - Felton, Annika M.
A1  - Ficetola, Gentile F.
A1  - Filgueiras, Bruno K. C.
A1  - Fonte, Steve J.
A1  - Fraser, Lauchlan H.
A1  - Fukuda, Daisuke
A1  - Furlani, Dario
A1  - Ganzhorn, Jörg U.
A1  - Garden, Jenni G.
A1  - Gheler-Costa, Carla
A1  - Giordani, Paolo
A1  - Giordano, Simonetta
A1  - Gottschalk, Marco S.
A1  - Goulson, Dave
A1  - Gove, Aaron D.
A1  - Grogan, James
A1  - Hanley, Mick E.
A1  - Hanson, Thor
A1  - Hashim, Nor R.
A1  - Hawes, Joseph E.
A1  - Hébert, Christian
A1  - Helden, Alvin J.
A1  - Henden, John-André
A1  - Hernández, Lionel
A1  - Herzog, Felix
A1  - Higuera-Diaz, Diego
A1  - Hilje, Branko
A1  - Horgan, Finbarr G.
A1  - Horváth, Roland
A1  - Hylander, Kristoffer
A1  - Horváth, Roland
A1  - Isaacs-Cubides, Paola
A1  - Ishitani, Mashiro
A1  - Jacobs, Carmen T.
A1  - Jaramillo, Victor J.
A1  - Jauker, Birgit
A1  - Jonsell, Matts
A1  - Jung, Thomas S.
A1  - Kapoor, Vena
A1  - Kati, Vassiliki
A1  - Katovai, Eric
A1  - Kessler, Michael
A1  - Knop, Eva
A1  - Kolb, Annette
A1  - Körösi, Àdám
A1  - Lachat, Thibault
A1  - Lantschner, Victoria
A1  - Le Féon, Violette
A1  - LeBuhn, Gretchen
A1  - Légaré, Jean-Philippe
A1  - Letcher, Susan G.
A1  - Littlewood, Nick A.
A1  - López-Quintero, Carlos A.
A1  - Louhaichi, Mounir
A1  - Lövei, Gabor L.
A1  - Lucas-Borja, Manuel Esteban
A1  - Luja, Victor H.
A1  - Maeto, Kaoru
A1  - Magura, Tibor
A1  - Mallari, Neil Aldrin
A1  - Marin-Spiotta, Erika
A1  - Marhall, E. J. P.
A1  - Martínez, Eliana
A1  - Mayfield, Margaret M.
A1  - Mikusinski, Gregorz
A1  - Milder, Jeffery C.
A1  - Miller, James R.
A1  - Morales, Carolina L.
A1  - Muchane, Mary N.
A1  - Muchane, Muchai
A1  - Naidoo, Robin
A1  - Nakamura, Akihiro
A1  - Naoe, Shoji
A1  - Nates-Parra, Guiomar
A1  - Navarerete Gutierrez, Dario A.
A1  - Neuschulz, Eike L.
A1  - Noreika, Norbertas
A1  - Norfolk, Olivia
A1  - Noriega, Jorge Ari
A1  - Nöske, Nicole M.
A1  - O'Dea, Niall
A1  - Oduro, William
A1  - Ofori-Boateng, Caleb
A1  - Oke, Chris O.
A1  - Osgathorpe, Lynne M.
A1  - Paritsis, Juan
A1  - Parrah, Alejandro
A1  - Pelegrin, Nicolás
A1  - Peres, Carlos A.
A1  - Persson, Anna S.
A1  - Petanidou, Theodora
A1  - Phalan, Ben
A1  - Philips, T. Keith
A1  - Poveda, Katja
A1  - Power, Eileen F.
A1  - Presley, Steven J.
A1  - Proença, Vânia
A1  - Quaranta, Marino
A1  - Quintero, Carolina
A1  - Redpath-Downing, Nicola A.
A1  - Reid, J. Leighton
A1  - Reis, Yana T.
A1  - Ribeiro, Danilo B.
A1  - Richardson, Barbara A.
A1  - Richardson, Michael J.
A1  - Robles, Carolina A.
A1  - Römbke, Jörg
A1  - Romero-Duque, Luz Piedad
A1  - Rosselli, Loreta
A1  - Rossiter, Stephen J.
A1  - Roulston, T'ai H.
A1  - Rousseau, Laurent
A1  - Sadler, Jonathan P.
A1  - Sáfián, Szbolcs
A1  - Saldaña-Vásquez, Romeo A.
A1  - Samnegård, Ulrika
A1  - Schüepp, Christof
A1  - Schweiger, Oliver
A1  - Sedlock, Jodi L.
A1  - Shahabuddin, Ghazala
A1  - Sheil, Douglas
A1  - Silva, Fernando A. B.
A1  - Slade, Eleanor
A1  - Smith-Pardo, Allan H.
A1  - Sodhi, Navjot S.
A1  - Somarriba, Eduardo J.
A1  - Sosa, Ramón A.
A1  - Stout, Jane C.
A1  - Struebig, Matthew J.
A1  - Sung, Yik-Hei
A1  - Threlfall, Caragh G.
A1  - Tonietto, Rebecca
A1  - Tóthmérész, Béla
A1  - Tscharntke, Teja
A1  - Turner, Edgar C.
A1  - Tylianakis, Jason M.
A1  - Vanbergen, Adam J.
A1  - Vassilev, Kiril
A1  - Verboven, Hans A. F.
A1  - Vergara, Carlos H.
A1  - Vergara, Pablo M.
A1  - Verhulst, Jort
A1  - Walker, Tony R.
A1  - Wang, Yanping
A1  - Watling, James I.
A1  - Wells, Konstans
A1  - Williams, Christopher D.
A1  - Willig, Michael R.
A1  - Woinarski, John C. Z.
A1  - Wolf, Jan H. D.
A1  - Woodcock, Ben A.
A1  - Yu, Douglas W.
A1  - Zailsev, Andreys
A1  - Collen, Ben
A1  - Ewers, Rob M.
A1  - Mace, Georgina M.
A1  - Purves, Drew W.
A1  - Scharlemann, Jörn P. W.
A1  - Pervis, Andy
T1  - The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts
JF  - Ecology and Evolution
N2  - Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
KW  - urban-rural gradient
KW  - instensively managed farmland
KW  - Mexican coffee plantations
KW  - Bombus Spp. Hymenoptera
KW  - bumblebee nest density
KW  - data sharing
KW  - land use
KW  - habitat destruction
KW  - global change
KW  - land-use change
KW  - plant community composition
KW  - Northeastern Costa Rica
KW  - dung beetle coleoptera
KW  - bird species richness
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114425
VL  - 4
IS  - 24
ER  - 
TY  - JOUR
A1  - Couch, Fergus J.
A1  - Wang, Xianshu
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Olswold, Curtis
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Fredericksen, Zachary
A1  - Barrowdale, Daniel
A1  - Dennis, Joe
A1  - Gaudet, Mia M.
A1  - Dicks, Ed
A1  - Kosel, Matthew
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Lee, Adam
A1  - Bacot, Françios
A1  - Vincent, Daniel
A1  - Hogervorst, Frans B. L.
A1  - Peock, Susan
A1  - Stoppa-Lyonnet, Dominique
A1  - Jakubowska, Anna
A1  - Radice, Paolo
A1  - Schmutzler, Rita Katharina
A1  - Domchek, Susan M.
A1  - Piedmonte, Marion
A1  - Singer, Christian F.
A1  - Friedman, Eitan
A1  - Thomassen, Mads
A1  - Hansen, Thomas V. O.
A1  - Neuhausen, Susan L.
A1  - Szabo, Csilla I.
A1  - Blanco, Ingnacio
A1  - Greene, Mark H.
A1  - Karlan, Beth Y.
A1  - Garber, Judy
A1  - Phelan, Catherine M.
A1  - Weitzel, Jeffrey N.
A1  - Montagna, Marco
A1  - Olah, Edith
A1  - Andrulis, Irene L.
A1  - Godwin, Andrew K.
A1  - Yannoukakos, Drakoulis
A1  - Goldgar, David E.
A1  - Caldes, Trinidad
A1  - Nevanlinna, Heli
A1  - Osorio, Ana
A1  - Terry, Mary Beth
A1  - Daly, Mary B.
A1  - van Rensburg, Elisabeth J.
A1  - Hamann, Ute
A1  - Ramus, Susan J.
A1  - Toland, Amanda Ewart
A1  - Caligo, Maria A.
A1  - Olopade, Olufunmilayo I.
A1  - Tung, Nadine
A1  - Claes, Kathleen
A1  - Beattie, Mary S.
A1  - Southey, Melissa C.
A1  - Imyanitov, Evgeny N.
A1  - Tischkowitz, Marc
A1  - Janavicius, Ramunas
A1  - John, Esther M.
A1  - Kwong, Ava
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Balmaña, Judith
A1  - Barkardottir, Rosa B.
A1  - Arun, Banu K.
A1  - Rennert, Gad
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Campbell, Ian
A1  - van der Hout, Annemarie H.
A1  - van Deurzen, Carolien H. M.
A1  - Seynaeve, Caroline
A1  - Garcia, Encarna B. Gómez
A1  - van Leeuwen, Flora E.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Gille, Johannes J. P.
A1  - Ausems, Magreet G. E. M.
A1  - Blok, Marinus J.
A1  - Ligtenberg, Marjolinjin J. L.
A1  - Rookus, Matti A.
A1  - Devilee, Peter
A1  - Verhoef, Senno
A1  - van Os, Theo A. M.
A1  - Wijnen, Juul T.
A1  - Frost, Debra
A1  - Ellis, Steve
A1  - Fineberg, Elena
A1  - Platte, Radke
A1  - Evans, D. Gareth
A1  - Izatt, Luise
A1  - Eeles, Rosalind A.
A1  - Adlard, Julian
A1  - Eccles, Diana M.
A1  - Cook, Jackie
A1  - Brewer, Carole
A1  - Douglas, Fiona
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Side, Lucy E.
A1  - Donaldson, Alan
A1  - Houghton, Catherine
A1  - Rogers, Mark T.
A1  - Dorkins, Huw
A1  - Eason, Jacqueline
A1  - Gregory, Helen
A1  - McCann, Emma
A1  - Murray, Alex
A1  - Calender, Alain
A1  - Hardouin, Agnès
A1  - Berthet, Pascaline
A1  - Delnatte, Capucine
A1  - Nogues, Catherine
A1  - Lasset, Christine
A1  - Houdayer, Claude
A1  - Leroux,, Dominique
A1  - Rouleau, Etienne
A1  - Prieur, Fabienne
A1  - Damiola, Francesca
A1  - Sobol, Hagay
A1  - Coupier, Isabelle
A1  - Venat-Bouvet, Laurence
A1  - Castera, Laurent
A1  - Gauthier-Villars, Marion
A1  - Léoné, Mélanie
A1  - Pujol, Pascal
A1  - Mazoyer, Sylvie
A1  - Bignon, Yves-Jean
A1  - Zlowocka-Perlowska, Elzbieta
A1  - Gronwald, Jacek
A1  - Lubinski,, Jan
A1  - Durda, Katarzyna
A1  - Jaworska, Katarzyna
A1  - Huzarski, Tomasz
A1  - Spurdle, Amanda B.
A1  - Viel, Alessandra
A1  - Peissel, Bernhard
A1  - Bonanni, Bernardo
A1  - Melloni, Guilia
A1  - Ottini, Laura
A1  - Papi, Laura
A1  - Varesco, Liliana
A1  - Tibiletti, Maria Grazia
A1  - Peterlongo, Paolo
A1  - Volorio, Sara
A1  - Manoukian, Siranoush
A1  - Pensotti, Valeria
A1  - Arnold, Norbert
A1  - Engel, Christoph
A1  - Deissler, Helmut
A1  - Gadzicki, Dorothea
A1  - Gehrig, Andrea
A1  - Kast, Karin
A1  - Rhiem, Kerstin
A1  - Meindl, Alfons
A1  - Niederacher, Dieter
A1  - Ditsch, Nina
A1  - Plendl, Hansjoerg
A1  - Preisler-Adams, Sabine
A1  - Engert, Stefanie
A1  - Sutter, Christian
A1  - Varon-Mateeva, Raymenda
A1  - Wappenschmidt, Barbara
A1  - Weber, Bernhard H. F.
A1  - Arver, Brita
A1  - Stenmark-Askmalm, Marie
A1  - Loman, Niklas
A1  - Rosenquist, Richard
A1  - Einbeigi, Zakaria
A1  - Nathanson, Katherine L.
A1  - Rebbeck, Timothy R.
A1  - Blank, Stephanie V.
A1  - Cohn, David E.
A1  - Rodriguez, Gustavo C.
A1  - Small, Laurie
A1  - Friedlander, Michael
A1  - Bae-Jump, Victoria L.
A1  - Fink-Retter, Anneliese
A1  - Rappaport, Christine
A1  - Gschwantler-Kaulich, Daphne
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Lindor, Noralane M.
A1  - Kaufman, Bella
A1  - Paluch, Shani Shimon
A1  - Laitman, Yael
A1  - Skytte, Anne-Bine
A1  - Gerdes, Anne-Marie
A1  - Pedersen, Inge Sokilde
A1  - Moeller, Sanne Traasdahl
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Vijai, Joseph
A1  - Sarrel, Kara
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Ozcelik, Hilmi
A1  - Ejlertsen, Bent
A1  - Nielsen, Finn C.
A1  - Jønson, Lars
A1  - Andersen, Mette K.
A1  - Ding, Yuan Chun
A1  - Steele, Linda
A1  - Foretova, Lenka
A1  - Teulé, Alex
A1  - Lazaro, Conxi
A1  - Brunet, Joan
A1  - Pujana, Miquel Angel
A1  - Mai, Phuong L.
A1  - Loud, Jennifer T.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - Orsulic, Sandra
A1  - Narod, Steven A.
A1  - Herzog, Josef
A1  - Sand, Sharon R.
A1  - Tognazzo, Silvia
A1  - Agata, Simona
A1  - Vaszko, Tibor
A1  - Weaver, Joellen
A1  - Stravropoulou, Alexandra V.
A1  - Buys, Saundra S.
A1  - Romero, Atocha
A1  - de la Hoya, Miguel
A1  - Aittomäki, Kristiina
A1  - Muranen, Taru A.
A1  - Duran, Mercedes
A1  - Chung, Wendy K.
A1  - Lasa, Adriana
A1  - Dorfling, Cecilia M.
A1  - Miron, Alexander
A1  - Benitez, Javier
A1  - Senter, Leigha
A1  - Huo, Dezheng
A1  - Chan, Salina B.
A1  - Sokolenko, Anna P.
A1  - Chiquette, Jocelyne
A1  - Tihomirova, Laima
A1  - Friebel, Tara M.
A1  - Agnarsson, Bjarne A.
A1  - Lu, Karen H.
A1  - Lejbkowicz, Flavio
A1  - James, Paul A.
A1  - Hall, Per
A1  - Dunning, Alison M.
A1  - Tessier, Daniel
A1  - Cunningham, Julie
A1  - Slager, Susan L.
A1  - Chen, Wang
A1  - Hart, Steven
A1  - Stevens, Kristen
A1  - Simard, Jacques
A1  - Pastinen, Tomi
A1  - Pankratz, Vernon S.
A1  - Offit, Kenneth
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
T1  - Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
JF  - PLOS Genetics
N2  - 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.
KW  - common variants
KW  - susceptibility alleles
KW  - genetic variants
KW  - modifiers
KW  - ZNF365
KW  - investigators
KW  - population
KW  - consortium
KW  - selection
KW  - subtypes
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127947
SN  - 1553-7404
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Antoniou, Antonis C.
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Beesley, Jonathan
A1  - Chen, Xiaoqing
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Barrowdale, Daniel
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Caligo, Maria A.
A1  - Loman, Niklas
A1  - Harbst, Katja
A1  - Lindblom, Annika
A1  - Arver, Brita
A1  - Rosenquist, Richard
A1  - Karlsson, Per
A1  - Nathanson, Kate
A1  - Domchek, Susan
A1  - Rebbeck, Tim
A1  - Jakubowska, Anna
A1  - Lubinski, Jan
A1  - Jaworska, Katarzyna
A1  - Durda, Katarzyna
A1  - Zlowowcka-Perłowska, Elżbieta
A1  - Osorio, Ana
A1  - Durán, Mercedes
A1  - Andrés, Raquel
A1  - Benítez, Javier
A1  - Hamann, Ute
A1  - Hogervorst, Frans B.
A1  - van Os, Theo A.
A1  - Verhoef, Senno
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Wijnen, Juul
A1  - Garcia, Encarna B. Gómez
A1  - Ligtenberg, Marjolijn J.
A1  - Kriege, Mieke
A1  - Collée, Margriet
A1  - Ausems, Margreet G. E. M.
A1  - Oosterwijk, Jan C.
A1  - Peock, Susan
A1  - Frost, Debra
A1  - Ellis, Steve D.
A1  - Platte, Radka
A1  - Fineberg, Elena
A1  - Evans, D. Gareth
A1  - Lalloo, Fiona
A1  - Jacobs, Chris
A1  - Eeles, Ros
A1  - Adlard, Julian
A1  - Davidson, Rosemarie
A1  - Cole, Trevor
A1  - Cook, Jackie
A1  - Paterson, Joan
A1  - Douglas, Fiona
A1  - Brewer, Carole
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Walker, Lisa
A1  - Rogers, Mark T.
A1  - Donaldson, Alan
A1  - Dorkins, Huw
A1  - Godwin, Andrew K.
A1  - Bove, Betsy
A1  - Stoppa-Lyonnet, Dominique
A1  - Houdayer, Claude
A1  - Buecher, Bruno
A1  - de Pauw, Antoine
A1  - Mazoyer, Sylvie
A1  - Calender, Alain
A1  - Léoné, Mélanie
A1  - Bressac-de Paillerets, Brigitte
A1  - Caron, Olivier
A1  - Sobol, Hagay
A1  - Frenay, Marc
A1  - Prieur, Fabienne
A1  - Ferrer, Sandra Fert
A1  - Mortemousque, Isabelle
A1  - Buys, Saundra
A1  - Daly, Mary
A1  - Miron, Alexander
A1  - Terry, Mary Beth
A1  - Hopper, John L.
A1  - John, Esther M.
A1  - Southey, Melissa
A1  - Goldgar, David
A1  - Singer, Christian F.
A1  - Fink-Retter, Anneliese
A1  - Muy-Kheng, Tea
A1  - Geschwantler Kaulich, Daphne
A1  - Hansen, Thomas V. O.
A1  - Nielsen, Finn C.
A1  - Barkardottir, Rosa B.
A1  - Gaudet, Mia
A1  - Kirchhoff, Tomas
A1  - Joseph, Vijai
A1  - Dutra-Clarke, Ana
A1  - Offit, Kenneth
A1  - Piedmonte, Marion
A1  - Kirk, Judy
A1  - Cohn, David
A1  - Hurteau, Jean
A1  - Byron, John
A1  - Fiorica, James
A1  - Toland, Amanda E.
A1  - Montagna, Marco
A1  - Oliani, Cristina
A1  - Imyanitov, Evgeny
A1  - Isaacs, Claudine
A1  - Tihomirova, Laima
A1  - Blanco, Ignacio
A1  - Lazaro, Conxi
A1  - Teulé, Alex
A1  - Del Valle, J.
A1  - Gayther, Simon A.
A1  - Odunsi, Kunle
A1  - Gross, Jenny
A1  - Karlan, Beth Y.
A1  - Olah, Edith
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Beattie, Mary S.
A1  - Dorfling, Cecelia M.
A1  - Jansen van Rensburg, Elizabeth
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Schmutzler, Rita K.
A1  - Wappenschmidt, Barbara
A1  - Engel, Christoph
A1  - Meindl, Alfons
A1  - Ditsch, Nina
A1  - Arnold, Norbert
A1  - Heidemann, Simone
A1  - Niederacher, Dieter
A1  - Preisler-Adams, Sabine
A1  - Gadzicki, Dorothea
A1  - Varon-Mateeva, Raymonda
A1  - Deissler, Helmut
A1  - Gehrig, Andrea
A1  - Sutter, Christian
A1  - Kast, Karin
A1  - Fiebig, Britta
A1  - Schäfer, Dieter
A1  - Caldes, Trinidad
A1  - de la Hoya, Miguel
A1  - Nevanlinna, Heli
A1  - Muranen, Taru A.
A1  - Lespérance, Bernard
A1  - Spurdle, Amanda B.
A1  - Neuhausen, Susan L.
A1  - Ding, Yuan C.
A1  - Wang, Xianshu
A1  - Fredericksen, Zachary
A1  - Pankratz, Vernon S.
A1  - Lindor, Noralane M.
A1  - Peterlongo, Paulo
A1  - Manoukian, Siranoush
A1  - Peissel, Bernard
A1  - Zaffaroni, Daniela
A1  - Bonanni, Bernardo
A1  - Bernard, Loris
A1  - Dolcetti, Riccardo
A1  - Papi, Laura
A1  - Ottini, Laura
A1  - Radice, Paolo
A1  - Greene, Mark H.
A1  - Loud, Jennifer T.
A1  - Andrulis, Irene L.
A1  - Ozcelik, Hilmi
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Thomassen, Mads
A1  - Gerdes, Anne-Marie
A1  - Jensen, Uffe B.
A1  - Skytte, Anne-Bine
A1  - Kruse, Torben A.
A1  - Chenevix-Trench, Georgia
A1  - Couch, Fergus J.
A1  - Simard, Jacques
A1  - Easton, Douglas F.
T1  - Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
JF  - Breast Cancer Research
N2  - 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.
KW  - investigators
KW  - genetic modifiers
KW  - mammographic density
KW  - susceptibility loci
KW  - ovarian cancer
KW  - hormone-related protein
KW  - genome-wide association
KW  - tumor subtypes
KW  - alleles
KW  - consortium
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130449
VL  - 14
IS  - R33
ER  - 
TY  - JOUR
A1  - Blein, Sophie
A1  - Bardel, Claire
A1  - Danjean, Vincent
A1  - McGuffog, Lesley
A1  - Healay, Sue
A1  - Barrowdale, Daniel
A1  - Lee, Andrew
A1  - Dennis, Joe
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Terry, Mary Beth
A1  - Chung, Wendy K.
A1  - Goldgar, David E.
A1  - Buys, Saundra S.
A1  - Janavicius, Ramunas
A1  - Tihomirova, Laima
A1  - Tung, Nadine
A1  - Dorfling, Cecilia M.
A1  - van Rensburg, Elizabeth J.
A1  - Neuhausen, Susan L.
A1  - Ding, Yuan Chun
A1  - Gerdes, Anne-Marie
A1  - Ejlertsen, Bent
A1  - Nielsen, Finn C.
A1  - Hansen, Thomas V. O.
A1  - Osorio, Ana
A1  - Benitez, Javier
A1  - Andreas Conejero, Raquel
A1  - Segota, Ena
A1  - Weitzel, Jeffrey N.
A1  - Thelander, Margo
A1  - Peterlongo, Paolo
A1  - Radice, Paolo
A1  - Pensotti, Valeria
A1  - Dolcetti, Riccardo
A1  - Bonanni, Bernardo
A1  - Peissel, Bernard
A1  - Zaffaroni, Daniela
A1  - Scuvera, Giulietta
A1  - Manoukian, Siranoush
A1  - Varesco, Liliana
A1  - Capone, Gabriele L.
A1  - Papi, Laura
A1  - Ottini, Laura
A1  - Yannoukakos, Drakoulis
A1  - Konstantopoulou, Irene
A1  - Garber, Judy
A1  - Hamann, Ute
A1  - Donaldson, Alan
A1  - Brady, Angela
A1  - Brewer, Carole
A1  - Foo, Claire
A1  - Evans, D. Gareth
A1  - Frost, Debra
A1  - Eccles, Diana
A1  - Douglas, Fiona
A1  - Cook, Jackie
A1  - Adlard, Julian
A1  - Barwell, Julian
A1  - Walker, Lisa
A1  - Izatt, Louise
A1  - Side, Lucy E.
A1  - Kennedy, M. John
A1  - Tischkowitz, Marc
A1  - Rogers, Mark T.
A1  - Porteous, Mary E.
A1  - Morrison, Patrick J.
A1  - Platte, Radka
A1  - Eeles, Ros
A1  - Davidson, Rosemarie
A1  - Hodgson, Shirley
A1  - Cole, Trevor
A1  - Godwin, Andrew K
A1  - Isaacs, Claudine
A1  - Claes, Kathleen
A1  - De Leeneer, Kim
A1  - Meindl, Alfons
A1  - Gehrig, Andrea
A1  - Wappenschmidt, Barbara
A1  - Sutter, Christian
A1  - Engel, Christoph
A1  - Niederacher, Dieter
A1  - Steinemann, Doris
A1  - Plendl, Hansjoerg
A1  - Kast, Karin
A1  - Rhiem, Kerstin
A1  - Ditsch, Nina
A1  - Arnold, Norbert
A1  - Varon-Mateeva, Raymonda
A1  - Schmutzler, Rita K.
A1  - Preisler-Adams, Sabine
A1  - Markov, Nadja Bogdanova
A1  - Wang-Gohrke, Shan
A1  - de Pauw, Antoine
A1  - Lefol, Cedrick
A1  - Lasset, Christine
A1  - Leroux, Dominique
A1  - Rouleau, Etienne
A1  - Damiola, Francesca
A1  - Dreyfus, Helene
A1  - Barjhoux, Laure
A1  - Golmard, Lisa
A1  - Uhrhammer, Nancy
A1  - Bonadona, Valerie
A1  - Sornin, Valerie
A1  - Bignon, Yves-Jean
A1  - Carter, Jonathan
A1  - Van Le, Linda
A1  - Piedmonte, Marion
A1  - DiSilvestro, Paul A.
A1  - de la Hoya, Miguel
A1  - Caldes, Trinidad
A1  - Nevanlinna, Heli
A1  - Aittomäki, Kristiina
A1  - Jager, Agnes
A1  - van den Ouweland, Ans M. W.
A1  - Kets, Carolien M.
A1  - Aalfs, Cora M.
A1  - van Leeuwen, Flora E.
A1  - Hogervorst, Frans B. L.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Oosterwijk, Jan C.
A1  - van Roozendaal, Kees E. P.
A1  - Rookus, Matti A.
A1  - Devilee, Peter
A1  - van der Luijt, Rob B.
A1  - Olah, Edith
A1  - Diez, Orland
A1  - Teule, Alex
A1  - Lazaro, Conxi
A1  - Blanco, Ignacio
A1  - Del Valle, Jesus
A1  - Jakubowska, Anna
A1  - Sukiennicki, Grzegorz
A1  - Gronwald, Jacek
A1  - Spurdle, Amanda B.
A1  - Foulkes, William
A1  - Olswold, Curtis
A1  - Lindor, Noralene M.
A1  - Pankratz, Vernon S.
A1  - Szabo, Csilla I.
A1  - Lincoln, Anne
A1  - Jacobs, Lauren
A1  - Corines, Marina
A1  - Robson, Mark
A1  - Vijai, Joseph
A1  - Berger, Andreas
A1  - Fink-Retter, Anneliese
A1  - Singer, Christian F.
A1  - Rappaport, Christine
A1  - Geschwantler Kaulich, Daphne
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Greene, Mark H.
A1  - Mai, Phuong L.
A1  - Rennert, Gad
A1  - Imyanitov, Evgeny N.
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Andrulis, Irene L.
A1  - Tchatchou, Andrine
A1  - Toland, Amanda Ewart
A1  - Pedersen, Inge Sokilde
A1  - Thomassen, Mads
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Caligo, Maria A.
A1  - Friedman, Eitan
A1  - Zidan, Jamal
A1  - Laitman, Yael
A1  - Lindblom, Annika
A1  - Melin, Beatrice
A1  - Arver, Brita
A1  - Loman, Niklas
A1  - Rosenquist, Richard
A1  - Olopade, Olufunmilayo I.
A1  - Nussbaum, Robert L.
A1  - Ramus, Susan J.
A1  - Nathanson, Katherine L.
A1  - Domchek, Susan M.
A1  - Rebbeck, Timothy R.
A1  - Arun, Banu K.
A1  - Mitchell, Gillian
A1  - Karlan, Bethy Y.
A1  - Lester, Jenny
A1  - Orsulic, Sandra
A1  - Stoppa-Lyonnet, Dominique
A1  - Thomas, Gilles
A1  - Simard, Jacques
A1  - Couch, Fergus J.
A1  - Offit, Kenenth
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
A1  - Mazoyer, Sylvie
A1  - Phelan, Catherine M.
A1  - Sinilnikova, Olga M.
A1  - Cox, David G.
T1  - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
JF  - Breast Cancer Research
N2  - 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.
KW  - single-nucleotide polymorphisms
KW  - genetic modifiers
KW  - oxidative stress
KW  - consortium
KW  - multiple diseases
KW  - DNA
KW  - haplogroups
KW  - susceptibility
KW  - Ovarian
KW  - variants
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145458
VL  - 17
IS  - 61
ER  - 
TY  - JOUR
A1  - Blanco, Ignacio
A1  - Kuchenbaecker, Karoline
A1  - Cuadras, Daniel
A1  - Wang, Xianshu
A1  - Barrowdale, Daniel
A1  - Ruiz de Garibay, Gorka
A1  - Librado, Pablo
A1  - Sanchez-Gracia, Alejandro
A1  - Rozas, Julio
A1  - Bonifaci, Núria
A1  - McGuffog, Lesley
A1  - Pankratz, Vernon S.
A1  - Islam, Abul
A1  - Mateo, Francesca
A1  - Berenguer, Antoni
A1  - Petit, Anna
A1  - Català, Isabel
A1  - Brunet, Joan
A1  - Feliubadaló, Lidia
A1  - Tornero, Eva
A1  - Benítez, Javier
A1  - Osorio, Ana
A1  - Ramón y Cajal, Teresa
A1  - Nevanlinna, Heli
A1  - Aittomäki, Kristina
A1  - Arun, Banu K.
A1  - Toland, Amanda E.
A1  - Karlan, Beth Y.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - Greene, Mark H.
A1  - Mai, Phuong L.
A1  - Nussbaum, Robert L.
A1  - Andrulis, Irene L.
A1  - Domchek, Susan M.
A1  - Nathanson, Katherine L.
A1  - Rebbeck, Timothy R.
A1  - Barkardottir, Rosa B.
A1  - Jakubowska, Anna
A1  - Lubinski, Jan
A1  - Durda, Katarzyna
A1  - Jaworska-Bieniek, Katarzyna
A1  - Claes, Kathleen
A1  - Van Maerken, Tom
A1  - Díez, Orland
A1  - Hansen, Thomas V.
A1  - Jønson, Lars
A1  - Gerdes, Anne-Marie
A1  - Ejlertsen, Bent
A1  - De la Hoya, Miguel
A1  - Caldés, Trinidad
A1  - Dunning, Alison M.
A1  - Oliver, Clare
A1  - Fineberg, Elena
A1  - Cook, Margaret
A1  - Peock, Susan
A1  - McCann, Emma
A1  - Murray, Alex
A1  - Jacobs, Chris
A1  - Pichert, Gabriella
A1  - Lalloo, Fiona
A1  - Chu, Carol
A1  - Dorkins, Huw
A1  - Paterson, Joan
A1  - Ong, Kai-Ren
A1  - Teixeira, Manuel R.
A1  - Hogervorst, Frans B. L.
A1  - Van der Hout, Annemarie H.
A1  - Seynaeve, Caroline
A1  - Van der Luijt, Rob B.
A1  - Ligtenberg, Marjolijn J. L.
A1  - Devilee, Peter
A1  - Wijnen, Juul T.
A1  - Rookus, Matti A.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Blok, Marinus J.
A1  - Van den Ouweland, Ans M. W.
A1  - Aalfs, Cora M.
A1  - Rodriguez, Gustavo C.
A1  - Phillips, Kelly-Anne A.
A1  - Piedmonte, Marion
A1  - Nerenstone, Stacy R.
A1  - Bae-Jump, Victoria L.
A1  - O'Malley, David M.
A1  - Schmutzler, Rita K.
A1  - Wappenschmidt, Barbara
A1  - Rhiem, Kerstin
A1  - Engel, Christoph
A1  - Meindl, Alfons
A1  - Ditsch, Nina
A1  - Arnold, Norbert
A1  - Plendl, Hansjoerg J.
A1  - Niederacher, Dieter
A1  - Sutter, Christian
A1  - Wang-Gohrke, Shan
A1  - Steinemann, Doris
A1  - Preisler-Adams, Sabine
A1  - Kast, Karin
A1  - Varon-Mateeva, Raymonda
A1  - Gehrig, Andrea
A1  - Bojesen, Anders
A1  - Pedersen, Inge Sokilde
A1  - Sunde, Lone
A1  - Birk Jensen, Uffe
A1  - Thomassen, Mads
A1  - Kruse, Torben A.
A1  - Foretova, Lenka
A1  - Peterlongo, Paolo
A1  - Bernard, Loris
A1  - Peissel, Bernard
A1  - Scuvera, Giulietta
A1  - Manoukian, Siranoush
A1  - Radice, Paolo
A1  - Ottini, Laura
A1  - Montagna, Marco
A1  - Agata, Simona
A1  - Maugard, Christine
A1  - Simard, Jacques
A1  - Soucy, Penny
A1  - Berger, Andreas
A1  - Fink-Retter, Anneliese
A1  - Singer, Christian F.
A1  - Rappaport, Christine
A1  - Geschwantler-Kaulich, Daphne
A1  - Tea, Muy-Kheng
A1  - Pfeiler, Georg
A1  - John, Esther M.
A1  - Miron, Alex
A1  - Neuhausen, Susan L.
A1  - Terry, Mary Beth
A1  - Chung, Wendy K.
A1  - Daly, Mary B.
A1  - Goldgar, David E.
A1  - Janavicius, Ramunas
A1  - Dorfling, Cecilia M.
A1  - Van Rensburg, Elisabeth J.
A1  - Fostira, Florentia
A1  - Konstantopoulou, Irene
A1  - Garber, Judy
A1  - Godwin, Andrew K.
A1  - Olah, Edith
A1  - Narod, Steven A.
A1  - Rennert, Gad
A1  - Paluch, Shani Shimon
A1  - Laitman, Yael
A1  - Friedman, Eitan
A1  - Liljegren, Annelie
A1  - Rantala, Johanna
A1  - Stenmark-Askmalm, Marie
A1  - Loman, Niklas
A1  - Imyanitov, Evgeny N.
A1  - Hamann, Ute
A1  - Spurdle, Amanda B.
A1  - Healey, Sue
A1  - Weitzel, Jeffrey N.
A1  - Herzog, Josef
A1  - Margileth, David
A1  - Gorrini, Chiara
A1  - Esteller, Manel
A1  - Gómez, Antonio
A1  - Sayols, Sergi
A1  - Vidal, Enrique
A1  - Heyn, Holger
A1  - Stoppa-Lyonnet, Dominique
A1  - Léoné, Melanie
A1  - Barjhoux, Laure
A1  - Fassy-Colcombet, Marion
A1  - Pauw, Antoine de
A1  - Lasset, Christine
A1  - Fert Ferrer, Sandra
A1  - Castera, Laurent
A1  - Berthet, Pascaline
A1  - Cornelis, François
A1  - Bignon, Yves-Jean
A1  - Damiola, Francesca
A1  - Mazoyer, Sylvie
A1  - Sinilnikova, Olga M.
A1  - Maxwell, Christopher A.
A1  - Vijai, Joseph
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Corines, Marina J.
A1  - Villano, Danylko
A1  - Cunningham, Julie
A1  - Lee, Adam
A1  - Lindor, Noralane
A1  - Lázaro, Conxi
A1  - Easton, Douglas F.
A1  - Offit, Kenneth
A1  - Chenevix-Trench, Georgia
A1  - Couch, Fergus J.
A1  - Antoniou, Antonis C.
A1  - Pujana, Miguel Angel
T1  - Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers
JF  - PLoS ONE
N2  - 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.
KW  - genetic interaction networks
KW  - genome-wide association
KW  - expression signature
KW  - susceptibility loci
KW  - survival
KW  - modifiers
KW  - polymorphism
KW  - cell
KW  - chip-seq
KW  - elements
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143469
VL  - 10
IS  - 4
ER  - 
TY  - THES
A1  - Vona, Barbara C.
T1  - Molecular Characterization of Genes Involved in Hearing Loss
T1  - Molekulare Charakterisierung der in Hörstörungen involvierten Genen
N2  - The auditory system is an exquisitely complex sensory organ dependent upon the synchronization of numerous processes for proper function. The molecular characterization of hereditary hearing loss is complicated by extreme genetic heterogeneity, wherein hundreds of genes dispersed genome-wide play a central and irreplaceable role in normal hearing function. The present study explores this area on a genome-wide and single gene basis for the detection of genetic mutations playing critical roles in human hearing.
This work initiated with a high resolution SNP array study involving 109 individuals. A 6.9 Mb heterozygous deletion on chromosome 4q35.1q35.2 was identified in a syndromic patient that was in agreement with a chromosome 4q deletion syndrome diagnosis. A 99.9 kb heterozygous deletion of exons 58-64 in USH2A was identified in one patient. Two homozygous deletions and five heterozygous deletions in STRC (DFNB16) were also detected. The homozygous deletions alone were enough to resolve the hearing impairment in the two patients. A Sanger sequencing assay was developed to exclude a pseudogene with a high percentage sequence identity to STRC from the analysis, which further solved three of the six heterozygous deletion patients with the hemizygous, in silico predicted pathogenic mutations c.2726A>T (p.H909L), c.4918C>T (p.L1640F), and c.4402C>T (p.R1468X). A single patient who was copy neutral for STRC and without pathogenic copy number variations had compound heterozygous mutations [c. 2303_2313+1del12 (p.G768Vfs*77) and c.5125A>G (p.T1709A)] in STRC. It has been shown that STRC has been previously underestimated as a hearing loss gene. One additional patient is described who does not have pathogenic copy number variation but is the only affected member of his family having hearing loss with a paternally segregating translocation t(10;15)(q26.13;q21.1). 
Twenty-four patients without chromosomal aberrations and the above described patient with an USH2A heterozygous deletion were subjected to a targeted hearing loss gene next generation sequencing panel consisting of either 80 or 129 hearing-relevant genes. The patient having the USH2A heterozygous deletion also disclosed a second mutation in this gene [c.2276G>T (p.C759F)]. This compound heterozygous mutation is the most likely cause of hearing loss in this patient. Nine mutations in genes conferring autosomal dominant hearing loss [ACTG1 (DFNA20/26); CCDC50 (DFNA44); EYA4 (DFNA10); GRHL2 (DFNA28); MYH14 (DFNA4A); MYO6 (DFNA22); TCF21 and twice in MYO1A (DFNA48)] and four genes causing autosomal recessive hearing loss were detected [GJB2 (DFNB1A); MYO7A (DFNB2); MYO15A (DFNB3), and USH2A]. Nine normal hearing controls were also included. Statistical significance was achieved comparing controls and patients that revealed an excess of mutations in the hearing loss patients compared to the control group. The family with the GRHL2 c.1258-1G>A mutation is only the second family published worldwide with a mutation described in this gene to date, supporting the initial claim of this gene causing DFNA28 hearing loss. Audiogram analysis of five affected family members uncovered the progressive nature of DFNA28 hearing impairment. Regression analysis predicted the annual threshold deterioration in each of the five family members with multiple audiograms available over a number of years.
N2  - Das Gehör als komplexes Sinnesorgan ist für eine einwandfreie Funktion abhängig von der Synchronisation zahlreicher Prozesse. Durch die extreme genetische Heterogenität wird die molekulare Charakterisierung einer erblich bedingten Schwerhörigkeit erschwert, da hunderte genomweit verteilter Gene eine zentrale und unersetzliche Rolle beim Hören spielen. Die vorliegende Studie untersucht dieses Forschungsgebiet auf genomweiter Ebene und auf der Basis von Einzelgenen, um genetische Mutationen zu ermitteln, die eine entscheidende Rolle bei der menschlichen auditiven Wahrnehmung besitzen. 
Diese Arbeit beginnt mit einer Studie an 109 Personen unter Zuhilfenahme von hochauflösenden SNP-Arrays. In dieser Studie wurde eine 6,9 Mb heterozygote Deletion auf Chromosom 4q35.1q35.2 bei einem syndromalen Patienten identifiziert, die eine Übereinstimmung mit einem Chromosom 4q-Deletionssyndrom aufwies. Bei einem weiteren Patienten wurde eine 99,9 kb heterozygote Deletion der Exons 58-64 in USH2A nachgewiesen. Zwei homozygote Deletionen und fünf heterozygote Deletionen in STRC (DFNB16) wurden ebenfalls detektiert. Die homozygoten Deletionen waren ausreichend, um die Schwerhörigkeit bei beiden Patienten zu klären. Ein Sanger-Sequenzierungs-Assay wurde entwickelt, um ein Pseudogen mit einer hohen prozentualen Sequenzidentität zu STRC von der Analyse auszuschließen. Dadurch konnten drei der sechs heterozygoten Deletionspatienten mit hemizygot in silico vorhergesagten pathogenen Mutationen, c.2726A>T (p.H909L), c.4918 C>T (p.L1640F) und c.4402C>T (p.R1468X), aufgeklärt werden. Ein Patient, der eine kopieneutrale STRC Variation und keine pathogenen Kopienzahlvariationen besaß, zeigte eine compound heterozygote Mutation [c.2303_2313+1del12 (p.G768Vfs*77) und c.5125A>G (p.T1709A)] in STRC. Es wurde gezeigt, daß die Beurteilung von STRC als Hörstörungsgen bisher unterschätzt wurde. Zusätzlich wird ein Patient beschrieben, der keine pathogenen Kopienzahlvariationen aufwies, aber das einzige Familienmitglied mit einer Schwerhörigkeit und einer paternalen segregierten Translokation t(10;15)(q26.13;q21.1) war. 
Vierundzwanzig Patienten ohne Chromosomenstörungen und der oben beschriebene Patient mit einer USH2A heterozygoten Deletion wurden mit einem Next Generation Sequencing Panel bestehend aus entweder 80 oder 129 für das Hören relevanter Gene untersucht. Der Patient mit einer USH2A heterozygoten Deletion zeigte eine zweite Mutation in diesem Gen [c.2276G>T (p.C759F)]. Diese compound heterozygote Mutation ist die wahrscheinlichste Ursache für die Schwerhörigkeit des Patienten. Neun Mutationen in Genen, die zu einem autosomal dominanten Hörverlust führen [ACTG1 (DFNA20/26); CCDC50 (DFNA44); EYA4 (DFNA10); GRHL2 (DFNA28); MYH14 (DFNA4A); MYO6 (DFNA22); TCF21], sowie zwei MYO1A (DFNA48) Mutationen und Mutationen in vier weiteren Genen, verantwortlich für autosomal rezessive Schwerhörigkeit [GJB2 (DFNB1A); MYO7A (DFNB2); MYO15A (DFNB3) und USH2A], konnten identifiziert werden. Neun normal hörende Kontrollen waren ebenfalls in diese Studie einbezogen worden. Durch einen Vergleich der Kontrollen mit den Patienten konnte eine statistische Signifikanz erreicht werden, die einen Überschuss an Mutationen bei der Patientengruppe gegenüber der Kontrollgruppe aufzeigte. Die Familie mit einer GRHL2 c.1258-1G>A Mutation ist die erst zweite Familie weltweit, die mit einer Mutation in diesem Gen publiziert worden ist. Dies unterstützt die initiale Behauptung, dass dieses Gen für eine DFNA28 Schwerhörigkeit verantwortlich ist. Die Audiogrammanalyse von fünf der betroffenen Familienmitglieder lässt eine voranschreitende Natur der DFNA28 Hörschädigung erkennen. Eine jährliche Verschlechterung der Hörschwelle bei jedem der fünf Familienmitglieder konnte eine Regressionsanalyse anhand von Audiogrammen, die über eine Anzahl von Jahren zur Verfügung standen, vorhersagen.
KW  - Molekularbiologie
KW  - Hearing loss
KW  - Hörverlust
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112170
N1  - Dieses Dokument wurde aus Datenschutzgründen - ohne inhaltliche Änderungen - erneut veröffentlicht.
Die ursprüngliche Veröffentlichung war am: 09.07.2014
ER  - 
TY  - JOUR
A1  - Herpin, Amaury
A1  - Adolfi, Mateus C.
A1  - Nicol, Barbara
A1  - Hinzmann, Maria
A1  - Schmidt, Cornelia
A1  - Klughammer, Johanna
A1  - Engel, Mareen
A1  - Tanaka, Minoru
A1  - Guiguen, Yann
A1  - Schartl, Manfred
T1  - Divergent Expression Regulation of Gonad Development Genes in Medaka Shows Incomplete Conservation of the Downstream Regulatory Network of Vertebrate Sex Determination
JF  - Molecular Biology and Evolution
N2  - Genetic control of male or female gonad development displays between different groups of organisms a remarkable diversity of “master sex-determining genes” at the top of the genetic hierarchies, whereas downstream components surprisingly appear to be evolutionarily more conserved. Without much further studies, conservation of sequence has been equalized to conservation of function. We have used the medaka fish to investigate the generality of this paradigm. In medaka, the master male sex-determining gene is dmrt1bY, a highly conserved downstream regulator of sex determination in vertebrates. To understand its function in orchestrating the complex gene regulatory network, we have identified targets genes and regulated pathways of Dmrt1bY. Monitoring gene expression and interactions by transgenic fluorescent reporter fish lines, in vivo tissue-chromatin immunoprecipitation and in vitro gene regulation assays revealed concordance but also major discrepancies between mammals and medaka, notably amongst spatial, temporal expression patterns and regulations of the canonical Hedgehog and R-spondin/Wnt/Follistatin signaling pathways. Examination of Foxl2 protein distribution in the medaka ovary defined a new subpopulation of theca cells, where ovarian-type aromatase transcriptional regulation appears to be independent of Foxl2. In summary, these data show that the regulation of the downstream regulatory network of sex determination is less conserved than previously thought.
KW  - gonadal development
KW  - divergent expression regulation
KW  - gene regulatory network evolution
KW  - adaptive evolution
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132262
VL  - 30
IS  - 10
ER  - 
TY  - JOUR
A1  - Tayebi, Naeimeh
A1  - Jamsheer, Aleksander
A1  - Flöttmann, Ricarda
A1  - Sowinska-Seidler, Anna
A1  - Doelken, Sandra C.
A1  - Oehl-Jaschkowitz, Barbara
A1  - Hülsemann, Wiebke
A1  - Habenicht, Rolf
A1  - Klopocki, Eva
A1  - Mundlos, Sefan
A1  - Spielmann, Malte
T1  - Deletions of exons with regulatory activity at the DYNC1I1 locus are associated with split-hand/split-foot malformation: array CGH screening of 134 unrelated families
JF  - Orphanet Journal of Rare Diseases
N2  - Background: A growing number of non-coding regulatory mutations are being identified in congenital disease. Very recently also some exons of protein coding genes have been identified to act as tissue specific enhancer elements and were therefore termed exonic enhancers or "eExons". 
Methods: We screened a cohort of 134 unrelated families with split-hand/split-foot malformation (SHFM) with high resolution array CGH for CNVs with regulatory potential.
Results: In three families with an autosomal dominant non-syndromic SHFM phenotype we detected microdeletions encompassing the exonic enhancer (eExons) 15 and 17 of DYNC1I1. In a fourth family, who had hearing loss in addition to SHFM, we found a larger deletion of 510 kb including the eExons of DYNC1I1 and, in addition, the human brain enhancer hs1642. Exons 15 and 17 of DYNC1I1 are known to act as tissue specific limb enhancers of DLX5/6, two genes that have been shown to be associated with SHFM in mice. In our cohort of 134 unrelated families with SHFM, deletions of the eExons of DYNC1I1 account for approximately 3% of the cases, while 17p13.3 duplications were identified in 13% of the families, 10q24 duplications in 12%, and TP63 mutations were detected in 4%. 
Conclusions: We reduce the minimal critical region for SHFM1 to 78 kb. Hearing loss, however, appears to be associated with deletions of a more telomeric region encompassing the brain enhancer element hs1642. Thus, SHFM1 as well as hearing loss at the same locus are caused by deletion of regulatory elements. Deletions of the exons with regulatory potential of DYNC1I1 are an example of the emerging role of exonic enhancer elements and their implications in congenital malformation syndromes.
KW  - SHFM
KW  - DLX5/6
KW  - DYNC1I1
KW  - regulatory mutations
KW  - eExons
KW  - tissue-specific enhancers
KW  - hand/foot malformation
KW  - II citrullinemia
KW  - limb development
KW  - human disease
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115759
SN  - 1750-1172
VL  - 9
IS  - 108
ER  - 
TY  - JOUR
A1  - Osorio, Ana
A1  - Milne, Roger L.
A1  - Kuchenbaecker, Karoline
A1  - Vaclová, Tereza
A1  - Pita, Guillermo
A1  - Alonso, Rosario
A1  - Peterlongo, Paolo
A1  - Blanco, Ignacio
A1  - de la Hoya, Miguel
A1  - Duran, Mercedes
A1  - Diez, Orland
A1  - Ramón y Cajal, Teresa
A1  - Konstantopoulou, Irene
A1  - Martínez-Bouzas, Christina
A1  - Conejero, Raquel Andrés
A1  - Soucy, Penny
A1  - McGuffog, Lesley
A1  - Barrowdale, Daniel
A1  - Lee, Andrew
A1  - Arver, Brita
A1  - Rantala, Johanna
A1  - Loman, Niklas
A1  - Ehrencrona, Hans
A1  - Olopade, Olufunmilayo I.
A1  - Beattie, Mary S.
A1  - Domchek, Susan M.
A1  - Nathanson, Katherine
A1  - Rebbeck, Timothy R.
A1  - Arun, Banu K.
A1  - Karlan, Beth Y.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - John, Esther M.
A1  - Whittemore, Alice S.
A1  - Daly, Mary B.
A1  - Southey, Melissa
A1  - Hopper, John
A1  - Terry, Mary B.
A1  - Buys, Saundra S.
A1  - Janavicius, Ramunas
A1  - Dorfling, Cecilia M.
A1  - van Rensburg, Elizabeth J.
A1  - Steele, Linda
A1  - Neuhausen, Susan L.
A1  - Ding, Yuan Chun
A1  - Hansen, Thomas V. O.
A1  - Jønson, Lars
A1  - Ejlertsen, Bent
A1  - Gerdes, Anne-Marie
A1  - Infante, Mar
A1  - Herráez, Belén
A1  - Moreno, Leticia Thais
A1  - Weitzel, Jeffrey N.
A1  - Herzog, Josef
A1  - Weeman, Kisa
A1  - Manoukian, Siranoush
A1  - Peissel, Bernard
A1  - Zaffaroni, Daniela
A1  - Scuvera, Guilietta
A1  - Bonanni, Bernardo
A1  - Mariette, Frederique
A1  - Volorio, Sara
A1  - Viel, Alessandra
A1  - Varesco, Liliana
A1  - Papi, Laura
A1  - Ottini, Laura
A1  - Tibiletti, Maria Grazia
A1  - Radice, Paolo
A1  - Yannoukakos, Drakoulis
A1  - Garber, Judy
A1  - Ellis, Steve
A1  - Frost, Debra
A1  - Platte, Radka
A1  - Fineberg, Elena
A1  - Evans, Gareth
A1  - Lalloo, Fiona
A1  - Izatt, Louise
A1  - Eeles, Ros
A1  - Adlard, Julian
A1  - Davidson, Rosemarie
A1  - Cole, Trevor
A1  - Eccles, Diana
A1  - Cook, Jackie
A1  - Hodgson, Shirley
A1  - Brewer, Carole
A1  - Tischkowitz, Marc
A1  - Douglas, Fiona
A1  - Porteous, Mary
A1  - Side, Lucy
A1  - Walker, Lisa
A1  - Morrison, Patrick
A1  - Donaldson, Alan
A1  - Kennedy, John
A1  - Foo, Claire
A1  - Godwin, Andrew K.
A1  - Schmutzler, Rita Katharina
A1  - Wappenschmidt, Barbara
A1  - Rhiem, Kerstin
A1  - Engel, Christoph
A1  - Meindl, Alftons
A1  - Ditsch, Nina
A1  - Arnold, Norbert
A1  - Plendl, Hans Jörg
A1  - Niederacher, Dieter
A1  - Sutter, Christian
A1  - Wang-Gohrke, Shan
A1  - Steinemann, Doris
A1  - Preisler-Adams, Sabine
A1  - Kast, Karin
A1  - Varon-Mateeva, Raymonda
A1  - Gehrig, Andrea
A1  - Stoppa-Lyonnet, Dominique
A1  - Sinilnikova, Olga M.
A1  - Mazoyer, Sylvie
A1  - Damiola, Francesca
A1  - Poppe, Bruce
A1  - Claes, Kathleen
A1  - Piedmonte, Marion
A1  - Tucker, Kathy
A1  - Backes, Floor
A1  - Rodríguez, Gustavo
A1  - Brewster, Wendy
A1  - Wakeley, Katie
A1  - Rutherford, Thomas
A1  - Caldés, Trinidad
A1  - Nevanlinna, Heli
A1  - Aittomäki, Kristiina
A1  - Rookus, Matti A.
A1  - van Os, Theo A. M.
A1  - van der Kolk, Lizet
A1  - de Lange, J. L.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - van der Hout, A. H.
A1  - van Asperen, Christi J.
A1  - Goméz Garcia, Encarna B.
A1  - Encarna, B.
A1  - Hoogerbrugge, Nicoline
A1  - Collée, J. Margriet
A1  - van Deurzen, Carolien H. M.
A1  - van der Luijt, Rob B.
A1  - Devilee, Peter
A1  - Olah, Edith
A1  - Lázaro, Conxi
A1  - Teulé, Alex
A1  - Menéndez, Mireia
A1  - Jakubowska, Anna
A1  - Cybulski, Cezary
A1  - Gronwald, Jecek
A1  - Lubinski, Jan
A1  - Durda, Katarzyna
A1  - Jaworska-Bieniek, Katarzyna
A1  - Johannsson, Oskar Th.
A1  - Maugard, Christine
A1  - Montagna, Marco
A1  - Tognazzo, Silvia
A1  - Teixeira, Manuel R.
A1  - Healey, Sue
A1  - Olswold, Curtis
A1  - Guidugli, Lucia
A1  - Lindor, Noralane
A1  - Slager, Susan
A1  - Szabo, Csilla I.
A1  - Vijai, Joseph
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Zhang, Liying
A1  - Rau-Murthy, Rohini
A1  - Fink-Retter, Anneliese
A1  - Singer, Christine F.
A1  - Rappaport, Christine
A1  - Kaulich, Daphne Geschwantler
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Berger, Andreas
A1  - Phelan, Catherine M.
A1  - Greene, Mark H.
A1  - Mai, Phuong L.
A1  - Lejbkowicz, Flavio
A1  - Andrulis, Irene
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Toland, Amanda Ewart
A1  - Bojesen, Anders
A1  - Pedersen, Inge Sokilde
A1  - Sunde, Lone
A1  - Thomassen, Mads
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Friedman, Eitan
A1  - Laitman, Yeal
A1  - Shimon, Shanie Paluch
A1  - Simard, Jaques
A1  - Easton, Douglas F.
A1  - Offit, Kenneth
A1  - Couch, Fergus J.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
A1  - Benitez, Javier
T1  - DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
JF  - PLOS Genetics
N2  - 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.
KW  - single-nucleotide polymorphisms
KW  - breast cancer
KW  - ovarian cancer
KW  - genetic modifiers
KW  - common variants
KW  - NEIL2
KW  - OGG1
KW  - investigators
KW  - consortium
KW  - damage
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116820
SN  - 1553-7404
VL  - 4
IS  - e1004256
ER  - 
TY  - THES
A1  - Vona, Barbara C.
T1  - Molecular Characterization of Genes Involved in Hearing Loss
T1  - Molekulare Charakterisierung der in Hörstörungen involvierten Genen
N2  - The auditory system is an exquisitely complex sensory organ dependent upon the synchronization of numerous processes for proper function. The molecular characterization of hereditary hearing loss is complicated by extreme genetic heterogeneity, wherein hundreds of genes dispersed genome-wide play a central and irreplaceable role in normal hearing function. The present study explores this area on a genome-wide and single gene basis for the detection of genetic mutations playing critical roles in human hearing.
This work initiated with a high resolution SNP array study involving 109 individuals. A 6.9 Mb heterozygous deletion on chromosome 4q35.1q35.2 was identified in a syndromic patient that was in agreement with a chromosome 4q deletion syndrome diagnosis. A 99.9 kb heterozygous deletion of exons 58-64 in USH2A was identified in one patient. Two homozygous deletions and five heterozygous deletions in STRC (DFNB16) were also detected. The homozygous deletions alone were enough to resolve the hearing impairment in the two patients. A Sanger sequencing assay was developed to exclude a pseudogene with a high percentage sequence identity to STRC from the analysis, which further solved three of the six heterozygous deletion patients with the hemizygous, in silico predicted pathogenic mutations c.2726A>T (p.H909L), c.4918C>T (p.L1640F), and c.4402C>T (p.R1468X). A single patient who was copy neutral for STRC and without pathogenic copy number variations had compound heterozygous mutations [c. 2303_2313+1del12 (p.G768Vfs*77) and c.5125A>G (p.T1709A)] in STRC. It has been shown that STRC has been previously underestimated as a hearing loss gene. One additional patient is described who does not have pathogenic copy number variation but is the only affected member of his family having hearing loss with a paternally segregating translocation t(10;15)(q26.13;q21.1). 
Twenty-four patients without chromosomal aberrations and the above described patient with an USH2A heterozygous deletion were subjected to a targeted hearing loss gene next generation sequencing panel consisting of either 80 or 129 hearing-relevant genes. The patient having the USH2A heterozygous deletion also disclosed a second mutation in this gene [c.2276G>T (p.C759F)]. This compound heterozygous mutation is the most likely cause of hearing loss in this patient. Nine mutations in genes conferring autosomal dominant hearing loss [ACTG1 (DFNA20/26); CCDC50 (DFNA44); EYA4 (DFNA10); GRHL2 (DFNA28); MYH14 (DFNA4A); MYO6 (DFNA22); TCF21 and twice in MYO1A (DFNA48)] and four genes causing autosomal recessive hearing loss were detected [GJB2 (DFNB1A); MYO7A (DFNB2); MYO15A (DFNB3), and USH2A]. Nine normal hearing controls were also included. Statistical significance was achieved comparing controls and patients that revealed an excess of mutations in the hearing loss patients compared to the control group. The family with the GRHL2 c.1258-1G>A mutation is only the second family published worldwide with a mutation described in this gene to date, supporting the initial claim of this gene causing DFNA28 hearing loss. Audiogram analysis of five affected family members uncovered the progressive nature of DFNA28 hearing impairment. Regression analysis predicted the annual threshold deterioration in each of the five family members with multiple audiograms available over a number of years.
N2  - Das Gehör als komplexes Sinnesorgan ist für eine einwandfreie Funktion abhängig von der Synchronisation zahlreicher Prozesse. Durch die extreme genetische Heterogenität wird die molekulare Charakterisierung einer erblich bedingten Schwerhörigkeit erschwert, da hunderte genomweit verteilter Gene eine zentrale und unersetzliche Rolle beim Hören spielen. Die vorliegende Studie untersucht dieses Forschungsgebiet auf genomweiter Ebene und auf der Basis von Einzelgenen, um genetische Mutationen zu ermitteln, die eine entscheidende Rolle bei der menschlichen auditiven Wahrnehmung besitzen. 
Diese Arbeit beginnt mit einer Studie an 109 Personen unter Zuhilfenahme von hochauflösenden SNP-Arrays. In dieser Studie wurde eine 6,9 Mb heterozygote Deletion auf Chromosom 4q35.1q35.2 bei einem syndromalen Patienten identifiziert, die eine Übereinstimmung mit einem Chromosom 4q-Deletionssyndrom aufwies. Bei einem weiteren Patienten wurde eine 99,9 kb heterozygote Deletion der Exons 58-64 in USH2A nachgewiesen. Zwei homozygote Deletionen und fünf heterozygote Deletionen in STRC (DFNB16) wurden ebenfalls detektiert. Die homozygoten Deletionen waren ausreichend, um die Schwerhörigkeit bei beiden Patienten zu klären. Ein Sanger-Sequenzierungs-Assay wurde entwickelt, um ein Pseudogen mit einer hohen prozentualen Sequenzidentität zu STRC von der Analyse auszuschließen. Dadurch konnten drei der sechs heterozygoten Deletionspatienten mit hemizygot in silico vorhergesagten pathogenen Mutationen, c.2726A>T (p.H909L), c.4918 C>T (p.L1640F) und c.4402C>T (p.R1468X), aufgeklärt werden. Ein Patient, der eine kopieneutrale STRC Variation und keine pathogenen Kopienzahlvariationen besaß, zeigte eine compound heterozygote Mutation [c.2303_2313+1del12 (p.G768Vfs*77) und c.5125A>G (p.T1709A)] in STRC. Es wurde gezeigt, daß die Beurteilung von STRC als Hörstörungsgen bisher unterschätzt wurde. Zusätzlich wird ein Patient beschrieben, der keine pathogenen Kopienzahlvariationen aufwies, aber das einzige Familienmitglied mit einer Schwerhörigkeit und einer paternalen segregierten Translokation t(10;15)(q26.13;q21.1) war. 
Vierundzwanzig Patienten ohne Chromosomenstörungen und der oben beschriebene Patient mit einer USH2A heterozygoten Deletion wurden mit einem Next Generation Sequencing Panel bestehend aus entweder 80 oder 129 für das Hören relevanter Gene untersucht. Der Patient mit einer USH2A heterozygoten Deletion zeigte eine zweite Mutation in diesem Gen [c.2276G>T (p.C759F)]. Diese compound heterozygote Mutation ist die wahrscheinlichste Ursache für die Schwerhörigkeit des Patienten. Neun Mutationen in Genen, die zu einem autosomal dominanten Hörverlust führen [ACTG1 (DFNA20/26); CCDC50 (DFNA44); EYA4 (DFNA10); GRHL2 (DFNA28); MYH14 (DFNA4A); MYO6 (DFNA22); TCF21], sowie zwei MYO1A (DFNA48) Mutationen und Mutationen in vier weiteren Genen, verantwortlich für autosomal rezessive Schwerhörigkeit [GJB2 (DFNB1A); MYO7A (DFNB2); MYO15A (DFNB3) und USH2A], konnten identifiziert werden. Neun normal hörende Kontrollen waren ebenfalls in diese Studie einbezogen worden. Durch einen Vergleich der Kontrollen mit den Patienten konnte eine statistische Signifikanz erreicht werden, die einen Überschuss an Mutationen bei der Patientengruppe gegenüber der Kontrollgruppe aufzeigte. Die Familie mit einer GRHL2 c.1258-1G>A Mutation ist die erst zweite Familie weltweit, die mit einer Mutation in diesem Gen publiziert worden ist. Dies unterstützt die initiale Behauptung, dass dieses Gen für eine DFNA28 Schwerhörigkeit verantwortlich ist. Die Audiogrammanalyse von fünf der betroffenen Familienmitglieder lässt eine voranschreitende Natur der DFNA28 Hörschädigung erkennen. Eine jährliche Verschlechterung der Hörschwelle bei jedem der fünf Familienmitglieder konnte eine Regressionsanalyse anhand von Audiogrammen, die über eine Anzahl von Jahren zur Verfügung standen, vorhersagen.
KW  - Hearing loss
KW  - Molekularbiologie
KW  - Hörverlust
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-98031
N1  - Aus datenschutzrechtlichen Gründen wurde der Zugriff auf den Volltext zu diesem Dokument gesperrt. Eine inhaltlich identische neue Version ist erhältlich unter:
http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112170
ER  - 
TY  - JOUR
A1  - Lepeta, Katarzyna
A1  - Lourenco, Mychael V.
A1  - Schweitzer, Barbara C.
A1  - Martino Adami, Pamela V.
A1  - Banerjee, Priyanjalee
A1  - Catuara-Solarz, Silvina
A1  - de la Fuente Revenga, Mario
A1  - Marc Guillem, Alain
A1  - Haider, Mouna
A1  - Ijomone, Omamuyovwi M.
A1  - Nadorp, Bettina
A1  - Qi, Lin
A1  - Perera, Nirma D.
A1  - Refsgaard, Louise K.
A1  - Reid, Kimberley M.
A1  - Sabbar, Mariam
A1  - Sahoo, Arghyadip
A1  - Schaefer, Natascha
A1  - Sheean, Rebecca K.
A1  - Suska, Anna
A1  - Verma, Rajkumar
A1  - Vicidomini, Cinzia
A1  - Wright, Dean
A1  - Zhang, Xing-Ding
A1  - Seidenbecher, Constanze
T1  - Synaptopathies: synaptic dysfunction in neurological disorders - a review from students to students
JF  - Journal of Neurochemistry
N2  - Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page .
KW  - Amyloid-beta oligomers;
KW  - Central nervous system
KW  - P75 Neurotrophin receptor
KW  - Cellular prion protein
KW  - Temporal-lobe epilepsy
KW  - Familial Alzheimers-disease
KW  - Inhibitory glycine receptor
KW  - Autism spectrum disorders
KW  - Alpha-synuclein oligomers
KW  - Dentate granule cells
KW  - Alzheimer disease
KW  - autism
KW  - Down syndrome
KW  - epilepsy
KW  - hyperekplexia
KW  - synapses
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187509
VL  - 138
IS  - 6
ER  - 
TY  - JOUR
A1  - Silvestri, Valentina
A1  - Barrowdale, Daniel
A1  - Mulligan, Anna Marie
A1  - Neuhausen, Susan L.
A1  - Fox, Stephen
A1  - Karlan, Beth Y.
A1  - Mitchell, Gillian
A1  - James, Paul
A1  - Thull, Darcy L.
A1  - Zorn, Kristin K.
A1  - Carter, Natalie J.
A1  - Nathanson, Katherine L.
A1  - Domchek, Susan M.
A1  - Rebbeck, Timothy R.
A1  - Ramus, Susan J.
A1  - Nussbaum, Robert L.
A1  - Olopade, Olufunmilayo I.
A1  - Rantala, Johanna
A1  - Yoon, Sook-Yee
A1  - Caligo, Maria A.
A1  - Spugnesi, Laura
A1  - Bojesen, Anders
A1  - Pedersen, Inge Sokilde
A1  - Thomassen, Mads
A1  - Jensen, Uffe Birk
A1  - Toland, Amanda Ewart
A1  - Senter, Leigha
A1  - Andrulis, Irene L.
A1  - Glendon, Gord
A1  - Hulick, Peter J.
A1  - Imyanitov, Evgeny N.
A1  - Greene, Mark H.
A1  - Mai, Phuong L.
A1  - Singer, Christian F.
A1  - Rappaport-Fuerhauser, Christine
A1  - Kramer, Gero
A1  - Vijai, Joseph
A1  - Offit, Kenneth
A1  - Robson, Mark
A1  - Lincoln, Anne
A1  - Jacobs, Lauren
A1  - Machackova, Eva
A1  - Foretova, Lenka
A1  - Navratilova, Marie
A1  - Vasickova, Petra
A1  - Couch, Fergus J.
A1  - Hallberg, Emily
A1  - Ruddy, Kathryn J.
A1  - Sharma, Priyanka
A1  - Kim, Sung-Won
A1  - Teixeira, Manuel R.
A1  - Pinto, Pedro
A1  - Montagna, Marco
A1  - Matricardi, Laura
A1  - Arason, Adalgeir
A1  - Johannsson, Oskar Th
A1  - Barkardottir, Rosa B.
A1  - Jakubowska, Anna
A1  - Lubinski, Jan
A1  - Izquierdo, Angel
A1  - Pujana, Miguel Angel
A1  - Balmaña, Judith
A1  - Diez, Orland
A1  - Ivady, Gabriella
A1  - Papp, Janos
A1  - Olah, Edith
A1  - Kwong, Ava
A1  - Nevanlinna, Heli
A1  - Aittomäki, Kristiina
A1  - Segura, Pedro Perez
A1  - Caldes, Trinidad
A1  - Van Maerken, Tom
A1  - Poppe, Bruce
A1  - Claes, Kathleen B. M.
A1  - Isaacs, Claudine
A1  - Elan, Camille
A1  - Lasset, Christine
A1  - Stoppa-Lyonnet, Dominique
A1  - Barjhoux, Laure
A1  - Belotti, Muriel
A1  - Meindl, Alfons
A1  - Gehrig, Andrea
A1  - Sutter, Christian
A1  - Engel, Christoph
A1  - Niederacher, Dieter
A1  - Steinemann, Doris
A1  - Hahnen, Eric
A1  - Kast, Karin
A1  - Arnold, Norbert
A1  - Varon-Mateeva, Raymonda
A1  - Wand, Dorothea
A1  - Godwin, Andrew K.
A1  - Evans, D. Gareth
A1  - Frost, Debra
A1  - Perkins, Jo
A1  - Adlard, Julian
A1  - Izatt, Louise
A1  - Platte, Radka
A1  - Eeles, Ros
A1  - Ellis, Steve
A1  - Hamann, Ute
A1  - Garber, Judy
A1  - Fostira, Florentia
A1  - Fountzilas, George
A1  - Pasini, Barbara
A1  - Giannini, Giuseppe
A1  - Rizzolo, Piera
A1  - Russo, Antonio
A1  - Cortesi, Laura
A1  - Papi, Laura
A1  - Varesco, Liliana
A1  - Palli, Domenico
A1  - Zanna, Ines
A1  - Savarese, Antonella
A1  - Radice, Paolo
A1  - Manoukian, Siranoush
A1  - Peissel, Bernard
A1  - Barile, Monica
A1  - Bonanni, Bernardo
A1  - Viel, Alessandra
A1  - Pensotti, Valeria
A1  - Tommasi, Stefania
A1  - Peterlongo, Paolo
A1  - Weitzel, Jeffrey N.
A1  - Osorio, Ana
A1  - Benitez, Javier
A1  - McGuffog, Lesley
A1  - Healey, Sue
A1  - Gerdes, Anne-Marie
A1  - Ejlertsen, Bent
A1  - Hansen, Thomas V. O.
A1  - Steele, Linda
A1  - Ding, Yuan Chun
A1  - Tung, Nadine
A1  - Janavicius, Ramunas
A1  - Goldgar, David E.
A1  - Buys, Saundra S.
A1  - Daly, Mary B.
A1  - Bane, Anita
A1  - Terry, Mary Beth
A1  - John, Esther M.
A1  - Southey, Melissa
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
A1  - Ottini, Laura
T1  - Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2
JF  - Breast Cancer Research
N2  - Background

BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).

Methods

We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.

Results

Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10−5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10−12).

Conclusions

On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
KW  - Male breast cancer
KW  - BRCA1/2
KW  - Pathology
KW  - Histologic grade
KW  - Genotype–phenotype correlations
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164769
VL  - 18
IS  - 15
ER  - 
TY  - JOUR
A1  - Schatton, Tobias
A1  - Yang, Jun
A1  - Kleffel, Sonja
A1  - Uehara, Mayuko
A1  - Barthel, Steven R.
A1  - Schlapbach, Christoph
A1  - Zhan, Qian
A1  - Dudeney, Stephen
A1  - Mueller, Hansgeorg
A1  - Lee, Nayoung
A1  - de Vries, Juliane C.
A1  - Meier, Barbara
A1  - Beken, Seppe Vander
A1  - Kluth, Mark A.
A1  - Ganss, Christoph
A1  - Sharpe, Arlene H.
A1  - Waaga-Gasser, Ana Maria
A1  - Sayegh, Mohamed H.
A1  - Abdi, Reza
A1  - Scharffetter-Kochanek, Karin
A1  - Murphy, George F.
A1  - Kupper, Thomas S.
A1  - Frank, Natasha Y.
A1  - Frank, Markus H.
T1  - ABCB5 Identifies Immunoregulatory Dermal Cells
JF  - Cell Reports
N2  - Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5\(^+\) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5\(^+\) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy.
KW  - mesenchymal stem cells
KW  - P-glycoprotein
KW  - regulatory T cells
KW  - maintain immune homeostasis
KW  - malignant melanoma
KW  - in vivo
KW  - skin
KW  - generation
KW  - transplant
KW  - tolerance
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149989
VL  - 12
SP  - 1564
EP  - 1574
ER  - 
TY  - JOUR
A1  - Doll, Julia
A1  - Vona, Barbara
A1  - Schnapp, Linda
A1  - Rüschendorf, Franz
A1  - Khan, Imran
A1  - Khan, Saadullah
A1  - Muhammad, Noor
A1  - Alam Khan, Sher
A1  - Nawaz, Hamed
A1  - Khan, Ajmal
A1  - Ahmad, Naseer
A1  - Kolb, Susanne M.
A1  - Kühlewein, Laura
A1  - Labonne, Jonathan D. J.
A1  - Layman, Lawrence C.
A1  - Hofrichter, Michaela A. H.
A1  - Röder, Tabea
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Graves, Tyler D.
A1  - Kong, Il-Keun
A1  - Nanda, Indrajit
A1  - Kim, Hyung-Goo
A1  - Haaf, Thomas
T1  - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families
JF  - Genes
N2  - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
KW  - genetic diagnosis
KW  - consanguinity
KW  - genome-wide linkage analysis
KW  - hearing loss
KW  - Pakistan
KW  - exome sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293
SN  - 2073-4425
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Dörk, Thilo
A1  - Peterlongo, Peter
A1  - Mannermaa, Arto
A1  - Bolla, Manjeet K.
A1  - Wang, Qin
A1  - Dennis, Joe
A1  - Ahearn, Thomas
A1  - Andrulis, Irene L.
A1  - Anton-Culver, Hoda
A1  - Arndt, Volker
A1  - Aronson, Kristan J.
A1  - Augustinsson, Annelie
A1  - Beane Freeman, Laura E.
A1  - Beckmann, Matthias W.
A1  - Beeghly-Fadiel, Alicia
A1  - Behrens, Sabine
A1  - Bermisheva, Marina
A1  - Blomqvist, Carl
A1  - Bogdanova, Natalia V.
A1  - Bojesen, Stig E.
A1  - Brauch, Hiltrud
A1  - Brenner, Hermann
A1  - Burwinkel, Barbara
A1  - Canzian, Federico
A1  - Chan, Tsun L.
A1  - Chang-Claude, Jenny
A1  - Chanock, Stephen J.
A1  - Choi, Ji-Yeob
A1  - Christiansen, Hans
A1  - Clarke, Christine L.
A1  - Couch, Fergus J.
A1  - Czene, Kamila
A1  - Daly, Mary B.
A1  - dos-Santos-Silva, Isabel
A1  - Dwek, Miriam
A1  - Eccles, Diana M.
A1  - Ekici, Arif B.
A1  - Eriksson, Mikael
A1  - Evans, D. Gareth
A1  - Fasching, Peter A.
A1  - Figueroa, Jonine
A1  - Flyger, Henrik
A1  - Fritschi, Lin
A1  - Gabrielson, Marike
A1  - Gago-Dominguez, Manuela
A1  - Gao, Chi
A1  - Gapstur, Susan M.
A1  - García-Closas, Montserrat
A1  - García-Sáenz, José A.
A1  - Gaudet, Mia M.
A1  - Giles, Graham G.
A1  - Goldberg, Mark S.
A1  - Goldgar, David E.
A1  - Guenél, Pascal
A1  - Haeberle, Lothar
A1  - Haimann, Christopher A.
A1  - Håkansson, Niclas
A1  - Hall, Per
A1  - Hamann, Ute
A1  - Hartman, Mikael
A1  - Hauke, Jan
A1  - Hein, Alexander
A1  - Hillemanns, Peter
A1  - Hogervorst, Frans B. L.
A1  - Hooning, Maartje J.
A1  - Hopper, John L.
A1  - Howell, Tony
A1  - Huo, Dezheng
A1  - Ito, Hidemi
A1  - Iwasaki, Motoki
A1  - Jakubowska, Anna
A1  - Janni, Wolfgang
A1  - John, Esther M.
A1  - Jung, Audrey
A1  - Kaaks, Rudolf
A1  - Kang, Daehee
A1  - Kapoor, Pooja Middha
A1  - Khusnutdinova, Elza
A1  - Kim, Sung-Won
A1  - Kitahara, Cari M.
A1  - Koutros, Stella
A1  - Kraft, Peter
A1  - Kristensen, Vessela N.
A1  - Kwong, Ava
A1  - Lambrechts, Diether
A1  - Le Marchand, Loic
A1  - Li, Jingmei
A1  - Lindström, Sara
A1  - Linet, Martha
A1  - Lo, Wing-Yee
A1  - Long, Jirong
A1  - Lophatananon, Artitaya
A1  - Lubiński, Jan
A1  - Manoochehri, Mehdi
A1  - Manoukian, Siranoush
A1  - Margolin, Sara
A1  - Martinez, Elena
A1  - Matsuo, Keitaro
A1  - Mavroudis, Dimitris
A1  - Meindl, Alfons
A1  - Menon, Usha
A1  - Milne, Roger L.
A1  - Mohd Taib, Nur Aishah
A1  - Muir, Kenneth
A1  - Mulligan, Anna Marie
A1  - Neuhausen, Susan L.
A1  - Nevanlinna, Heli
A1  - Neven, Patrick
A1  - Newman, William G.
A1  - Offit, Kenneth
A1  - Olopade, Olufunmilayo I.
A1  - Olshan, Andrew F.
A1  - Olson, Janet E.
A1  - Olsson, Håkan
A1  - Park, Sue K.
A1  - Park-Simon, Tjoung-Won
A1  - Peto, Julian
A1  - Plaseska-Karanfilska, Dijana
A1  - Pohl-Rescigno, Esther
A1  - Presneau, Nadege
A1  - Rack, Brigitte
A1  - Radice, Paolo
A1  - Rashid, Muhammad U.
A1  - Rennert, Gad
A1  - Rennert, Hedy S.
A1  - Romero, Atocha
A1  - Ruebner, Matthias
A1  - Saloustros, Emmanouil
A1  - Schmidt, Marjanka K.
A1  - Schmutzler, Rita K.
A1  - Schneider, Michael O.
A1  - Schoemaker, Minouk J.
A1  - Scott, Christopher
A1  - Shen, Chen-Yang
A1  - Shu, Xiao-Ou
A1  - Simard, Jaques
A1  - Slager, Susan
A1  - Smichkoska, Snezhana
A1  - Southey, Melissa C.
A1  - Spinelli, John J.
A1  - Stone, Jennifer
A1  - Surowy, Harald
A1  - Swerdlow, Anthony J.
A1  - Tamimi, Rulla M.
A1  - Tapper, William J.
A1  - Teo, Soo H.
A1  - Terry, Mary Beth
A1  - Toland, Amanda E.
A1  - Tollenaar, Rob A. E. M.
A1  - Torres, Diana
A1  - Torres-Mejía, Gabriela
A1  - Troester, Melissa A.
A1  - Truong, Thérèse
A1  - Tsugane, Shoichiro
A1  - Untch, Michael
A1  - Vachon, Celine M.
A1  - van den Ouweland, Ans M. W.
A1  - van Veen, Elke M.
A1  - Vijai, Joseph
A1  - Wendt, Camilla
A1  - Wolk, Alicja
A1  - Yu, Jyh-Cherng
A1  - Zheng, Wei
A1  - Ziogas, Argyrios
A1  - Ziv, Elad
A1  - Dunnig, Alison
A1  - Pharaoh, Paul D. P.
A1  - Schindler, Detlev
A1  - Devilee, Peter
A1  - Easton, Douglas F.
T1  - Two truncating variants in FANCC and breast cancer risk
JF  - Scientific Reports
N2  - Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
KW  - oncology
KW  - risk factors
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222838
VL  - 9
ER  - 
TY  - JOUR
A1  - Lu, Yuan
A1  - Boswell, Wiliam
A1  - Boswell, Mikki
A1  - Klotz, Barbara
A1  - Kneitz, Susanne
A1  - Regneri, Janine
A1  - Savage, Markita
A1  - Mendoza, Cristina
A1  - Postlethwait, John
A1  - Warren, Wesley C.
A1  - Schartl, Manfred
A1  - Walter, Ronald B.
T1  - Application of the Transcriptional Disease Signature (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model
JF  - Scientific Reports
N2  - Cell culture and protein target-based compound screening strategies, though broadly utilized in selecting candidate compounds, often fail to eliminate candidate compounds with non-target effects and/or safety concerns until late in the drug developmental process. Phenotype screening using intact research animals is attractive because it can help identify small molecule candidate compounds that have a high probability of proceeding to clinical use. Most FDA approved, first-in-class small molecules were identified from phenotypic screening. However, phenotypic screening using rodent models is labor intensive, low-throughput, and very expensive. As a novel alternative for small molecule screening, we have been developing gene expression disease profiles, termed the Transcriptional Disease Signature (TDS), as readout of small molecule screens for therapeutic molecules. In this concept, compounds that can reverse, or otherwise affect known disease-associated gene expression patterns in whole animals may be rapidly identified for more detailed downstream direct testing of their efficacy and mode of action. To establish proof of concept for this screening strategy, we employed a transgenic strain of a small aquarium fish, medaka (Oryzias latipes), that overexpresses the malignant melanoma driver gene xmrk, a mutant egfr gene, that is driven by a pigment cell-specific mitf promoter. In this model, melanoma develops with 100% penetrance. Using the transgenic medaka malignant melanoma model, we established a screening system that employs the NanoString nCounter platform to quantify gene expression within custom sets of TDS gene targets that we had previously shown to exhibit differential transcription among xmrk-transgenic and wild-type medaka. Compound-modulated gene expression was identified using an internet-accessible custom-built data processing pipeline. The effect of a given drug on the entire TDS profile was estimated by comparing compound-modulated genes in the TDS using an activation Z-score and Kolmogorov-Smirnov statistics. TDS gene probes were designed that target common signaling pathways that include proliferation, development, toxicity, immune function, metabolism and detoxification. These pathways may be utilized to evaluate candidate compounds for potential favorable, or unfavorable, effects on melanoma-associated gene expression. Here we present the logistics of using medaka to screen compounds, as well as, the development of a user-friendly NanoString data analysis pipeline to support feasibility of this novel TDS drug-screening strategy.
KW  - bioinformatics
KW  - phenotypic screening
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237322
VL  - 9
ER  -