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1. Redundancy-aware unsupervised rankings for collections of gene sets

Author

Balestra, Chiara, Maj, Carlo, Müller, Emmanuel, and Mayr, Andreas

Subjects
Quantitative Biology - Quantitative Methods, Computer Science - Computer Science and Game Theory, Computer Science - Machine Learning
Abstract

The biological roles of gene sets are used to group them into collections. These collections are often characterized by being high-dimensional, overlapping, and redundant families of sets, thus precluding a straightforward interpretation and study of their content. Bioinformatics looked for solutions to reduce their dimension or increase their intepretability. One possibility lies in aggregating overlapping gene sets to create larger pathways, but the modified biological pathways are hardly biologically justifiable. We propose to use importance scores to rank the pathways in the collections studying the context from a set covering perspective. The proposed Shapley values-based scores consider the distribution of the singletons and the size of the sets in the families; Furthermore, a trick allows us to circumvent the usual exponential complexity of Shapley values' computation. Finally, we address the challenge of including a redundancy awareness in the obtained rankings where, in our case, sets are redundant if they show prominent intersections. The rankings can be used to reduce the dimension of collections of gene sets, such that they show lower redundancy and still a high coverage of the genes. We further investigate the impact of our selection on Gene Sets Enrichment Analysis. The proposed method shows a practical utility in bioinformatics to increase the interpretability of the collections of gene sets and a step forward to include redundancy into Shapley values computations., Comment: arXiv admin note: substantial text overlap with arXiv:2207.12184

Published
2023

5. Redundancy-aware unsupervised ranking based on game theory -- application to gene enrichment analysis

Author

Balestra, Chiara, Maj, Carlo, Mueller, Emmanuel, and Mayr, Andreas

Subjects
Quantitative Biology - Genomics, Computer Science - Computer Science and Game Theory, Computer Science - Machine Learning
Abstract

Gene set collections are a common ground to study the enrichment of genes for specific phenotypic traits. Gene set enrichment analysis aims to identify genes that are over-represented in gene sets collections and might be associated with a specific phenotypic trait. However, as this involves a massive number of hypothesis testing, it is often questionable whether a pre-processing step to reduce gene sets collections' sizes is helpful. Moreover, the often highly overlapping gene sets and the consequent low interpretability of gene sets' collections demand for a reduction of the included gene sets. Inspired by this bioinformatics context, we propose a method to rank sets within a family of sets based on the distribution of the singletons and their size. We obtain sets' importance scores by computing Shapley values without incurring into the usual exponential number of evaluations of the value function. Moreover, we address the challenge of including a redundancy awareness in the rankings obtained where, in our case, sets are redundant if they show prominent intersections. We finally evaluate our approach for gene sets collections; the rankings obtained show low redundancy and high coverage of the genes. The unsupervised nature of the proposed ranking does not allow for an evident increase in the number of significant gene sets for specific phenotypic traits when reducing the size of the collections. However, we believe that the rankings proposed are of use in bioinformatics to increase interpretability of the gene sets collections and a step forward to include redundancy into Shapley values computations.

Published
2022

10. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

Author

Hassanin, Emadeldin, Spier, Isabel, Bobbili, Dheeraj R., Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, and Maj, Carlo

Published
2023
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11. Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus

Author

Mathey, Carina M., Maj, Carlo, Eriksson, Niclas, Krebs, Kristi, Westmeier, Julia, David, Friederike S., Koromina, Maria, Scheer, Annika B., Szabo, Nora, Wedi, Bettina, Wieczorek, Dorothea, Amann, Philipp M., Löffler, Harald, Koch, Lukas, Schöffl, Clemens, Dickel, Heinrich, Ganjuur, Nomun, Hornung, Thorsten, Buhl, Timo, Greve, Jens, Wurpts, Gerda, Aygören-Pürsün, Emel, Steffens, Michael, Herms, Stefan, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Schmidt, Börge, Mavarani, Laven, Andresen, Trine, Sørensen, Signe Bek, Andersen, Vibeke, Vogel, Ulla, Landén, Mikael, Bulik, Cynthia M., Bygum, Anette, Magnusson, Patrik K.E., von Buchwald, Christian, Hallberg, Pär, Rye Ostrowski, Sisse, Sørensen, Erik, Pedersen, Ole B., Ullum, Henrik, Erikstrup, Christian, Bundgaard, Henning, Milani, Lili, Rasmussen, Eva Rye, Wadelius, Mia, Ghouse, Jonas, Sachs, Bernhardt, Nöthen, Markus M., and Forstner, Andreas J.

Published
2024
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14. Next Generation Sequencing Analysis in Early Onset Dementia Patients.

Author

Bonvicini, Cristian, Scassellati, Catia, Benussi, Luisa, Di Maria, Emilio, Maj, Carlo, Ciani, Miriam, Fostinelli, Silvia, Mega, Anna, Bocchetta, Martina, Lanzi, Gaetana, Giacopuzzi, Edoardo, Ferraboli, Sergio, Pievani, Michela, Fedi, Virginia, Defanti, Carlo Alberto, Giliani, Silvia, Alzheimer’s Disease Neuroimaging Initiative, Frisoni, Giovanni Battista, Ghidoni, Roberta, and Gennarelli, Massimo

Subjects
Alzheimer’s Disease Neuroimaging Initiative, Humans, Dementia, Apolipoproteins E, Risk Assessment, Retrospective Studies, Age of Onset, Alleles, Aged, Middle Aged, Female, Male, Presenilin-2, Genetic Variation, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Prion Proteins, C9orf72 Protein, Alzheimer’s disease, Lewy body dementia, common variants, early onset dementia, frontotemporal dementia, next generation sequencing, rare mutations, Alzheimer's disease, frontotemporal dementia, Clinical Sciences, Cognitive Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

BackgroundEarly onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia.ObjectiveTo identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed.MethodsWe studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping.ResultsWe detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (n = 9) of our early onset Alzheimer's disease (EAOD) patients, compared with 34% (n = 13) of sporadic late onset Alzheimer's disease (LOAD) patients and 27% (n = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations.ConclusionThis study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.

Published
2019

16. A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Author

Mingardo, Enrico, Beaman, Glenda, Grote, Philip, Nordenskjöld, Agneta, Newman, William, Woolf, Adrian S., Eckstein, Markus, Hilger, Alina C., Dworschak, Gabriel C., Rösch, Wolfgang, Ebert, Anne-Karolin, Stein, Raimund, Brusco, Alfredo, Di Grazia, Massimo, Tamer, Ali, Torres, Federico M., Hernandez, Jose L., Erben, Philipp, Maj, Carlo, Olmos, Jose M., Riancho, Jose A., Valero, Carmen, Hostettler, Isabel C., Houlden, Henry, Werring, David J., Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Buerfent, Benedikt C., Arkani, Samara, Åkesson, Elisabeth, Rotstein, Emilia, Ludwig, Michael, Holmdahl, Gundela, Giorgio, Elisa, Berettini, Alfredo, Keene, David, Cervellione, Raimondo M., Younsi, Nina, Ortlieb, Melissa, Oswald, Josef, Haid, Bernhard, Promm, Martin, Neissner, Claudia, Hirsch, Karin, Stehr, Maximilian, Schäfer, Frank-Mattias, Schmiedeke, Eberhard, Boemers, Thomas M., van Rooij, Iris A. L. M., Feitz, Wouter F. J., Marcelis, Carlo L. M., Lacher, Martin, Nelson, Jana, Ure, Benno, Fortmann, Caroline, Gale, Daniel P., Chan, Melanie M. Y., Ludwig, Kerstin U., Nöthen, Markus M., Heilmann, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Odermatt, Benjamin, Knapp, Michael, and Reutter, Heiko

Published
2022
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17. Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease

Author

Uellendahl-Werth, Florian, Maj, Carlo, Borisov, Oleg, Juzenas, Simonas, Wacker, Eike Matthias, Jørgensen, Isabella Friis, Steiert, Tim Alexander, Bej, Saptarshi, Krawitz, Peter, Hoffmann, Per, Schramm, Christoph, Wolkenhauer, Olaf, Banasik, Karina, Brunak, Søren, Schreiber, Stefan, Karlsen, Tom Hemming, Degenhardt, Franziska, Nöthen, Markus, Franke, Andre, Folseraas, Trine, and Ellinghaus, David

Published
2022
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18. Imatinib treatment and longitudinal growth in pediatric patients with chronic myeloid leukemia: Influence of demographic, pharmacological, and genetic factors in the German CML-PAED cohort

Author

Stiehler, Sophie, primary, Sembill, Stephanie, additional, Schleicher, Oliver, additional, Marx, Michaela, additional, Rauh, Manfred, additional, Krumbholz, Manuela, additional, Karow, Axel, additional, Suttorp, Meinolf, additional, Woelfle, Joachim, additional, Maj, Carlo, additional, and Metzler, Markus, additional

Published
2024
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19. Polygenic Modeling of Muscle Fibers Composition

Author

Borisov, Oleg, Maj, Carlo, Kulemin, Nikolay, Semenova, Ekaterina, Krawitz, Peter, Ahmetov, Ildus, Generozov, Edward, Kacprzyk, Janusz, Series Editor, Pal, Nikhil R., Advisory Editor, Bello Perez, Rafael, Advisory Editor, Corchado, Emilio S., Advisory Editor, Hagras, Hani, Advisory Editor, Kóczy, László T., Advisory Editor, Kreinovich, Vladik, Advisory Editor, Lin, Chin-Teng, Advisory Editor, Lu, Jie, Advisory Editor, Melin, Patricia, Advisory Editor, Nedjah, Nadia, Advisory Editor, Nguyen, Ngoc Thanh, Advisory Editor, Wang, Jun, Advisory Editor, Lames, Martin, editor, Danilov, Alexander, editor, Timme, Egor, editor, and Vassilevski, Yuri, editor

Published
2020
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21. Analysis of Evolutionary Conservation, Expression Level, and Genetic Association at a Genome-wide Scale Reveals Heterogeneity Across Polygenic Phenotypes.

Author

Giel, Ann-Sophie, Bigge, Jessica, Schumacher, Johannes, Maj, Carlo, and Dasmeh, Pouria

Subjects
GENE expression, NATURAL selection, GENETIC correlations, CORONARY artery disease, GENOME-wide association studies
Abstract

Understanding the expression level and evolutionary rate of associated genes with human polygenic diseases provides crucial insights into their disease-contributing roles. In this work, we leveraged genome-wide association studies (GWASs) to investigate the relationship between the genetic association and both the evolutionary rate (d N /d S) and expression level of human genes associated with the two polygenic diseases of schizophrenia and coronary artery disease. Our findings highlight a distinct variation in these relationships between the two diseases. Genes associated with both diseases exhibit a significantly greater variance in evolutionary rate compared to those implicated in monogenic diseases. Expanding our analyses to 4,756 complex traits in the GWAS atlas database, we unraveled distinct trait categories with a unique interplay among the evolutionary rate, expression level, and genetic association of human genes. In most polygenic traits, highly expressed genes were more associated with the polygenic phenotypes compared to lowly expressed genes. About 69% of polygenic traits displayed a negative correlation between genetic association and evolutionary rate, while approximately 30% of these traits showed a positive correlation between genetic association and evolutionary rate. Our results demonstrate the presence of a spectrum among complex traits, shaped by natural selection. Notably, at opposite ends of this spectrum, we find metabolic traits being more likely influenced by purifying selection, and immunological traits that are more likely shaped by positive selection. We further established the polygenic evolution portal (evopolygen.de) as a resource for investigating relationships and generating hypotheses in the field of human polygenic trait evolution. [ABSTRACT FROM AUTHOR]

Published
2024
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22. The genetic regulation of the gastric transcriptome is associated with metabolic and obesity-related traits and diseases.

Author

Koebbe, Laura L., Hess, Timo, Giel, Ann-Sophie, Bigge, Jessica, Gehlen, Jan, Schueller, Vitalia, Geppert, Michael, Dumoulin, Franz Ludwig, Heller, Joerg, Schepke, Michael, Plaßmann, Dominik, Vieth, Michael, Venerito, Marino, Schumacher, Johannes, and Maj, Carlo

Subjects
GENETIC regulation, GENE expression, LOCUS (Genetics), BODY composition, TRANSCRIPTOMES, PLANT protection
Abstract

Tissue-specific gene expression and gene regulation lead to a better understanding of tissue-specific physiology and pathophysiology. We analyzed the transcriptome and genetic regulatory profiles of two distinct gastric sites, corpus and antrum, to identify tissue-specific gene expression and its regulation. Gastric corpus and antrum mucosa biopsies were collected during routine gastroscopies from up to 431 healthy individuals. We obtained genotype and transcriptome data and performed transcriptome profiling and expression quantitative trait locus (eQTL) studies. We further used data from genome-wide association studies (GWAS) of various diseases and traits to partition their heritability and to perform transcriptome-wide association studies (TWAS). The transcriptome data from corpus and antral mucosa highlights the heterogeneity of gene expression in the stomach. We identified enriched pathways revealing distinct and common physiological processes in gastric corpus and antrum. Furthermore, we found an enrichment of the single nucleotide polymorphism (SNP)-based heritability of metabolic, obesity-related, and cardiovascular traits and diseases by considering corpus- and antrum-specifically expressed genes. Particularly, we could prioritize gastric-specific candidate genes for multiple metabolic traits, like NQO1 which is involved in glucose metabolism, MUC1 which contributes to purine and protein metabolism or RAB27B being a regulator of weight and body composition. Our findings show that gastric corpus and antrum vary in their transcriptome and genetic regulatory profiles indicating physiological differences which are mostly related to digestion and epithelial protection. Moreover, our findings demonstrate that the genetic regulation of the gastric transcriptome is linked to biological mechanisms associated with metabolic, obesity-related, and cardiovascular traits and diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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26. A Model of Colonic Crypts using SBML Spatial

Author

Ramazzotti, Daniele, Maj, Carlo, and Antoniotti, Marco

Subjects
Computer Science - Computational Engineering, Finance, and Science, Quantitative Biology - Molecular Networks
Abstract

The Spatial Processes package enables an explicit definition of a spatial environment on top of the normal dynamic modeling SBML capabilities. The possibility of an explicit representation of spatial dynamics increases the representation power of SBML. In this work we used those new SBML features to define an extensive model of colonic crypts composed of the main cellular types (from stem cells to fully differentiated cells), alongside their spatial dynamics., Comment: In Proceedings Wivace 2013, arXiv:1309.7122

Published
2013
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29. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”

Author

Hess, Timo, primary, Maj, Carlo, additional, Gehlen, Jan, additional, Borisov, Oleg, additional, Haas, Stephan L., additional, Gockel, Ines, additional, Vieth, Michael, additional, Piessen, Guillaume, additional, Alakus, Hakan, additional, Vashist, Yogesh, additional, Pereira, Carina, additional, Knapp, Michael, additional, Schüller, Vitalia, additional, Quaas, Alexander, additional, Grabsch, Heike I., additional, Trautmann, Jessica, additional, Malecka-Wojciesko, Ewa, additional, Mokrowiecka, Anna, additional, Speller, Jan, additional, Mayr, Andreas, additional, Schröder, Julia, additional, Hillmer, Axel M., additional, Heider, Dominik, additional, Lordick, Florian, additional, Pérez-Aísa, Ángeles, additional, Campo, Rafael, additional, Espinel, Jesús, additional, Geijo, Fernando, additional, Thomson, Concha, additional, Bujanda, Luis, additional, Sopeña, Federico, additional, Lanas, Ángel, additional, Pellisé, María, additional, Pauligk, Claudia, additional, Goetze, Thorsten Oliver, additional, Zelck, Carolin, additional, Reingruber, Julian, additional, Hassanin, Emadeldin, additional, Elbe, Peter, additional, Alsabeah, Sandra, additional, Lindblad, Mats, additional, Nilsson, Magnus, additional, Kreuser, Nicole, additional, Thieme, René, additional, Tavano, Francesca, additional, Pastorino, Roberta, additional, Arzani, Dario, additional, Persiani, Roberto, additional, Jung, Jin-On, additional, Nienhüser, Henrik, additional, Ott, Katja, additional, Schumann, Ralf R., additional, Kumpf, Oliver, additional, Burock, Susen, additional, Arndt, Volker, additional, Jakubowska, Anna, additional, Ławniczak, Małgorzta, additional, Moreno, Victor, additional, Martín, Vicente, additional, Kogevinas, Manolis, additional, Pollán, Marina, additional, Dąbrowska, Justyna, additional, Salas, Antonio, additional, Cussenot, Olivier, additional, Boland-Auge, Anne, additional, Daian, Delphine, additional, Deleuze, Jean-Francois, additional, Salvi, Erika, additional, Teder-Laving, Maris, additional, Tomasello, Gianluca, additional, Ratti, Margherita, additional, Senti, Chiara, additional, De Re, Valli, additional, Steffan, Agostino, additional, Hölscher, Arnulf H., additional, Messerle, Katharina, additional, Bruns, Christiane Josephine, additional, Sīviņš, Armands, additional, Bogdanova, Inga, additional, Skieceviciene, Jurgita, additional, Arstikyte, Justina, additional, Moehler, Markus, additional, Lang, Hauke, additional, Grimminger, Peter P., additional, Kruschewski, Martin, additional, Vassos, Nikolaos, additional, Schildberg, Claus, additional, Lingohr, Philipp, additional, Ridwelski, Karsten, additional, Lippert, Hans, additional, Fricker, Nadine, additional, Krawitz, Peter, additional, Hoffmann, Per, additional, Nöthen, Markus M., additional, Veits, Lothar, additional, Izbicki, Jakob R., additional, Mostowska, Adrianna, additional, Martinón-Torres, Federico, additional, Cusi, Daniele, additional, Adolfsson, Rolf, additional, Cancel-Tassin, Geraldine, additional, Höblinger, Aksana, additional, Rodermann, Ernst, additional, Ludwig, Monika, additional, Keller, Gisela, additional, Metspalu, Andres, additional, Brenner, Hermann, additional, Heller, Joerg, additional, Neef, Markus, additional, Schepke, Michael, additional, Dumoulin, Franz Ludwig, additional, Hamann, Lutz, additional, Cannizzaro, Renato, additional, Ghidini, Michele, additional, Plaßmann, Dominik, additional, Geppert, Michael, additional, Malfertheiner, Peter, additional, Glehen, Olivier, additional, Skoczylas, Tomasz, additional, Majewski, Marek, additional, Lubiński, Jan, additional, Palmieri, Orazio, additional, Boccia, Stefania, additional, Latiano, Anna, additional, Aragones, Nuria, additional, Schmidt, Thomas, additional, Dinis-Ribeiro, Mário, additional, Medeiros, Rui, additional, Al-Batran, Salah-Eddin, additional, Leja, Mārcis, additional, Kupcinskas, Juozas, additional, García-González, María A., additional, Venerito, Marino, additional, and Schumacher, Johannes, additional

Published
2023
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33. Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease

Author

Kumar, Sheetal, primary, Borisov, Oleg, additional, Maj, Carlo, additional, Ralser, Damian J., additional, Humbatova, Aytaj, additional, Hanneken, Sandra, additional, Schmieder, Astrid, additional, Groß, Janina, additional, Maintz, Laura, additional, Heineke, Andre, additional, Knuever, Jana, additional, Fagerberg, Christina, additional, Parmentier, Laurent, additional, Anemüller, Waltraud, additional, Oji, Vinzenz, additional, Tantcheva-Poór, Iliana, additional, Fölster-Holst, Regina, additional, Wenzel, Joerg, additional, Krawitz, Peter M., additional, Frank, Jorge, additional, and Betz, Regina C., additional

Published
2023
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35. Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome

Author

Dueñas, Nuria, primary, Klinkhammer, Hannah, additional, Bonifaci, Nuria, additional, Spier, Isabel, additional, Mayr, Andreas, additional, Hassanin, Emadeldin, additional, Diez-Villanueva, Anna, additional, Moreno, Victor, additional, Pineda, Marta, additional, Maj, Carlo, additional, Capellà, Gabriel, additional, Aretz, Stefan, additional, and Brunet, Joan, additional

Published
2023
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36. Dissecting the genetic heterogeneity of gastric cancer

Author

Hess, Timo, primary, Maj, Carlo, additional, Gehlen, Jan, additional, Borisov, Oleg, additional, Haas, Stephan L., additional, Gockel, Ines, additional, Vieth, Michael, additional, Piessen, Guillaume, additional, Alakus, Hakan, additional, Vashist, Yogesh, additional, Pereira, Carina, additional, Knapp, Michael, additional, Schüller, Vitalia, additional, Quaas, Alexander, additional, Grabsch, Heike I., additional, Trautmann, Jessica, additional, Malecka-Wojciesko, Ewa, additional, Mokrowiecka, Anna, additional, Speller, Jan, additional, Mayr, Andreas, additional, Schröder, Julia, additional, Hillmer, Axel M., additional, Heider, Dominik, additional, Lordick, Florian, additional, Pérez-Aísa, Ángeles, additional, Campo, Rafael, additional, Espinel, Jesús, additional, Geijo, Fernando, additional, Thomson, Concha, additional, Bujanda, Luis, additional, Sopeña, Federico, additional, Lanas, Ángel, additional, Pellisé, María, additional, Pauligk, Claudia, additional, Goetze, Thorsten Oliver, additional, Zelck, Carolin, additional, Reingruber, Julian, additional, Hassanin, Emadeldin, additional, Elbe, Peter, additional, Alsabeah, Sandra, additional, Lindblad, Mats, additional, Nilsson, Magnus, additional, Kreuser, Nicole, additional, Thieme, René, additional, Tavano, Francesca, additional, Pastorino, Roberta, additional, Arzani, Dario, additional, Persiani, Roberto, additional, Jung, Jin-On, additional, Nienhüser, Henrik, additional, Ott, Katja, additional, Schumann, Ralf R., additional, Kumpf, Oliver, additional, Burock, Susen, additional, Arndt, Volker, additional, Jakubowska, Anna, additional, Ławniczak, Małgorzta, additional, Moreno, Victor, additional, Martín, Vicente, additional, Kogevinas, Manolis, additional, Pollán, Marina, additional, Dąbrowska, Justyna, additional, Salas, Antonio, additional, Cussenot, Olivier, additional, Boland-Auge, Anne, additional, Daian, Delphine, additional, Deleuze, Jean-Francois, additional, Salvi, Erika, additional, Teder-Laving, Maris, additional, Tomasello, Gianluca, additional, Ratti, Margherita, additional, Senti, Chiara, additional, De Re, Valli, additional, Steffan, Agostino, additional, Hölscher, Arnulf H., additional, Messerle, Katharina, additional, Bruns, Christiane Josephine, additional, Sīviņš, Armands, additional, Bogdanova, Inga, additional, Skieceviciene, Jurgita, additional, Arstikyte, Justina, additional, Moehler, Markus, additional, Lang, Hauke, additional, Grimminger, Peter P., additional, Kruschewski, Martin, additional, Vassos, Nikolaos, additional, Schildberg, Claus, additional, Lingohr, Philipp, additional, Ridwelski, Karsten, additional, Lippert, Hans, additional, Fricker, Nadine, additional, Krawitz, Peter, additional, Hoffmann, Per, additional, Nöthen, Markus M., additional, Veits, Lothar, additional, Izbicki, Jakob R., additional, Mostowska, Adrianna, additional, Martinón-Torres, Federico, additional, Cusi, Daniele, additional, Adolfsson, Rolf, additional, Cancel-Tassin, Geraldine, additional, Höblinger, Aksana, additional, Rodermann, Ernst, additional, Ludwig, Monika, additional, Keller, Gisela, additional, Metspalu, Andres, additional, Brenner, Hermann, additional, Heller, Joerg, additional, Neef, Markus, additional, Schepke, Michael, additional, Dumoulin, Franz Ludwig, additional, Hamann, Lutz, additional, Cannizzaro, Renato, additional, Ghidini, Michele, additional, Plaßmann, Dominik, additional, Geppert, Michael, additional, Malfertheiner, Peter, additional, Gehlen, Olivier, additional, Skoczylas, Tomasz, additional, Majewski, Marek, additional, Lubiński, Jan, additional, Palmieri, Orazio, additional, Boccia, Stefania, additional, Latiano, Anna, additional, Aragones, Nuria, additional, Schmidt, Thomas, additional, Dinis-Ribeiro, Mário, additional, Medeiros, Rui, additional, Al-Batran, Salah-Eddin, additional, Leja, Mārcis, additional, Kupcinskas, Juozas, additional, García-González, María A., additional, Venerito, Marino, additional, and Schumacher, Johannes, additional

Published
2023
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39. Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease

Author

Kumar, Sheetal, Borisov, Oleg, Maj, Carlo, Ralser, Damian J., Humbatova, Aytaj, Hanneken, Sandra, Schmieder, Astrid, Groß, Janina, Maintz, Laura, Heineke, Andre, Knuever, Jana, Fagerberg, Christina, Parmentier, Laurent, Anemüller, Waltraud, Oji, Vinzenz, Tantcheva-Poór, Iliana, Fölster-Holst, Regina, Wenzel, Joerg, Krawitz, Peter M., Frank, Jorge, and Betz, Regina C.

Published
2024
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40. Contributors

Author

Abbott, Ryan, primary, Ahmed, Ahmed T., additional, Alda, Martin, additional, Amstadter, Ananda B., additional, Andreassen, Ole A., additional, Arnet, Victoria K., additional, Bardy, Cedric, additional, Barta, Csaba, additional, Baune, Bernhard T., additional, Becker, Elisabeth R.B., additional, Bewernick, Bettina H., additional, Biernacka, Joanna M., additional, Bleich, Stefan, additional, Blumenthal, Marissa S., additional, Bonvicini, Cristian, additional, Bousman, Chad A., additional, Brown, Lisa C., additional, Burton, Christie L., additional, Cao, Han, additional, Carpenter, Joanne S., additional, Cath, Danielle, additional, Cearns, Micah, additional, Chang, Donald D., additional, Charney, Alexander, additional, Ching, Christopher R.K., additional, Chitty, Kate M., additional, Ciobanu, Liliana G., additional, Clark, Scott R., additional, Cole, A.M., additional, Collinson, Jane L., additional, Colodro-Conde, Lucía, additional, Corvin, A., additional, Cotter, David R., additional, Cross, Shane P.M., additional, Crouse, Jacob J., additional, Cryan, John F, additional, Czamara, Darina, additional, Dalvie, Shareefa, additional, Degenhardt, Franziska, additional, Delahanty, Douglas L., additional, Dinan, Timothy G, additional, Eapen, Valsamma, additional, Eyre, Harris A., additional, Forstner, Andreas J., additional, Frieling, Helge, additional, Frye, Mark A., additional, Gehue, Lillian J., additional, Geller, Daniel, additional, Glozier, Nicholas, additional, Godlewska, Beata R., additional, Goldstein-Piekarski, Andrea N., additional, Gorbovskaya, Ilona, additional, Grabe, Hans Jörgen, additional, Grande, Iria, additional, Grant, Paul, additional, Greenberg, Zarina, additional, Grünblatt, Edna, additional, Guastella, Adam J., additional, Gururajan, Anand, additional, Hahn, Tim, additional, Hall, Alisha S.M., additional, Hamilton, Blake A., additional, Hamm, Alfons O., additional, Harmer, Catherine J., additional, Hartmann, Jessica, additional, Hauser, Michael A., additional, Hermens, Daniel F., additional, Hickie, Ian B., additional, Iorfino, Frank, additional, Jahanshad, Neda, additional, Jansen, Iris E., additional, Junglen, Angela G., additional, Karim, Helmet T., additional, Kaur, Manreena, additional, Koen, Nastassja, additional, Koethe, Dagmar, additional, Lagopoulos, Jim, additional, Lee, Rico S.Z., additional, Legge, Sophie E., additional, Levinson, Douglas F., additional, Leweke, F. Markus, additional, Licinio, Julio, additional, Linden, David E.J., additional, Liu, Jonathan C.W., additional, Lo, Anita, additional, Lohoff, Falk W., additional, Lori, Adriana, additional, Lueken, Ulrike, additional, Maj, Carlo, additional, McGorry, Patrick D., additional, McIntyre, Roger S., additional, McMahon, Agnes B., additional, Mehta, Divya, additional, Mei, Cristina, additional, Morey, Rajendra A., additional, Müller, Daniel J., additional, Naismith, Sharon L., additional, Nelson, Barnaby, additional, Neyazi, Alexandra, additional, Nichles, Alissa, additional, Nievergelt, Caroline M., additional, Nugent, Nicole R., additional, Ormond, C., additional, Pardiñas, Antonio F., additional, Perry, Seth W., additional, Pisanu, Claudia, additional, Posthuma, Danielle, additional, Ragguett, Renee-Marie, additional, Raji, Cyrus, additional, Raygada, Margarita, additional, Rennert, Owen M., additional, Reynolds, Charles F., additional, Sabherwal, Sophie, additional, Salagre, Estela, additional, Saunders, Pamela H., additional, Scassellati, Catia, additional, Schlaepfer, Thomas E., additional, Schmaal, Lianne, additional, Schubert, Klaus Oliver, additional, Schwarz, Emanuel, additional, Scott, Elizabeth M., additional, Scott, Jan, additional, Sebat, Jonathan, additional, Severino, Giovanni, additional, Sheerin, Christina, additional, Singh, Ajeet B., additional, Singh, Balwinder, additional, Smagula, Stephen F., additional, Smeland, Olav B., additional, Smith, Alicia K., additional, Sorcher, Jill L., additional, Spooner, Rachael, additional, Squassina, Alessio, additional, Stahl, Eli A., additional, Stein, Dan J., additional, Streit, Fabian, additional, Sullivan, Patrick F., additional, Sumner, Jennifer A., additional, Thompson, Paul M., additional, Tickell, Ashleigh M., additional, Toben, Catherine, additional, Uddin, Monica, additional, Vahabzadeh, Arshya, additional, Van, Linh K., additional, van de Weijer, Margot P., additional, van den Heuvel, Odile A., additional, Van der Auwera, Sandra, additional, Verboven, Anouk H.A., additional, Vieta, Eduard, additional, Wainer, Zoe, additional, Walters, James T.R., additional, Watson, Hunna J., additional, White, Django, additional, Williams, Leanne M., additional, Witt, Stephanie H., additional, Yao, Yin, additional, Yilmaz, Zeynep, additional, Zai, Gwyneth, additional, and Zmicerevska, Natalia, additional

Published
2019
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41. Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome

Author

Duenas Cid, Nuria, primary, klinkhammer, Hannah, additional, Bonifaci, Nuria, additional, Spier, Isabel, additional, Mayr, Andreas, additional, Hassanin, Emadeldin, additional, Diez-Villanueva, Anna, additional, Moreno, Victor, additional, Pineda, Marta, additional, Maj, Carlo, additional, Capella, Gabriel, additional, Aretz, Stefan, additional, and Brunet, Joan, additional

Published
2023
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43. Supplementary Information from Common Germline Risk Variants Impact Somatic Alterations and Clinical Features across Cancers

Author

Namba, Shinichi, primary, Saito, Yuki, primary, Kogure, Yasunori, primary, Masuda, Tatsuo, primary, Bondy, Melissa L., primary, Gharahkhani, Puya, primary, Gockel, Ines, primary, Heider, Dominik, primary, Hillmer, Axel, primary, Jankowski, Janusz, primary, MacGregor, Stuart, primary, Maj, Carlo, primary, Melin, Beatrice, primary, Ostrom, Quinn T., primary, Palles, Claire, primary, Schumacher, Johannes, primary, Tomlinson, Ian, primary, Whiteman, David C., primary, Okada, Yukinori, primary, and Kataoka, Keisuke, primary

Published
2023
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44. Risk factors for eight common cancers revealed from a phenome-wide Mendelian randomisation analysis of 378,142 cases and 485,715 controls

Author

Went, Molly, primary, Sud, Amit, additional, Mills, Charlie, additional, Hyde, Abi, additional, Culliford, Richard, additional, Law, Philip, additional, Vijayakrishnan, Jayaram, additional, Gockel, Ines, additional, Maj, Carlo, additional, Schumacher, Johannes, additional, Palles, Claire, additional, Kaiser, Martin, additional, and Houlston, Richard, additional

Published
2023
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46. Genomic analyses of hair from Ludwig van Beethoven

Author

Begg, Tristan James Alexander, primary, Schmidt, Axel, additional, Kocher, Arthur, additional, Larmuseau, Maarten H.D., additional, Runfeldt, Göran, additional, Maier, Paul Andrew, additional, Wilson, John D., additional, Barquera, Rodrigo, additional, Maj, Carlo, additional, Szolek, András, additional, Sager, Michael, additional, Clayton, Stephen, additional, Peltzer, Alexander, additional, Hui, Ruoyun, additional, Ronge, Julia, additional, Reiter, Ella, additional, Freund, Cäcilia, additional, Burri, Marta, additional, Aron, Franziska, additional, Tiliakou, Anthi, additional, Osborn, Joanna, additional, Behar, Doron M., additional, Boecker, Malte, additional, Brandt, Guido, additional, Cleynen, Isabelle, additional, Strassburg, Christian, additional, Prüfer, Kay, additional, Kühnert, Denise, additional, Meredith, William Rhea, additional, Nöthen, Markus M., additional, Attenborough, Robert David, additional, Kivisild, Toomas, additional, and Krause, Johannes, additional

Published
2023
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47. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, and Maj, Carlo

Abstract

Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes ( APC, MLH1, MSH2, MSH6, PMS2) , 2. low (\textless 20\%), intermediate (20–80\%), or high PRS (\textgreater 80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.

Published
2023

48. Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history 2023.03.20.23287470

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, Bobbili, Dheeraj Reddy, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, and Bobbili, Dheeraj Reddy

Abstract

Background & Aims We aimed to investigate the effect of polygenic risk scores (PRSs) derived from individuals of European (EUR) ancestry on common diseases among individuals of South Asian (SAS) ancestry in the UK Biobank (UKB). Additionally, we studied the interaction between PRS and family history (FH) in the same population.Methods To calculate the PRS, we used a previously published panel of SNPs derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. We applied the PRS using summary statistics from genome-wide association studies (GWAS) for cardiometabolic and lifestyle diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D). Each PRS was adjusted according to an individual\textquoterights predicted genetic ancestry to derive an adjusted PRS (aPRS). We calculated the percentiles based on aPRS and divided them according to the percentiles into three categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates.Results The risk of developing severe obesity for individuals of SAS ancestry was almost threefold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 3.67 (95% CI = 2.47-5.48, P < 0.01). While the risk of severe obesity was lower in the low-aPRS group (OR = 0.19, CI = 0.05\textendash0.52, P < 0.01). Comparable results were found in the EUR data, where the low-PRS group had an OR of 0.26 (95% CI= 0.24-0.3, P < 0.01) and the high-PRS group had an OR of 3.2 (95% CI = 3.1-3.3, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS exhibit further higher risk to these diseases, thereby implying a greater genetic predisposition to these conditions.Conclusion Our findings suggest that using CAD, obesity, and T2D GWAS summary statistic

Published
2023

49. Common germline risk variants impact somatic alterations and clinical features across cancers

Author

Namba, Shinichi, Saito, Yuki, Kogure, Yasunori, Masuda, Tatsuo, Bondy, Melissa L., Gharahkhani, Puya, Gockel, Ines, Heider, Dominik, Hillmer, Axel, Jankowski, Janusz, MacGregor, Stuart, Maj, Carlo, Melin, Beatrice S., Ostrom, Quinn T., Palles, Claire, Schumacher, Johannes, Tomlinson, Ian, Whiteman, David C., Okada, Yukinori, Kataoka, Keisuke, Namba, Shinichi, Saito, Yuki, Kogure, Yasunori, Masuda, Tatsuo, Bondy, Melissa L., Gharahkhani, Puya, Gockel, Ines, Heider, Dominik, Hillmer, Axel, Jankowski, Janusz, MacGregor, Stuart, Maj, Carlo, Melin, Beatrice S., Ostrom, Quinn T., Palles, Claire, Schumacher, Johannes, Tomlinson, Ian, Whiteman, David C., Okada, Yukinori, and Kataoka, Keisuke

Abstract

Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome-wide association studies (median n = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank resources (n = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas (n = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., BRCA1/2 variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis. SIGNIFICANCE: Meta-analyses across cancers show that common germline risk variants affect not only cancer predisposition but the age of cancer onset and burden of somatic alterations, including total mutations and copy-number alterations.

Published
2023
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50. Dissecting the genetic heterogeneity of gastric cancer

Author

Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, Schumacher, Johannes, Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, and Schumacher, Johannes

Abstract

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709

Published
2023
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