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Start Over Author "Lichtner P." Publisher escholarship, university of california
15 results on '"Lichtner P."'

2. Fatty Acid and Alcohol Metabolism in Pseudomonas putida: Functional Analysis Using Random Barcode Transposon Sequencing (vol 86, e01665-20, 2020)

Author

Thompson, Mitchell G, Incha, Matthew R, Pearson, Allison N, Schmidt, Matthias, Sharpless, William A, Eiben, Christopher B, Cruz-Morales, Pablo, Blake-Hedges, Jacquelyn M, Liu, Yuzhong, Adams, Catharine A, Haushalter, Robert W, Krishna, Rohith N, Lichtner, Patrick, Blank, Lars M, Mukhopadhyay, Aindrila, Deutschbauer, Adam M, Shih, Patrick M, and Keasling, Jay D

Subjects
Microbiology
Published
2021

3. Fatty Acid and Alcohol Metabolism in Pseudomonas putida: Functional Analysis Using Random Barcode Transposon Sequencing

Author

Thompson, Mitchell G, Incha, Matthew R, Pearson, Allison N, Schmidt, Matthias, Sharpless, William A, Eiben, Christopher B, Cruz-Morales, Pablo, Blake-Hedges, Jacquelyn M, Liu, Yuzhong, Adams, Catharine A, Haushalter, Robert W, Krishna, Rohith N, Lichtner, Patrick, Blank, Lars M, Mukhopadhyay, Aindrila, Deutschbauer, Adam M, Shih, Patrick M, and Keasling, Jay D

Subjects
Biological Sciences, Industrial Biotechnology, Biotechnology, Prevention, Bioengineering, Genetics, Alcohols, DNA Transposable Elements, DNA, Bacterial, Fatty Acids, Metabolic Networks and Pathways, Pseudomonas putida, Sequence Analysis, DNA, Fatty acid, RB-Tn-Seq, transposon, RB–Tn-Seq, Microbiology, Medical microbiology
Abstract

With its ability to catabolize a wide variety of carbon sources and a growing engineering toolkit, Pseudomonas putida KT2440 is emerging as an important chassis organism for metabolic engineering. Despite advances in our understanding of the organism, many gaps remain in our knowledge of the genetic basis of its metabolic capabilities. The gaps are particularly noticeable in our understanding of both fatty acid and alcohol catabolism, where many paralogs putatively coding for similar enzymes coexist, making biochemical assignment via sequence homology difficult. To rapidly assign function to the enzymes responsible for these metabolisms, we leveraged random barcode transposon sequencing (RB-Tn-Seq). Global fitness analyses of transposon libraries grown on 13 fatty acids and 10 alcohols produced strong phenotypes for hundreds of genes. Fitness data from mutant pools grown on fatty acids of varying chain lengths indicated specific enzyme substrate preferences and enabled us to hypothesize that DUF1302/DUF1329 family proteins potentially function as esterases. From the data, we also postulate catabolic routes for the two biogasoline molecules isoprenol and isopentanol, which are catabolized via leucine metabolism after initial oxidation and activation with coenzyme A (CoA). Because fatty acids and alcohols may serve as both feedstocks and final products of metabolic-engineering efforts, the fitness data presented here will help guide future genomic modifications toward higher titers, rates, and yields.IMPORTANCE To engineer novel metabolic pathways into P. putida, a comprehensive understanding of the genetic basis of its versatile metabolism is essential. Here, we provide functional evidence for the putative roles of hundreds of genes involved in the fatty acid and alcohol metabolism of the bacterium. These data provide a framework facilitating precise genetic changes to prevent product degradation and to channel the flux of specific pathway intermediates as desired.

Published
2020

4. Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.

Author

Wagner, Matias, Skorobogatko, Yuliya, Pode-Shakked, Ben, Powell, Cynthia, Alhaddad, Bader, Seibt, Annette, Barel, Ortal, Heimer, Gali, Hoffmann, Chen, Demmer, Laurie, Perilla-Young, Yezmin, Remke, Marc, Wieczorek, Dagmar, Navaratnarajah, Tharsini, Lichtner, Peter, Klee, Dirk, Shamseldin, Hanan, Al Mutairi, Fuad, Mayatepek, Ertan, Strom, Tim, Meitinger, Thomas, Alkuraya, Fowzan, Anikster, Yair, Distelmaier, Felix, and Saltiel, Alan

Subjects
GARNL1, RalA signaling, TULIP1, West syndrome, epilepsy, muscular hypotonia, neurodevelopmental disorder, Alleles, Cell Movement, Cell Proliferation, Child, Preschool, Family, Feeding and Eating Disorders, Female, GTPase-Activating Proteins, Humans, Infant, Male, Muscle Hypotonia, Mutation, Nerve Tissue Proteins, Neurodevelopmental Disorders, Phenotype, Spasms, Infantile
Abstract

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

Published
2020

5. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Author

van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick AA, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry Tc, Tazelaar, Gijs HP, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine AM, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, and Blauw, Hylke M

Subjects
PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, Humans, Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease, Proteins, Cytoskeletal Proteins, Myelin Proteins, Case-Control Studies, Cohort Studies, Mutation, Netherlands, Munc18 Proteins, Genome-Wide Association Study, Neurosciences, Rare Diseases, Brain Disorders, Biotechnology, Prevention, Human Genome, Neurodegenerative, Genetics, ALS, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Published
2016

6. Reactive transport codes for subsurface environmental simulation

Author

Steefel, CI, Appelo, CAJ, Arora, B, Jacques, D, Kalbacher, T, Kolditz, O, Lagneau, V, Lichtner, PC, Mayer, KU, Meeussen, JCL, Molins, S, Moulton, D, Shao, H, Šimůnek, J, Spycher, N, Yabusaki, SB, and Yeh, GT

Subjects
Reactive transport, Modeling, Environmental simulation, Computer software, Code benchmark, Numerical & Computational Mathematics, Other Earth Sciences
Abstract

A general description of the mathematical and numerical formulations used in modern numerical reactive transport codes relevant for subsurface environmental simulations is presented. The formulations are followed by short descriptions of commonly used and available subsurface simulators that consider continuum representations of flow, transport, and reactions in porous media. These formulations are applicable to most of the subsurface environmental benchmark problems included in this special issue. The list of codes described briefly here includes PHREEQC, HPx, PHT3D, OpenGeoSys (OGS), HYTEC, ORCHESTRA, TOUGHREACT, eSTOMP, HYDROGEOCHEM, CrunchFlow, MIN3P, and PFLOTRAN. The descriptions include a high-level list of capabilities for each of the codes, along with a selective list of applications that highlight their capabilities and historical development.

Published
2015

7. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Author

Lin, Wei-Yu, Camp, Nicola J, Ghoussaini, Maya, Beesley, Jonathan, Michailidou, Kyriaki, Hopper, John L, Apicella, Carmel, Southey, Melissa C, Stone, Jennifer, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Th Rutgers, Emiel J, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Cheng, Timothy, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marmé, Frederik, Surowy, Harald M, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Mulot, Claire, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Arias Perez, Jose Ignacio, Menéndez, Primitiva, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Alvarez, Nuria, Herrero, Daniel, Anton-Culver, Hoda, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Müller-Myhsok, Bertram, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, GENICA Network, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Horio, Akiyo, Bogdanova, Natalia V, Antonenkova, Natalia N, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Neven, Patrick, Wauters, Els, Wildiers, Hans, Lambrechts, Diether, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, and Flesch-Janys, Dieter

Subjects
GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Chromosomes, Human, Pair 2, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Proteins, Case-Control Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Caspase 8, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-Wide Association Study, Genotyping Techniques, Chromosomes, Human, Pair 2, Polymorphism, Single Nucleotide, Prevention, Genetics, Human Genome, Breast Cancer, Cancer, Biotechnology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

Published
2015

8. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author

Sawyer, Elinor, Roylance, Rebecca, Petridis, Christos, Brook, Mark, Nowinski, Salpie, Papouli, Efterpi, Fletcher, Olivia, Pinder, Sarah, Hanby, Andrew, Kohut, Kelly, Gorman, Patricia, Caneppele, Michele, Peto, Julian, Dos Santos Silva, Isabel, Johnson, Nichola, Swann, Ruth, Dwek, Miriam, Perkins, Katherine-Anne, Gillett, Cheryl, Houlston, Richard, Ross, Gillian, De Ieso, Paolo, Southey, Melissa, Hopper, John, Provenzano, Elena, Apicella, Carmel, Wesseling, Jelle, Cornelissen, Sten, Keeman, Renske, Fasching, Peter, Jud, Sebastian, Ekici, Arif, Beckmann, Matthias, Kerin, Michael, Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Therese, Laurent-Puig, Pierre, Kerbrat, Pierre, Bojesen, Stig, Nordestgaard, Børge, Nielsen, Sune, Flyger, Henrik, Milne, Roger, Perez, Jose, Menéndez, Primitiva, Benitez, Javier, Brenner, Hermann, Dieffenbach, Aida, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita, Lochmann, Magdalena, Brauch, Hiltrud, Fischer, Hans-Peter, Ko, Yon-Dschun, Nevanlinna, Heli, Muranen, Taru, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana, Chenevix-Trench, Georgia, Lambrechts, Diether, Weltens, Caroline, Van Limbergen, Erik, Hatse, Sigrid, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Volorio, Sara, Giles, Graham, Severi, Gianluca, Baglietto, Laura, McLean, Catriona, Haiman, Christopher, Henderson, Brian, Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark, Labrèche, France, Dumont, Martine, Kristensen, Vessela, and Winqvist, Robert

Subjects
Breast Neoplasms, Carcinoma in Situ, Carcinoma, Lobular, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide
Abstract

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P

Published
2014

9. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

Author

Michailidou, Kyriaki, Hall, Per, Gonzalez-Neira, Anna, Ghoussaini, Maya, Dennis, Joe, Milne, Roger L, Schmidt, Marjanka K, Chang-Claude, Jenny, Bojesen, Stig E, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Lee, Andrew, Turnbull, Clare, Rahman, Nazneen, Fletcher, Olivia, Peto, Julian, Gibson, Lorna, dos Santos Silva, Isabel, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Czene, Kamila, Irwanto, Astrid, Liu, Jianjun, Waisfisz, Quinten, Meijers-Heijboer, Hanne, Adank, Muriel, van der Luijt, Rob B, Hein, Rebecca, Dahmen, Norbert, Beckman, Lars, Meindl, Alfons, Schmutzler, Rita K, Müller-Myhsok, Bertram, Lichtner, Peter, Hopper, John L, Southey, Melissa C, Makalic, Enes, Schmidt, Daniel F, Uitterlinden, Andre G, Hofman, Albert, Hunter, David J, Chanock, Stephen J, Vincent, Daniel, Bacot, François, Tessier, Daniel C, Canisius, Sander, Wessels, Lodewyk FA, Haiman, Christopher A, Shah, Mitul, Luben, Robert, Brown, Judith, Luccarini, Craig, Schoof, Nils, Humphreys, Keith, Li, Jingmei, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Couch, Fergus J, Wang, Xianshu, Vachon, Celine, Stevens, Kristen N, Lambrechts, Diether, Moisse, Matthieu, Paridaens, Robert, Christiaens, Marie-Rose, Rudolph, Anja, Nickels, Stefan, Flesch-Janys, Dieter, Johnson, Nichola, Aitken, Zoe, Aaltonen, Kirsimari, Heikkinen, Tuomas, Broeks, Annegien, Veer, Laura J Van't, van der Schoot, C Ellen, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Menegaux, Florence, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Zamora, M Pilar, Perez, Jose Ignacio Arias, Pita, Guillermo, Alonso, M Rosario, Cox, Angela, Brock, Ian W, Cross, Simon S, Reed, Malcolm WR, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, and Henderson, Brian E

Subjects
Biological Sciences, Genetics, Human Genome, Prevention, Breast Cancer, Cancer, Breast Neoplasms, Case-Control Studies, Cooperative Behavior, Female, Gene-Environment Interaction, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk Factors, Breast and Ovarian Cancer Susceptibility Collaboration, Hereditary Breast and Ovarian Cancer Research Group Netherlands, kConFab Investigators, Australian Ovarian Cancer Study Group, GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.

Published
2013

10. Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

Author

French, Juliet D, Ghoussaini, Maya, Edwards, Stacey L, Meyer, Kerstin B, Michailidou, Kyriaki, Ahmed, Shahana, Khan, Sofia, Maranian, Mel J, O’Reilly, Martin, Hillman, Kristine M, Betts, Joshua A, Carroll, Thomas, Bailey, Peter J, Dicks, Ed, Beesley, Jonathan, Tyrer, Jonathan, Maia, Ana-Teresa, Beck, Andrew, Knoblauch, Nicholas W, Chen, Constance, Kraft, Peter, Barnes, Daniel, González-Neira, Anna, Alonso, M Rosario, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Baynes, Caroline, Conroy, Don, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Verhoef, Senno, Cornelissen, Sten, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Loehberg, Christian R, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos Santos Silva, Isabel, Johnson, Nichola, Aitken, Zoe, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Zamora, M Pilar, Perez, Jose Ignacio Arias, Benitez, Javier, Anton-Culver, Hoda, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Engel, Christoph, Brauch, Hiltrud, Hamann, Ute, Justenhoven, Christina, Network, The GENICA, Aaltonen, Kirsimari, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Sueta, Aiko, Bogdanova, Natalia V, Antonenkova, Natalia N, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, and Kataja, Vesa

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Cancer, Aetiology, 2.1 Biological and endogenous factors, Binding Sites, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 11, Cyclin D1, Electrophoretic Mobility Shift Assay, Enhancer Elements, Genetic, Female, GATA3 Transcription Factor, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Silencer Elements, Transcriptional, ets-Domain Protein Elk-4, GENICA Network, kConFab Investigators, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Published
2013

11. Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

Author

Garcia-Closas, Montserrat, Couch, Fergus J, Lindstrom, Sara, Michailidou, Kyriaki, Schmidt, Marjanka K, Brook, Mark N, Orr, Nick, Rhie, Suhn Kyong, Riboli, Elio, Feigelson, Heather S, Le Marchand, Loic, Buring, Julie E, Eccles, Diana, Miron, Penelope, Fasching, Peter A, Brauch, Hiltrud, Chang-Claude, Jenny, Carpenter, Jane, Godwin, Andrew K, Nevanlinna, Heli, Giles, Graham G, Cox, Angela, Hopper, John L, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Dicks, Ed, Howat, Will J, Schoof, Nils, Bojesen, Stig E, Lambrechts, Diether, Broeks, Annegien, Andrulis, Irene L, Guénel, Pascal, Burwinkel, Barbara, Sawyer, Elinor J, Hollestelle, Antoinette, Fletcher, Olivia, Winqvist, Robert, Brenner, Hermann, Mannermaa, Arto, Hamann, Ute, Meindl, Alfons, Lindblom, Annika, Zheng, Wei, Devillee, Peter, Goldberg, Mark S, Lubinski, Jan, Kristensen, Vessela, Swerdlow, Anthony, Anton-Culver, Hoda, Dörk, Thilo, Muir, Kenneth, Matsuo, Keitaro, Wu, Anna H, Radice, Paolo, Teo, Soo Hwang, Shu, Xiao-Ou, Blot, William, Kang, Daehee, Hartman, Mikael, Sangrajrang, Suleeporn, Shen, Chen-Yang, Southey, Melissa C, Park, Daniel J, Hammet, Fleur, Stone, Jennifer, Veer, Laura J Van't, Rutgers, Emiel J, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Peto, Julian, Schrauder, Michael G, Ekici, Arif B, Beckmann, Matthias W, Dos Santos Silva, Isabel, Johnson, Nichola, Warren, Helen, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Truong, Therese, Laurent-Puig, Pierre, Kerbrat, Pierre, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Lichtner, Peter, Lochmann, Magdalena, and Justenhoven, Christina

Subjects
Gene ENvironmental Interaction and breast CAncer (GENICA) Network, kConFab Investigators, Familial Breast Cancer Study, Australian Breast Cancer Tissue Bank (ABCTB) Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Receptors, Estrogen, Oligonucleotide Array Sequence Analysis, Risk Factors, Case-Control Studies, Cooperative Behavior, Genotype, Polymorphism, Single Nucleotide, Female, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Genetics, Human Genome, Estrogen, Breast Cancer, Cancer, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

Published
2013

12. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

Author

Siddiq, Afshan, Couch, Fergus J, Chen, Gary K, Lindström, Sara, Eccles, Diana, Millikan, Robert C, Michailidou, Kyriaki, Stram, Daniel O, Beckmann, Lars, Rhie, Suhn Kyong, Ambrosone, Christine B, Aittomäki, Kristiina, Amiano, Pilar, Apicella, Carmel, Investigators, Australian Breast Cancer Tissue Bank, Baglietto, Laura, Bandera, Elisa V, Beckmann, Matthias W, Berg, Christine D, Bernstein, Leslie, Blomqvist, Carl, Brauch, Hiltrud, Brinton, Louise, Bui, Quang M, Buring, Julie E, Buys, Saundra S, Campa, Daniele, Carpenter, Jane E, Chasman, Daniel I, Chang-Claude, Jenny, Chen, Constance, Clavel-Chapelon, Françoise, Cox, Angela, Cross, Simon S, Czene, Kamila, Deming, Sandra L, Diasio, Robert B, Diver, W Ryan, Dunning, Alison M, Durcan, Lorraine, Ekici, Arif B, Fasching, Peter A, Study, Familial Breast Cancer, Feigelson, Heather Spencer, Fejerman, Laura, Figueroa, Jonine D, Fletcher, Olivia, Flesch-Janys, Dieter, Gaudet, Mia M, Consortium, The GENICA, Gerty, Susan M, Rodriguez-Gil, Jorge L, Giles, Graham G, van Gils, Carla H, Godwin, Andrew K, Graham, Nikki, Greco, Dario, Hall, Per, Hankinson, Susan E, Hartmann, Arndt, Hein, Rebecca, Heinz, Judith, Hoover, Robert N, Hopper, John L, Hu, Jennifer J, Huntsman, Scott, Ingles, Sue A, Irwanto, Astrid, Isaacs, Claudine, Jacobs, Kevin B, John, Esther M, Justenhoven, Christina, Kaaks, Rudolf, Kolonel, Laurence N, Coetzee, Gerhard A, Lathrop, Mark, Le Marchand, Loic, Lee, Adam M, Lee, I-Min, Lesnick, Timothy, Lichtner, Peter, Liu, Jianjun, Lund, Eiliv, Makalic, Enes, Martin, Nicholas G, McLean, Catriona A, Meijers-Heijboer, Hanne, Meindl, Alfons, Miron, Penelope, Monroe, Kristine R, Montgomery, Grant W, Müller-Myhsok, Bertram, Nickels, Stefan, Nyante, Sarah J, Olswold, Curtis, Overvad, Kim, Palli, Domenico, Park, Daniel J, Palmer, Julie R, and Pathak, Harsh

Subjects
Biological Sciences, Genetics, Human Genome, Cancer Genomics, Cancer, Aging, Prevention, Women's Health, Breast Cancer, 2.1 Biological and endogenous factors, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Australian Breast Cancer Tissue Bank Investigators, Familial Breast Cancer Study, GENICA Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

Published
2012

13. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author

Ghoussaini, Maya, Fletcher, Olivia, Michailidou, Kyriaki, Turnbull, Clare, Schmidt, Marjanka K, Dicks, Ed, Dennis, Joe, Wang, Qin, Humphreys, Manjeet K, Luccarini, Craig, Baynes, Caroline, Conroy, Don, Maranian, Melanie, Ahmed, Shahana, Driver, Kristy, Johnson, Nichola, Orr, Nicholas, dos Santos Silva, Isabel, Waisfisz, Quinten, Meijers-Heijboer, Hanne, Uitterlinden, Andre G, Rivadeneira, Fernando, Hall, Per, Czene, Kamila, Irwanto, Astrid, Liu, Jianjun, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Meindl, Alfons, Schmutzler, Rita K, Müller-Myhsok, Bertram, Lichtner, Peter, Chang-Claude, Jenny, Hein, Rebecca, Nickels, Stefan, Flesch-Janys, Dieter, Tsimiklis, Helen, Makalic, Enes, Schmidt, Daniel, Bui, Minh, Hopper, John L, Apicella, Carmel, Park, Daniel J, Southey, Melissa, Hunter, David J, Chanock, Stephen J, Broeks, Annegien, Verhoef, Senno, Hogervorst, Frans BL, Fasching, Peter A, Lux, Michael P, Beckmann, Matthias W, Ekici, Arif B, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Alonso, M Rosario, González-Neira, Anna, Benítez, Javier, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Dur, Christina Clarke, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Justenhoven, Christina, Brauch, Hiltrud, Brüning, Thomas, Wang-Gohrke, Shan, Eilber, Ursula, Dörk, Thilo, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Bogdanova, Natalia V, Antonenkova, Natalia N, Rogov, Yuri I, Karstens, Johann H, Bermisheva, Marina, Prokofieva, Darya, Khusnutdinova, Elza, Lindblom, Annika, Margolin, Sara, and Mannermaa, Arto

Subjects
Biological Sciences, Genetics, Estrogen, Human Genome, Prevention, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide, Principal Component Analysis, White People, Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer, Familial Breast Cancer Study, Gene Environment Interaction of Breast Cancer in Germany (GENICA) Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Published
2012

15. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author

Ghoussaini, M, Fletcher, O, Michailidou, K, Turnbull, C, Schmidt, MK, Dicks, E, Dennis, J, Wang, Q, Humphreys, MK, Luccarini, C, Baynes, C, Conroy, D, Maranian, M, Ahmed, S, Driver, K, Johnson, N, Orr, N, Dos Santos Silva, I, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Hall, P, Czene, K, Irwanto, A, Liu, J, Nevanlinna, H, Aittom Currency Signki, K, Blomqvist, C, Meindl, A, Schmutzler, RK, Müller-Myhsok, B, Lichtner, P, Chang-Claude, J, Hein, R, Nickels, S, Flesch-Janys, D, Tsimiklis, H, Makalic, E, Schmidt, D, Bui, M, Hopper, JL, Apicella, C, Park, DJ, Southey, M, Hunter, DJ, Chanock, SJ, Broeks, A, Verhoef, S, Hogervorst, FBL, Fasching, PA, Lux, MP, Beckmann, MW, Ekici, AB, Sawyer, E, Tomlinson, I, Kerin, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guénel, P, Truong, T, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Alonso, MR, Gonzlez-Neira, A, Ben-tez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Müller, H, Arndt, V, Stegmaier, C, Justenhoven, C, and Brauch, H

Abstract

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for g1/48% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in g1/470,000 cases and ĝ̂1/468,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 - 10 g35), 12q24 (rs1292011; P = 4.3 - 10 g19) and 21q21 (rs2823093; P = 1.1 - 10 g12). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth. © 2012 Nature America, Inc. All rights reserved.

Published
2012
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