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  - 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  - Preiser, J. C.
A1  - Schmartz, D.
A1  - Van der Linden, P.
A1  - Content, J.
A1  - Vanden Bussche, P.
A1  - Buurman, W.
A1  - Sebald, Werner
A1  - Dupont, E.
A1  - Pinsky, M. R.
A1  - Vincent, J. L.
T1  - Interleukin-6 administration has no acute hemodynamic or hematologic effect in the dog
N2  - To investigate the possible hemodynamic efl'ects of interleukin-6 (IL-6), a single dose of 15 mcg/kg of recombinant IL-6 isolated from Escherichia coli was injected intravenously in six pentobarbital-anesthetized dogs. After 30 min, saline infusion was performed to maintain the - pulmonary artery balloon-occluded pressure at baseline Ievel. The animals were observed for up to 5 hours. No other hemodynamic alteration was observed than a gradual decline in cardiac output attributed to anesthesia. Hematologic variables, blood glucose, and total serum proteins were also constant. IL-6 levels were markedly elevated in the blood, bot no tumor necrosis factor activity was detected. Thus a primary role for IL-6 in the early cardiovascular alterations associated with septic shock seems unlikely.
KW  - Biochemie
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62511
ER  - 
TY  - JOUR
A1  - Mencacci, Niccoló E.
A1  - Isaias, Ioannis U.
A1  - Reich, Martin M.
A1  - Ganos, Christos
A1  - Plagnol, Vincent
A1  - Polke, James M.
A1  - Bras, Jose
A1  - Hersheson, Joshua
A1  - Stamelou, Maria
A1  - Pittman, Alan M.
A1  - Noyce, Alastair J.
A1  - Mok, Kin Y.
A1  - Opladen, Thomas
A1  - Kunstmann, Erdmute
A1  - Hodecker, Sybille
A1  - Münchau, Alexander
A1  - Volkmann, Jens
A1  - Samnick, Samuel
A1  - Sidle, Katie
A1  - Nanji, Tina
A1  - Sweeney, Mary G.
A1  - Houlden, Henry
A1  - Batla, Amit
A1  - Zecchinelli, Anna L.
A1  - Pezzoli, Gianni
A1  - Marotta, Giorgio
A1  - Lees, Andrew
A1  - Alegria, Paulo
A1  - Krack, Paul
A1  - Cormier-Dequaire, Florence
A1  - Lesage, Suzanne
A1  - Brice, Alexis
A1  - Heutink, Peter
A1  - Gasser, Thomas
A1  - Lubbe, Steven J.
A1  - Morris, Huw R.
A1  - Taba, Pille
A1  - Koks, Sulev
A1  - Majounie, Elisa
A1  - Gibbs, J. Raphael
A1  - Singleton, Andrew
A1  - Hardy, John
A1  - Klebe, Stephan
A1  - Bhatia, Kailash P.
A1  - Wood, Nicholas W.
T1  - Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
JF  - Brain
N2  - GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
KW  - DOPA-responsive-dystonia
KW  - GCH1
KW  - Parkinson's disease
KW  - dopamine
KW  - exome sequencing
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121268
VL  - 137
IS  - 9
ER  - 
TY  - JOUR
A1  - Kleijn, David
A1  - Winfree, Rachael
A1  - Bartomeus, Ignasi
A1  - Carvalheiro, Luísa G.
A1  - Henry, Mickael
A1  - Isaacs, Rufus
A1  - Klein, Alexandra-Maria
A1  - Kremen, Claire
A1  - M'Gonigle, Leithen K.
A1  - Rader, Romina
A1  - Ricketts, Taylor H.
A1  - Williams, Neal M.
A1  - Adamson, Nancy Lee
A1  - Ascher, John S.
A1  - Báldi, András
A1  - Batáry, Péter
A1  - Benjamin, Faye
A1  - Biesmeijer, Jacobus C.
A1  - Blitzer, Eleanor J.
A1  - Bommarco, Riccardo
A1  - Brand, Mariette R.
A1  - Bretagnolle, Vincent
A1  - Button, Lindsey
A1  - Cariveau, Daniel P.
A1  - Chifflet, Rémy
A1  - Colville, Jonathan F.
A1  - Danforth, Bryan N.
A1  - Elle, Elizabeth
A1  - Garratt, Michael P. D.
A1  - Herzog, Felix
A1  - Holzschuh, Andrea
A1  - Howlett, Brad G.
A1  - Jauker, Frank
A1  - Jha, Shalene
A1  - Knop, Eva
A1  - Krewenka, Kristin M.
A1  - Le Féon, Violette
A1  - Mandelik, Yael
A1  - May, Emily A.
A1  - Park, Mia G.
A1  - Pisanty, Gideon
A1  - Reemer, Menno
A1  - Riedinger, Verena
A1  - Rollin, Orianne
A1  - Rundlöf, Maj
A1  - Sardiñas, Hillary S.
A1  - Scheper, Jeroen
A1  - Sciligo, Amber R.
A1  - Smith, Henrik G.
A1  - Steffan-Dewenter, Ingolf
A1  - Thorp, Robbin
A1  - Tscharntke, Teja
A1  - Verhulst, Jort
A1  - Viana, Blandina F.
A1  - Vaissière, Bernard E.
A1  - Veldtman, Ruan
A1  - Ward, Kimiora L.
A1  - Westphal, Catrin
A1  - Potts, Simon G.
T1  - Delivery of crop pollination services is an insufficient argument for wild pollinator conservation
JF  - Nature Communications
N2  - There is compelling evidence that more diverse ecosystems deliver greater benefits to people, and these ecosystem services have become a key argument for biodiversity conservation. However, it is unclear how much biodiversity is needed to deliver ecosystem services in a cost- effective way. Here we show that, while the contribution of wild bees to crop production is significant, service delivery is restricted to a limited subset of all known bee species. Across crops, years and biogeographical regions, crop-visiting wild bee communities are dominated by a small number of common species, and threatened species are rarely observed on crops. Dominant crop pollinators persist under agricultural expansion and many are easily enhanced by simple conservation measures, suggesting that cost- effective management strategies to promote crop pollination should target a different set of species than management strategies to promote threatened bees. Conserving the biological diversity of bees therefore requires more than just ecosystem-service-based arguments.
KW  - ecosystem services
KW  - european countries
KW  - abundance
KW  - native bees
KW  - biodiversity conservation
KW  - plant diversity
KW  - fruit set
KW  - productivity
KW  - decline
KW  - pollen
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151879
VL  - 6
IS  - 7414
ER  -