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5. Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia

Author

Tulstrup, Morten, Moriyama, Takaya, Jiang, Chuang, Grosjean, Marie, Nersting, Jacob, Abrahamsson, Jonas, Grell, Kathrine, Hjalgrim, Lisa Lyngsie, Jónsson, Ólafur Gísli, Kanerva, Jukka, Lund, Bendik, Nielsen, Stine Nygaard, Nielsen, Rikke Linnemann, Overgaard, Ulrik, Quist-Paulsen, Petter, Pruunsild, Kaie, Vaitkeviciene, Goda, Wolthers, Benjamin Ole, Zhang, Hui, Gupta, Ramneek, Yang, Jun J., and Schmiegelow, Kjeld

Published
2020
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7. Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium

Author

Koivula, Robert W., Forgie, Ian M., Kurbasic, Azra, Viñuela, Ana, Heggie, Alison, Giordano, Giuseppe N., Hansen, Tue H., Hudson, Michelle, Koopman, Anitra D. M., Rutters, Femke, Siloaho, Maritta, Allin, Kristine H., Brage, Søren, Brorsson, Caroline A., Dawed, Adem Y., De Masi, Federico, Groves, Christopher J., Kokkola, Tarja, Mahajan, Anubha, Perry, Mandy H., Rauh, Simone P., Ridderstråle, Martin, Teare, Harriet J. A., Thomas, E. Louise, Tura, Andrea, Vestergaard, Henrik, White, Tom, Adamski, Jerzy, Bell, Jimmy D., Beulens, Joline W., Brunak, Søren, Dermitzakis, Emmanouil T., Froguel, Philippe, Frost, Gary, Gupta, Ramneek, Hansen, Torben, Hattersley, Andrew, Jablonka, Bernd, Kaye, Jane, Laakso, Markku, McDonald, Timothy J., Pedersen, Oluf, Schwenk, Jochen M., Pavo, Imre, Mari, Andrea, McCarthy, Mark I., Ruetten, Hartmut, Walker, Mark, Pearson, Ewan, Franks, Paul W., and for the IMI DIRECT Consortium

Published
2019
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8. Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study

Author

Gudmundsdottir, Valborg, Pedersen, Helle Krogh, Mazzoni, Gianluca, Allin, Kristine H., Artati, Anna, Beulens, Joline W., Banasik, Karina, Brorsson, Caroline, Cederberg, Henna, Chabanova, Elizaveta, De Masi, Federico, Elders, Petra J., Forgie, Ian, Giordano, Giuseppe N., Grallert, Harald, Gupta, Ramneek, Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison, Hong, Mun-Gwan, Jones, Angus G., Koivula, Robert, Kokkola, Tarja, Laakso, Markku, Løngreen, Peter, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Musholt, Petra B., Pavo, Imre, Prehn, Cornelia, Ruetten, Hartmut, Ridderstråle, Martin, Rutters, Femke, Sharma, Sapna, Slieker, Roderick C., Syed, Ali, Tajes, Juan Fernandez, Thomas, Cecilia Engel, Thomsen, Henrik S., Vangipurapu, Jagadish, Vestergaard, Henrik, Viñuela, Ana, Wesolowska-Andersen, Agata, Walker, Mark, Adamski, Jerzy, Schwenk, Jochen M., McCarthy, Mark I., Pearson, Ewan, Dermitzakis, Emmanouil, Franks, Paul W., Pedersen, Oluf, and Brunak, Søren

Published
2020
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9. Data integration for prediction of weight loss in randomized controlled dietary trials

Author

Nielsen, Rikke Linnemann, Helenius, Marianne, Garcia, Sara L., Roager, Henrik M., Aytan-Aktug, Derya, Hansen, Lea Benedicte Skov, Lind, Mads Vendelbo, Vogt, Josef K., Dalgaard, Marlene Danner, Bahl, Martin I., Jensen, Cecilia Bang, Muktupavela, Rasa, Warinner, Christina, Aaskov, Vincent, Gøbel, Rikke, Kristensen, Mette, Frøkiær, Hanne, Sparholt, Morten H., Christensen, Anders F., Vestergaard, Henrik, Hansen, Torben, Kristiansen, Karsten, Brix, Susanne, Petersen, Thomas Nordahl, Lauritzen, Lotte, Licht, Tine Rask, Pedersen, Oluf, and Gupta, Ramneek

Published
2020
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10. NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia

Author

Tulstrup, Morten, Grosjean, Marie, Nielsen, Stine Nygaard, Grell, Kathrine, Wolthers, Benjamin Ole, Wegener, Peder Skov, Jonsson, Olafur Gisli, Lund, Bendik, Harila-Saari, Arja, Abrahamsson, Jonas, Vaitkeviciene, Goda, Pruunsild, Kaie, Toft, Nina, Holm, Mette, Hulegårdh, Erik, Liestøl, Sigurd, Griskevicius, Laimonas, Punab, Mari, Wang, Jinhua, Carroll, William L., Zhang, Zeyu, Dalgaard, Marlene D., Gupta, Ramneek, Nersting, Jacob, and Schmiegelow, Kjeld

Published
2018
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12. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance

Author

Jensen, Niels F., Stenvang, Jan, Beck, Mette K., Hanáková, Barbora, Belling, Kirstine C., Do, Khoa N., Viuff, Birgitte, Nygård, Sune B., Gupta, Ramneek, Rasmussen, Mads H., Tarpgaard, Line S., Hansen, Tine P., Budinská, Eva, Pfeiffer, Per, Bosman, Fred, Tejpar, Sabine, Roth, Arnaud, Delorenzi, Mauro, Andersen, Claus L., Rømer, Maria U., Brünner, Nils, and Moreira, José M.A.

Published
2015
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13. Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., de Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, S. ren, Froguel, Philippe, Thomas, Cecilia Engel, Haussler, Ragna, Beulens, Joline, Rutters, Femke, Nijpels, Giel, van Oort, Sabine, Groeneveld, Lenka, Elders, Petra, Giorgino, Toni, Rodriquez, Marianne, Nice, Rachel, Perry, Mandy, Bianzano, Susanna, Graefe-Mody, Ulrike, Hennige, Anita, Grempler, Rolf, Baum, Patrick, Stærfeldt, Hans-Henrik, Shah, Nisha, Teare, Harriet, Ehrhardt, Beate, Tillner, Joachim, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinevich, Iryna, Cabrelli, Louise, Loftus, Heather, Bizzotto, Roberto, Tura, Andrea, Dekkers, Koen, van Leeuwen, Nienke, Groop, Leif, Slieker, Roderick, Ramisch, Anna, Jennison, Christopher, McVittie, Ian, Frau, Francesca, Steckel-Hamann, Birgit, Adragni, Kofi, Thomas, Melissa, Pasdar, Naeimeh Atabaki, Fitipaldi, Hugo, Kurbasic, Azra, Mutie, Pascal, Pomares-Millan, Hugo, Bonnefond, Amelie, Canouil, Mickael, Caiazzo, Robert, Verkindt, Helene, Holl, Reinhard, Kuulasmaa, Teemu, Deshmukh, Harshal, Cederberg, Henna, Laakso, Markku, Vangipurapu, Jagadish, Dale, Matilda, Thorand, Barbara, Nicolay, Claudia, Fritsche, Andreas, Hill, Anita, Hudson, Michelle, Thorne, Claire, Allin, Kristine, Arumugam, Manimozhiyan, Jonsson, Anna, Engelbrechtsen, Line, Forman, Annemette, Dutta, Avirup, Sondertoft, Nadja, Fan, Yong, Gough, Stephen, Robertson, Neil, McRobert, Nicky, Wesolowska-Andersen, Agata, Brown, Andrew, Davtian, David, Dawed, Adem, Donnelly, Louise, Palmer, Colin, White, Margaret, Ferrer, Jorge, Whitcher, Brandon, Artati, Anna, Prehn, Cornelia, Adam, Jonathan, Grallert, Harald, Gupta, Ramneek, Sackett, Peter Wad, Nilsson, Birgitte, Tsirigos, Konstantinos, Eriksen, Rebeca, Jablonka, Bernd, Uhlen, Mathias, Gassenhuber, Johann, Baltauss, Tania, de Preville, Nathalie, Klintenberg, Maria, Abdalla, Moustafa, Lundgaard, Agnete Troen [0000-0001-7447-6560], Hernández Medina, Ricardo [0000-0001-6373-2362], Johansen, Joachim [0000-0001-7052-1870], Niu, Lili [0000-0003-4571-4368], Biel, Jorge Hernansanz [0000-0002-3125-2951], Benros, Michael Eriksen [0000-0003-4939-9465], Pedersen, Anders Gorm [0000-0001-9650-8965], Jacobsen, Ulrik Plesner [0000-0001-9181-6854], Koivula, Robert [0000-0002-1646-4163], Vinuela, Ana [0000-0003-3771-8537], Haid, Mark [0000-0001-6118-1333], Hong, Mun-Gwan [0000-0001-8603-8293], Kennedy, Gwen [0000-0002-9856-3236], Thomas, E Louise [0000-0003-4235-4694], Frost, Gary [0000-0003-0529-6325], Hansen, Tue Haldor [0000-0001-5948-8993], Kaye, Jane [0000-0002-7311-4725], Hattersley, Andrew [0000-0001-5620-473X], Ridderstråle, Martin [0000-0002-3270-9167], Pedersen, Oluf [0000-0002-3321-3972], Hansen, Torben [0000-0001-8748-3831], Schwenk, Jochen M [0000-0001-8141-8449], Rasmussen, Simon [0000-0001-6323-9041], Brunak, Søren [0000-0003-0316-5866], Apollo - University of Cambridge Repository, Epidemiology and Data Science, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, General practice, ACS - Heart failure & arrhythmias, APH - Aging & Later Life, Graduate School, and APH - Methodology

Subjects
Biomedical Engineering, Type 2 diabetes, Bioengineering, Applied Microbiology and Biotechnology, Deep Learning, SDG 3 - Good Health and Well-being, Diabetes Mellitus, Type 2, Machine learning, Molecular Medicine, Humans, Data integration, IMI DIRECT Consortium, Systems biology, Algorithms, Biotechnology
Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Published
2023
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14. Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study

Author

Molnos, Sophie, Wahl, Simone, Haid, Mark, Eekhoff, E. Marelise W., Pool, René, Floegel, Anna, Deelen, Joris, Much, Daniela, Prehn, Cornelia, Breier, Michaela, Draisma, Harmen H., van Leeuwen, Nienke, Simonis-Bik, Annemarie M. C., Jonsson, Anna, Willemsen, Gonneke, Bernigau, Wolfgang, Wang-Sattler, Rui, Suhre, Karsten, Peters, Annette, Thorand, Barbara, Herder, Christian, Rathmann, Wolfgang, Roden, Michael, Gieger, Christian, Kramer, Mark H. H., van Heemst, Diana, Pedersen, Helle K., Gudmundsdottir, Valborg, Schulze, Matthias B., Pischon, Tobias, de Geus, Eco J. C., Boeing, Heiner, Boomsma, Dorret I., Ziegler, Anette G., Slagboom, P. Eline, Hummel, Sandra, Beekman, Marian, Grallert, Harald, Brunak, Søren, McCarthy, Mark I., Gupta, Ramneek, Pearson, Ewan R., Adamski, Jerzy, and ’t Hart, Leen M.

Published
2017
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15. Predicting Hearing Loss in Testicular Cancer Patients after Cisplatin-Based Chemotherapy.

Author

Garcia, Sara L., Lauritsen, Jakob, Christiansen, Bernadette K., Hansen, Ida F., Bandak, Mikkel, Dalgaard, Marlene D., Daugaard, Gedske, and Gupta, Ramneek

Subjects
GERM cell tumors, SEQUENCE analysis, DEAFNESS, CANCER chemotherapy, PATIENT selection, EARLY detection of cancer, MACHINE learning, RISK assessment, TREATMENT effectiveness, CANCER patients, HEARING disorders, TESTIS tumors, CISPLATIN, OTOTOXICITY, QUALITY of life, GENES, RESEARCH funding, LOGISTIC regression analysis, TUMORS, RECEIVER operating characteristic curves, LONGITUDINAL method, COMORBIDITY, DISEASE complications
Abstract

Simple Summary: To our knowledge, this is the first study that presents a machine learning setup incorporating genetics and clinical factors to predict hearing loss in a large and fairly unique cohort of testicular cancer patients, with follow-up data examining long-range side effects of chemotherapy. Genetic variants in SOD2 and MGST3 are proposed as mechanistically associated with cisplatin-induced hearing loss. Further, the models in this study focus on individual patient benefit and incorporation of quality of life measures to identify hearing loss impact. To study short- and long-term effects of chemotherapy, testicular cancer is ideal as a model disease for other cancers, as patients are young with long life-expectancy and without significant comorbidity. With small adjustments, the model can likely be applied in the treatment of other cancers where cisplatin is used, thus helping with choice of treatment without risking a trade-off in efficacy, standing to influence clinical practice. Testicular cancer is predominantly curable, but the long-term side effects of chemotherapy have a severe impact on life quality. In this research study, we focus on hearing loss as a part of overall chemotherapy-induced ototoxicity. This is a unique approach where we combine clinical data from the acclaimed nationwide Danish Testicular Cancer (DaTeCa)-Late database. Clinical and genetic data on 433 patients were collected from hospital files in October 2014. Hearing loss was classified according to the FACT/GOG-Ntx-11 version 4 self-reported Ntx6. Machine learning models combining a genome-wide association study within a nested cross-validated logistic regression were applied to identify patients at high risk of hearing loss. The model comprising clinical and genetic data identified 67% of the patients with hearing loss; however, this was with a false discovery rate of 49%. For the non-affected patients, the model identified 66% of the patients with a false omission rate of 19%. An area under the receiver operating characteristic (ROC-AUC) curve of 0.73 (95% CI, 0.71–0.74) was obtained, and the model suggests genes SOD2 and MGST3 as important in improving prediction over the clinical-only model with a ROC-AUC of 0.66 (95% CI, 0.65–0.66). Such prediction models may be used to allow earlier detection and prevention of hearing loss. We suggest a possible biological mechanism for cisplatin-induced hearing loss development. On confirmation in larger studies, such models can help balance treatment in clinical practice. [ABSTRACT FROM AUTHOR]

Published
2023
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16. A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults

Author

Hansen, Lea B. S., Roager, Henrik M., Søndertoft, Nadja B., Gøbel, Rikke J., Kristensen, Mette, Vallès-Colomer, Mireia, Vieira-Silva, Sara, Ibrügger, Sabine, Lind, Mads V., Mærkedahl, Rasmus B., Bahl, Martin I., Madsen, Mia L., Havelund, Jesper, Falony, Gwen, Tetens, Inge, Nielsen, Trine, Allin, Kristine H., Frandsen, Henrik L., Hartmann, Bolette, Holst, Jens Juul, Sparholt, Morten H., Holck, Jesper, Blennow, Andreas, Moll, Janne Marie, Meyer, Anne S., Hoppe, Camilla, Poulsen, Jørgen H., Carvalho, Vera, Sagnelli, Domenico, Dalgaard, Marlene D., Christensen, Anders F., Lydolph, Magnus Christian, Ross, Alastair B., Villas-Bôas, Silas, Brix, Susanne, Sicheritz-Pontén, Thomas, Buschard, Karsten, Linneberg, Allan, Rumessen, Jüri J., Ekstrøm, Claus T., Ritz, Christian, Kristiansen, Karsten, Nielsen, H. Bjørn, Vestergaard, Henrik, Færgeman, Nils J., Raes, Jeroen, Frøkiær, Hanne, Hansen, Torben, Lauritzen, Lotte, Gupta, Ramneek, Licht, Tine Rask, and Pedersen, Oluf

Published
2018
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18. Acquisition of docetaxel resistance in breast cancer cells reveals upregulation of ABCB1 expression as a key mediator of resistance accompanied by discrete upregulation of other specific genes and pathways

Author

Hansen, Stine Ninel, Westergaard, David, Thomsen, Mathilde Borg Houlberg, Vistesen, Mette, Do, Khoa Nguyen, Fogh, Louise, Belling, Kirstine C., Wang, Jun, Yang, Huanming, Gupta, Ramneek, Ditzel, Henrik J., Moreira, José, Brünner, Nils, Stenvang, Jan, and Schrohl, Anne-Sofie

Published
2015
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19. An Aboriginal Australian Genome Reveals Separate Human Dispersals into Asia

Author

Rasmussen, Morten, Guo, Xiaosen, Wang, Yong, Lohmueller, Kirk E., Rasmussen, Simon, Albrechtsen, Anders, Skotte, Line, Lindgreen, Stinus, Metspalu, Mait, Jombart, Thibaut, Kivisild, Toomas, Zhai, Weiwei, Eriksson, Anders, Manica, Andrea, Orlando, Ludovic, De La Vega, Francisco M., Tridico, Silvana, Metspalu, Ene, Nielsen, Kasper, Ávila-Arcos, María C., Moreno-Mayar, J. Víctor, Muller, Craig, Dortch, Joe, Gilbert, M. Thomas P., Lund, Ole, Wesolowska, Agata, Karmin, Monika, Weinert, Lucy A., Wang, Bo, Li, Jun, Tai, Shuaishuai, Xiao, Fei, Hanihara, Tsunehiko, van Driem, George, Jha, Aashish R., Ricaut, François-Xavier, de Knijff, Peter, Migliano, Andrea B, Romero, Irene Gallego, Kristiansen, Karsten, Lambert, David M., Brunak, Søren, Forster, Peter, Brinkmann, Bernd, Nehlich, Olaf, Bunce, Michael, Richards, Michael, Gupta, Ramneek, Bustamante, Carlos D., Krogh, Anders, Foley, Robert A., Lahr, Marta M., Balloux, Francois, Sicheritz-Pontén, Thomas, Villems, Richard, Nielsen, Rasmus, Wang, Jun, and Willerslev, Eske

Published
2011
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20. Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT Consortium

Author

Koivula, Robert W., Heggie, Alison, Barnett, Anna, Cederberg, Henna, Hansen, Tue H., Koopman, Anitra D., Ridderstråle, Martin, Rutters, Femke, Vestergaard, Henrik, Gupta, Ramneek, Herrgård, Sanna, Heymans, Martijn W., Perry, Mandy H., Rauh, Simone, Siloaho, Maritta, Teare, Harriet J. A., Thorand, Barbara, Bell, Jimmy, Brunak, Søren, Frost, Gary, Jablonka, Bernd, Mari, Andrea, McDonald, Tim J., Dekker, Jacqueline M., Hansen, Torben, Hattersley, Andrew, Laakso, Markku, Pedersen, Oluf, Koivisto, Veikko, Ruetten, Hartmut, Walker, Mark, Pearson, Ewan, Franks, Paul W., and for the DIRECT Consortium

Published
2014
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21. The genome of a Late Pleistocene human from a Clovis burial site in western Montana

Author

Rasmussen, Morten, Anzick, Sarah L., Waters, Michael R., Skoglund, Pontus, DeGiorgio, Michael, Stafford, Jr, Thomas W., Rasmussen, Simon, Moltke, Ida, Albrechtsen, Anders, Doyle, Shane M., Poznik, G. David, Gudmundsdottir, Valborg, Yadav, Rachita, Malaspinas, Anna-Sapfo, V, Samuel Stockton White, Allentoft, Morten E., Cornejo, Omar E., Tambets, Kristiina, Eriksson, Anders, Heintzman, Peter D., Karmin, Monika, Korneliussen, Thorfinn Sand, Meltzer, David J., Pierre, Tracey L., Stenderup, Jesper, Saag, Lauri, Warmuth, Vera M., Lopes, Margarida C., Malhi, Ripan S., Brunak, Søren, Sicheritz-Ponten, Thomas, Barnes, Ian, Collins, Matthew, Orlando, Ludovic, Balloux, Francois, Manica, Andrea, Gupta, Ramneek, Metspalu, Mait, Bustamante, Carlos D., Jakobsson, Mattias, Nielsen, Rasmus, and Willerslev, Eske

Published
2014
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28. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios

Author

Besenbacher, Søren, Liu, Siyang, Izarzugaza, José M. G., Grove, Jakob, Belling, Kirstine, Bork-Jensen, Jette, Huang, Shujia, Als, Thomas D., Li, Shengting, Yadav, Rachita, Rubio-García, Arcadio, Lescai, Francesco, Demontis, Ditte, Rao, Junhua, Ye, Weijian, Mailund, Thomas, Friborg, Rune M., Pedersen, Christian N. S., Xu, Ruiqi, Sun, Jihua, Liu, Hao, Wang, Ou, Cheng, Xiaofang, Flores, David, Rydza, Emil, Rapacki, Kristoffer, Damm Sørensen, John, Chmura, Piotr, Westergaard, David, Dworzynski, Piotr, Sørensen, Thorkild I. A., Lund, Ole, Hansen, Torben, Xu, Xun, Li, Ning, Bolund, Lars, Pedersen, Oluf, Eiberg, Hans, Krogh, Anders, Børglum, Anders D., Brunak, Søren, Kristiansen, Karsten, Schierup, Mikkel H., Wang, Jun, Gupta, Ramneek, Villesen, Palle, and Rasmussen, Simon

Published
2015
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29. Identification of 22 novel loci associated with susceptibility to testicular germ cell tumors

Author

Pluta, John B., Pyle, Louise C., Bishop, D. Timothy, Benitez, Javier, Cortessis, Victoria K., Ferlin, Alberto, Gietema, Jourik A., Greene, Mark H., Grotmol, Tom, Gupta, Ramneek, Hamilton, Robert M, Hildebrandt, Michelle, Kiemeney, Lambertus A, Lessel, Davor, Rafnar, Thorunn, Richiardi, Lorenzo, Skotheim, Rolf I., Turnbull, Clare, Wiklund, Fredrik, Zheng, Tongzhang, Rajpert-De Meyts, Ewa, Schwartz, Stephen M., McGlynn, Katherine A., Kanetsky, Peter A, Nathanson, Katherine L., Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Abstract

Background: Testicular germ cell tumors (TGCT) are the most common cancers in young men of European ancestry aged 20 to 39 years. The incidence of TGCT has doubled over the past 20 years, yet no robust environmental risk factors for disease have been identified. Although TGCTs are treatable by surgery, radiation, and platinum-based chemotherapy, multiple long-term toxicities of treatment often occur impacting morbidity and mortality. Due to their high heritability and homogenous cell of origin, TGCTs are well suited to genome-wide association methods. The Testicular Cancer Consortium (TECAC) has brought together the largest genome-wise association study (GWAS) study of TGCT to date. Methods: We conducted a GWAS of 5,602 cases and 5,006 controls aggregated from 12 locations in the US and Europe. Logistic regression models adjusted for study center and genomic ancestry. Genotypes were imputed against the Human Haplotype Reference Consortium. Meta-analysis was performed to combine GWAS results with summary statistics from five previously published TGCT studies, UK Biobank, deCODE Genetics, and an independent set of cases and controls, for a total of 10,156 cases and 179,683 controls. Biologic function of loci was explored using PAINTOR annotated with ATAC-seq data of four TGCT cell lines, SPATIAL-seq data of the NTERA2 TGCT cell-line, and publicly available data from ENCODE. Polygenic risk scores (PRS) were computed using subject-level data from the 5,602 cases and 5,006 controls, and effect sizes of the novel hits derived from the meta-analysis. Results: 22 novel and 45 previously reported loci associated with TGCT surpassed genome-wide significance (p < 5e-08). We discovered additional markers in known susceptibility loci and identified novel regions associated with germ cell development and sex determination (e.g., BCL11, AR), immune function (e.g., TNXB, ITIH5), and for the first time identified genes associated with kinetochore activity (e.g., PPP2R5A, ANAPC2). All identified risk SNPs to date account for 42.3% of heritability. Men in the highest 1% of PRS had over a 15-fold increased risk of TGCT compared to those at the median PRS, and PRS overall had an AUC of 74.29%. Conclusions: Results from our TGCT meta-analysis continue to provide insights into biological pathways affecting germ cell specification, expression, and epigenetic reprogramming, and sex determination. Our results also uniquely place TGCT as the only cancer type in which inherited variants implicating kinetochore activity, critical for chromosomal segregation, have been identified. Citation Format: John Pluta, Louisa Pyle, Timothy Bishop, Javier Benitez, Victoria Cortessis, Alberto Ferlin, Jourik Gietema, Mark Greene, Thomas Grotmol, Ramneek Gupta, Robert Hamilton, Michelle Hildebrandt, Lambertus Kiemeney, Davor Lessel, Thorunn Rafnar, Lorenzo Richiardi, Rolf Skotheim, Clare Turnbull, Fredrik Wiklund, Tongzhang Zheng, Ewa Rajpert- De Meyts, Stephen Schwartz, Katherine McGlynn, Peter Kanetsky, Katherine Nathanson. Identification of 22 novel loci associated with susceptibility to testicular germ cell tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1203.

Published
2020

30. Sequencing and de novo assembly of 150 genomes from Denmark as a population reference

Author

Maretty, Lasse, Jensen, Jacob Malte, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Villesen, Palle, Skov, Laurits, Belling, Kirstine, Theil Have, Christian, Izarzugaza, Jose M. G., Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, van Beusekom, Johan, Espeseth, Thomas, Flindt, Esben, Friborg, Rune M., Halager, Anders E., Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Lngren, Peter, Mailund, Thomas, Matey-Hernandez, Maria Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontn, Thomas, Sullivan, Patrick, Syed, Ali, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Srensen, Thorkild I. A., Pedersen, Oluf, Gupta, Ramneek, Rasmussen, Simon, Besenbacher, Sren, Brglum, Anders D., Wang, Jun, Eiberg, Hans, Kristiansen, Karsten, Brunak, Sren, and Schierup, Mikkel Heide

Subjects
DNA sequencing -- Methods, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Lasse Maretty [1]; Jacob Malte Jensen [2, 3]; Bent Petersen [4]; Jonas Andreas Sibbesen [1]; Siyang Liu [1, 5]; Palle Villesen [2, 3, 6]; Laurits Skov [2, 3]; Kirstine [...]

Published
2017
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33. Characteristics of white blood cell count in acute lymphoblastic leukemia: A COST LEGEND phenotype–genotype study.

Author

Helenius, Marianne, Vaitkeviciene, Goda, Abrahamsson, Jonas, Jonsson, Ólafur Gisli, Lund, Bendik, Harila‐Saari, Arja, Vettenranta, Kim, Mikkel, Sirje, Stanulla, Martin, Lopez‐Lopez, Elixabet, Waanders, Esmé, Madsen, Hans O., Marquart, Hanne Vibeke, Modvig, Signe, Gupta, Ramneek, Schmiegelow, Kjeld, and Nielsen, Rikke Linnemann

Published
2022
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35. A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation

Author

Dalgaard, Marlene D, Weinhold, Nils, Edsgärd, Daniel, Silver, Jeremy D, Pers, Tune H, Nielsen, John E, Jørgensen, Niels, Juul, Anders, Gerds, Thomas A, Giwercman, Aleksander, Giwercman, Yvonne L, Cohn-Cedermark, Gabriella, Virtanen, Helena E, Toppari, Jorma, Daugaard, Gedske, Jensen, Thomas S, Brunak, Søren, Rajpert-De Meyts, Ewa, Skakkebæk, Niels E, Leffers, Henrik, and Gupta, Ramneek

Published
2012
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36. Ancient human genome sequence of an extinct Palaeo-Eskimo

Author

Rasmussen, Morten, Li, Yingrui, Lindgreen, Stinus, Pedersen, Jakob Skou, Albrechtsen, Anders, Moltke, Ida, Metspalu, Mait, Metspalu, Ene, Kivisild, Toomas, Gupta, Ramneek, Bertalan, Marcelo, Nielsen, Kasper, Gilbert, Thomas M. P., Wang, Yong, Raghavan, Maanasa, Campos, Paula F., Kamp, Hanne Munkholm, Wilson, Andrew S., Gledhill, Andrew, Tridico, Silvana, Bunce, Michael, Lorenzen, Eline D., Binladen, Jonas, Guo, Xiaosen, Zhao, Jing, Zhang, Xiuqing, Zhang, Hao, Li, Zhuo, Chen, Minfeng, Orlando, Ludovic, Kristiansen, Karsten, Bak, Mads, Tommerup, Niels, Bendixen, Christian, Pierre, Tracey L., Grønnow, Bjarne, Meldgaard, Morten, Andreasen, Claus, Fedorova, Sardana A., Osipova, Ludmila P., Higham, Thomas F. G., Ramsey, Christopher Bronk, Hansen, Thomas v. O., Nielsen, Finn C., Crawford, Michael H., Brunak, Søren, Sicheritz-Pontén, Thomas, Villems, Richard, Nielsen, Rasmus, Krogh, Anders, Wang, Jun, and Willerslev, Eske

Published
2010
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41. Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios

Author

Matey-Hernandez, María Luisa, Maretty, Lasse, Jensen, Jacob Malte, Petersen, Bent, Andreas Sibbesen, Jonas, Liu, Siyang, Villesen, Palle, Skov, Laurits, Belling, Kirstine, Theil Have, Christian, Gonzalez-Izarzugaza, Jose Maria, Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, Beusekom, Johan v., Espeseth, Thomas, Flindt, Esben N., Friborg, Rune M., Halager, Anders Egerup, Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Mailund, Thomas, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick F., Ali , Syed, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Sørensen, Thorkild I. A., Pedersen, Oluf, Gupta, Ramneek, Besenbacher, Søren, Børglum, Anders D., Wang, Jun, Eiberg, Hans, Kristiansen, Karsten, Brunak, Søren, Schierup, Mikkel Heide, and Izarzugaza, Jose M. G.

Subjects
0301 basic medicine, Parents, Clinical genomics, Genotyping Techniques, Population genetics, Computational biology, Human leukocyte antigen, Biology, lcsh:Computer applications to medicine. Medical informatics, Biochemistry, Genome, Deep sequencing, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Structural Biology, HLA Antigens, Humans, HLA genotyping, Family, Allele, lcsh:QH301-705.5, Molecular Biology, Allele frequency, Whole genome sequencing, Sweden, Applied Mathematics, Histocompatibility Testing, Genomics, Computer Science Applications, Benchmarking, 030104 developmental biology, lcsh:Biology (General), 030220 oncology & carcinogenesis, NGS, lcsh:R858-859.7, DNA microarray, Prediction, Research Article
Abstract

BACKGROUND: The adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. Concomitantly, correct HLA phenotyping is crucial for successful donor-patient matching in organ transplantation. The cost and technical limitations of current laboratory techniques, together with advances in next-generation sequencing (NGS) methodologies, have increased the need for precise computational typing methods.RESULTS: We tested two widespread HLA typing methods using high quality full genome sequencing data from 150 individuals in 50 family trios from the Genome Denmark project. First, we computed descendant accuracies assessing the agreement in the inheritance of alleles from parents to offspring. Second, we compared the locus-specific homozygosity rates as well as the allele frequencies; and we compared those to the observed values in related populations. We provide guidelines for testing the accuracy of HLA typing methods by comparing family information, which is independent of the availability of curated alleles.CONCLUSIONS: Although current computational methods for HLA typing generally provide satisfactory results, our benchmark - using data with ultra-high sequencing depth - demonstrates the incompleteness of current reference databases, and highlights the importance of providing genomic databases addressing current sequencing standards, a problem yet to be resolved before benefiting fully from personalised medicine approaches HLA phenotyping is essential.

Published
2018
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42. Analysis of 62 hybrid assembled human Y chromosomes exposes rapid structural changes and high rates of gene conversion

Author

Gonzalez-Izarzugaza, Jose Maria, Skov, Laurits, Maretty, Lasse, Jensen, Jacob Malte, Petersen, Bent, Andreas Sibbesen, Jonas, Liu, Siyang, Villesen, Palle, Belling, Kirstine González-Izarzugaza, Theil Have, Christian, Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, van Beusekom, Johan, Espeseth, Thomas, Flindt, Esben, Friborg, Rune M., Halager, Anders E., Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Mailund, Thomas, Matey-Hernandez, María Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick F., Qaswar Ali Shah, Syed, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Sørensen, Thorkild I. A., Pedersen, Oluf, Gupta, Ramneek, Rasmussen, Simon, Besenbacher, Søren, Børglum, Anders D., Wang, Jun, Eiberg, Hans, Kristiansen, Karsten, Brunak, Søren, and Schierup, Mikkel Heide

Subjects
0301 basic medicine, Male, Cancer Research, Inverted repeat, Denmark, Biochemistry, Haplogroup, Fathers, 0302 clinical medicine, INDEL Mutation, Heterochromatin, MUTATION, Genetics (clinical), Phylogeny, POPULATION, Data Management, Genetics, Sex Chromosomes, Insertion Mutation, Chromosome Biology, Phylogenetic Analysis, Y Chromosomes, Nucleic acids, Phylogenetics, GENOME, ALIGNMENT, Deletion Mutation, Mutation (genetic algorithm), Research Article, EXPRESSION, Computer and Information Sciences, lcsh:QH426-470, DNA recombination, Gene Conversion, Biology, Y chromosome, Polymorphism, Single Nucleotide, SEQUENCE, Chromosomes, Nuclear Family, Evolution, Molecular, 03 medical and health sciences, Humans, Evolutionary Systematics, Gene conversion, Insertion, Indel, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Infertility, Male, Taxonomy, COPY NUMBER VARIATION, Evolutionary Biology, Chromosomes, Human, Y, Population Biology, MALE-INFERTILITY, Inverted Repeat Sequences, Biology and Life Sciences, Cell Biology, DNA, POLYMORPHISM, EVOLUTION, lcsh:Genetics, 030104 developmental biology, Evolutionary biology, Mutation, Haplogroups, 030217 neurology & neurosurgery, Population Genetics, Reference genome
Abstract

The human Y-chromosome does not recombine across its male-specific part and is therefore an excellent marker of human migrations. It also plays an important role in male fertility. However, its evolution is difficult to fully understand because of repetitive sequences, inverted repeats and the potentially large role of gene conversion. Here we perform an evolutionary analysis of 62 Y-chromosomes of Danish descent sequenced using a wide range of library insert sizes and high coverage, thus allowing large regions of these chromosomes to be well assembled. These include 17 father-son pairs, which we use to validate variation calling. Using a recent method that can integrate variants based on both mapping and de novo assembly, we genotype 10898 SNVs and 2903 indels (max length of 27241 bp) in our sample and show by father-son concordance and experimental validation that the non-recurrent SNP and indel variation on the Y chromosome tree is called very accurately. This includes variation called in a 0.9 Mb centromeric heterochromatic region, which is by far the most variable in the Y chromosome. Among the variation is also longer sequence-stretches not present in the reference genome but shared with the chimpanzee Y chromosome. We analyzed 2.7 Mb of large inverted repeats (palindromes) for variation patterns among the two palindrome arms and identified 603 mutation and 416 gene conversions events. We find clear evidence for GC-biased gene conversion in the palindromes (and a balancing AT mutation bias), but irrespective of this, also a strong bias towards gene conversion towards the ancestral state, suggesting that palindromic gene conversion may alleviate Muller’s ratchet. Finally, we also find a large number of large-scale gene duplications and deletions in the palindromic regions (at least 24) and find that such events can consist of complex combinations of simultaneous insertions and deletions of long stretches of the Y chromosome., Author summary The Y chromosome is extraordinary in many respects; it is non-recombining along most of its length, it carries many testis-expressed genes that are often found in palindromes and thus in several copies, and it is generally highly repetitive with very few unique genes. Its evolutionary process is not well understood in general because short-read mapping in such complex sequence is difficult. We combine de novo assembly and mapping to investigate evolution in more than 60% of the length of 62 Y chromosomes of Danish descent. We find that Y chromosome evolution is very dynamic even among the set of closely related Y chromosomes in Denmark with many cases of complex duplications and deletions of large regions including whole genes, clear evidence of GC-biased gene conversion in the palindromes and a tendency for gene conversion to revert mutations to their ancestral state.

Published
2017
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43. Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high frequency of cancer prone syndromes.

Author

Byrjalsen, Anna, Hansen, Thomas V. O., Stoltze, Ulrik K., Mehrjouy, Mana M., Barnkob, Nanna Moeller, Hjalgrim, Lisa L., Mathiasen, René, Lautrup, Charlotte K., Gregersen, Pernille A., Hasle, Henrik, Wehner, Peder S., Tuckuviene, Ruta, Sackett, Peter Wad, Laspiur, Adrian O., Rossing, Maria, Marvig, Rasmus L., Tommerup, Niels, Olsen, Tina Elisabeth, Scheie, David, and Gupta, Ramneek

Subjects
CHILD patients, NUCLEOTIDE sequencing, CHILDHOOD cancer, CANCER patients, GERM cells
Abstract

PURPOSE: Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS.METHODS: Children (0–17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries. RESULTS: 198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene. CONCLUSION: These results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed. Author summary: Traditionally cancer in childhood have been thought to be–mostly–caused by pure bad luck. In recent years, however, this notion has been challenged by novel findings as both maternal environmental exposure and genetic causes have been identified. With this study we have investigated a national cohort of childhood cancer patients in Denmark. We have mapped family pedigree, made physical examination of the patients, and sequenced their genome, to get a 360-degree understanding of these patients. This revealed that a tenth of all patients carried a genetic variant causative of their cancer development. In addition, almost half of all patients were suspected of carrying a causative genetic variant based on tools that evaluate type of cancer, physical characteristics and family history. It also showed that tools to predict which patients carried a genetic variant did not identify all patients who in fact carried a genetic variant. Overall, roughly half of all patients were suspected of carrying an underlying genetic cause of their cancer, and a tenth had a verified underlying genetic variant predisposing to cancer development in childhood. This could suggest that the amount of childhood cancer cases attributed to genetic factors may be even higher. [ABSTRACT FROM AUTHOR]

Published
2020
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44. The intestinal microbiome is a co-determinant of the postprandial plasma glucose response.

Author

Søndertoft, Nadja B., Vogt, Josef K., Arumugam, Manimozhiyan, Kristensen, Mette, Gøbel, Rikke J., Fan, Yong, Lyu, Liwei, Bahl, Martin I., Eriksen, Carsten, Ängquist, Lars, Frøkiær, Hanne, Hansen, Tue H., Brix, Susanne, Nielsen, H. Bjørn, Hansen, Torben, Vestergaard, Henrik, Gupta, Ramneek, Licht, Tine R., Lauritzen, Lotte, and Pedersen, Oluf

Subjects
BLOOD sugar, GLYCEMIC index, INTESTINAL physiology, SYSTOLIC blood pressure, BLOOD pressure, PEARSON correlation (Statistics), BLOOD cholesterol, SPECIES diversity
Abstract

Elevated postprandial plasma glucose is a risk factor for development of type 2 diabetes and cardiovascular disease. We hypothesized that the inter-individual postprandial plasma glucose response varies partly depending on the intestinal microbiome composition and function. We analyzed data from Danish adults (n = 106), who were self-reported healthy and attended the baseline visit of two previously reported randomized controlled cross-over trials within the Gut, Grain and Greens project. Plasma glucose concentrations at five time points were measured before and during three hours after a standardized breakfast. Based on these data, we devised machine learning algorithms integrating bio-clinical, as well as shotgun-sequencing-derived taxa and functional potentials of the intestinal microbiome to predict individual postprandial glucose excursions. In this post hoc study, we found microbial and clinical features, which predicted up to 48% of the inter-individual variance of postprandial plasma glucose responses (Pearson correlation coefficient of measured vs. predicted values, R = 0.69, 95% CI: 0.45 to 0.84, p<0.001). The features were age, fasting serum triglycerides, systolic blood pressure, BMI, fasting total serum cholesterol, abundance of Bifidobacterium genus, richness of metagenomics species and abundance of a metagenomic species annotated to Clostridiales at order level. A model based only on microbial features predicted up to 14% of the variance in postprandial plasma glucose excursions (R = 0.37, 95% CI: 0.02 to 0.64, p = 0.04). Adding fasting glycaemic measures to the model including microbial and bio-clinical features increased the predictive power to R = 0.78 (95% CI: 0.59 to 0.89, p<0.001), explaining more than 60% of the inter-individual variance of postprandial plasma glucose concentrations. The outcome of the study points to a potential role of the taxa and functional potentials of the intestinal microbiome. If validated in larger studies our findings may be included in future algorithms attempting to develop personalized nutrition, especially for prediction of individual blood glucose excursions in dys-glycaemic individuals. [ABSTRACT FROM AUTHOR]

Published
2020
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45. Prediction of Nephrotoxicity Associated With Cisplatin-Based Chemotherapy in Testicular Cancer Patients.

Author

Garcia, Sara L, Lauritsen, Jakob, Zhang, Zeyu, Bandak, Mikkel, Dalgaard, Marlene D, Nielsen, Rikke L, Daugaard, Gedske, and Gupta, Ramneek

Subjects
NEPHROTOXICOLOGY, CISPLATIN, CANCER chemotherapy
Abstract

Background Cisplatin-based chemotherapy may induce nephrotoxicity. This study presents a random forest predictive model that identifies testicular cancer patients at risk of nephrotoxicity before treatment. Methods Clinical data and DNA from saliva samples were collected for 433 patients. These were genotyped on Illumina HumanOmniExpressExome-8 v1.2 (964 193 markers). Clinical and genomics-based random forest models generated a risk score for each individual to develop nephrotoxicity defined as a 20% drop in isotopic glomerular filtration rate during chemotherapy. The area under the receiver operating characteristic curve was the primary measure to evaluate models. Sensitivity, specificity, and positive and negative predictive values were used to discuss model clinical utility. Results Of 433 patients assessed in this study, 26.8% developed nephrotoxicity after bleomycin-etoposide-cisplatin treatment. Genomic markers found to be associated with nephrotoxicity were located at NAT1 , NAT2 , and the intergenic region of CNTN6 and CNTN4. These, in addition to previously associated markers located at ERCC1 , ERCC2 , and SLC22A2 , were found to improve predictions in a clinical feature–trained random forest model. Using only clinical data for training the model, an area under the receiver operating characteristic curve of 0.635 (95% confidence interval [CI] = 0.629 to 0.640) was obtained. Retraining the classifier by adding genomics markers increased performance to 0.731 (95% CI = 0.726 to 0.736) and 0.692 (95% CI = 0.688 to 0.696) on the holdout set. Conclusions A clinical and genomics-based machine learning algorithm improved the ability to identify patients at risk of nephrotoxicity compared with using clinical variables alone. Novel genetics associations with cisplatin-induced nephrotoxicity were found for NAT1 , NAT2 , CNTN6 , and CNTN4 that require replication in larger studies before application to clinical practice. [ABSTRACT FROM AUTHOR]

Published
2020
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47. Discovery, genotyping and characterization of structural variation and novel sequence at single nucleotide resolution from de novo genome assemblies on a population scale

Author

Liu, Siyang, Huang, Shujia, Rao, Junhua, Ye, Weijian, Schierup, Mikkel H., Villesen, Palle, Xu, Xun, Li, Ning, Kristiansen, Karsten, Sørensen, Thorkild I. A., Hansen, Torben, Pedersen, Oluf, Brunak, Søren, Gupta, Ramneek, Rasmussen, Simon, Lund, Ole, Bolund, Lars, Børglum, Anders D., Eiberg, Hans, Nørgaard Flindt, Esben, Xu, Ruiqi, Sun, Jihua, Liu, Hao, Jiang, Hui, Wang, Ou, Cheng, Xiaofang, Demontis, Ditte, Besenbacher, Søren, Mailund, Thomas, Friborg, Rune M., Pedersen, Christian N. S., Chang, Yuqi, Li, Shengting, Guo, Xiaosen, Cao, Hongzhi, Ye, Chen, Maretty, Lasse, Andreas Sibbesen, Jonas, Albrechtsen, Anders, Bork-Jensen, Jette, Theil Have, Christian, Gonzalez-Izarzugaza, Jose Maria, Belling, Kirstine González-Izarzugaza, Yadav, Rachita, Grove, Jakob, Dam-Als, Thomas, Lescai, Francesco, Krogh, Anders, and Wang, Jun

Subjects
Novel sequence, Genotype, Sequence analysis, Population, Sequence assembly, Health Informatics, Single-nucleotide polymorphism, Genomics, Computational biology, Biology, de novo assembly, Genome, Structural variation, SDG 3 - Good Health and Well-being, Technical Note, De novo assembly, Humans, education, Genetics, education.field_of_study, Genome, Human, Genetic Variation, High-Throughput Nucleotide Sequencing, Computer Science Applications, Human genome, Sequence Analysis, Software
Abstract

Background Comprehensive recognition of genomic variation in one individual is important for understanding disease and developing personalized medication and treatment. Many tools based on DNA re-sequencing exist for identification of single nucleotide polymorphisms, small insertions and deletions (indels) as well as large deletions. However, these approaches consistently display a substantial bias against the recovery of complex structural variants and novel sequence in individual genomes and do not provide interpretation information such as the annotation of ancestral state and formation mechanism. Findings We present a novel approach implemented in a single software package, AsmVar, to discover, genotype and characterize different forms of structural variation and novel sequence from population-scale de novo genome assemblies up to nucleotide resolution. Application of AsmVar to several human de novo genome assemblies captures a wide spectrum of structural variants and novel sequences present in the human population in high sensitivity and specificity. Conclusions Our method provides a direct solution for investigating structural variants and novel sequences from de novo genome assemblies, facilitating the construction of population-scale pan-genomes. Our study also highlights the usefulness of the de novo assembly strategy for definition of genome structure. Electronic supplementary material The online version of this article (doi:10.1186/s13742-015-0103-4) contains supplementary material, which is available to authorized users.

Published
2015
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48. Genetic predisposition to PEG‐asparaginase hypersensitivity in children treated according to NOPHO ALL2008.

Author

Højfeldt, Sofie G., Wolthers, Benjamin O., Tulstrup, Morten, Abrahamsson, Jonas, Gupta, Ramneek, Harila‐Saari, Arja, Heyman, Mats, Henriksen, Louise T., Jónsson, Òlafur G., Lähteenmäki, Päivi M., Lund, Bendik, Pruunsild, Kaie, Vaitkeviciene, Goda, Schmiegelow, Kjeld, and Albertsen, Birgitte K.

Abstract

Summary: Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG‐asparaginase) hampers anti‐neoplastic efficacy. Patients with PEG‐asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG‐asparaginase hypersensitivity in a genome‐wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG‐asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty‐nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG‐asparaginase allergy (P = 4·68 × 10−8). We further identified two signals on chromosome 6 in relation to HLA‐DQA1 (P = 9·37 × 10−6) and TAP2 (P = 1·59 × 10−5). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG‐asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG‐asparaginase hypersensitivity. [ABSTRACT FROM AUTHOR]

Published
2019
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49. Meta-analysis of genome-wide association studies identifies 10 loci influencing allergic sensitization

Author

Bønnelykke, Klaus, Matheson, Melanie C, Pers, Tune H, Granell, Raquel, Strachan, David P, Alves, Alexessander Couto, Linneberg, Allan, Curtin, John A, Warrington, Nicole M, Standl, Marie, Kerkhof, Marjan, Jonsdottir, Ingileif, Bukvic, Blazenka K, Kaakinen, Marika, Sleimann, Patrick, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Schramm, Katharina, Baltic, Svetlana, Kreiner-Møller, Eskil, Simpson, Angela, St Pourcain, Beate, Coin, Lachlan, Hui, Jennie, Walters, Eugene H, Tiesler, Carla M T, Duffy, David L, Jones, Graham, Ring, Susan M, McArdle, Wendy L, Price, Loren, Robertson, Colin F, Pekkanen, Juha, Tang, Clara S, Thiering, Elisabeth, Montgomery, Grant W, Hartikainen, Anna-Liisa, Dharmage, Shyamali C, Husemoen, Lise L, Herder, Christian, Kemp, John P, Elliot, Paul, James, Alan, Waldenberger, Melanie, Abramson, Michael J, Fairfax, Benjamin P, Knight, Julian C, Gupta, Ramneek, Thompson, Philip J, Holt, Patrick, Sly, Peter, Hirschhorn, Joel N, Blekic, Mario, Weidinger, Stephan, Hakonarsson, Hakon, Stefansson, Kari, Heinrich, Joachim, Postma, Dirkje S, Custovic, Adnan, Pennell, Craig E, Jarvelin, Marjo-Riitta, Koppelman, Gerard H, Timpson, Nicholas, Ferreira, Manuel A, Bisgaard, Hans, and Henderson, A John

Subjects
Phenotype, Genetic Loci, Quantitative Trait Loci, Hypersensitivity, Computational Biology, Humans, Gene Regulatory Networks, Genomics, Polymorphism, Single Nucleotide, Article, Alleles, Genome-Wide Association Study, Signal Transduction
Abstract

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Published
2013

50. Transcriptome analysis of root‐knot nematode (<italic>Meloidogyne incognita</italic>)‐infected tomato (<italic>Solanum lycopersicum</italic>) roots reveals complex gene expression profiles and metabolic networks of both host and nematode during susceptible and resistance responses

Author

Shukla, Neha, Yadav, Rachita, Kaur, Pritam, Rasmussen, Simon, Goel, Shailendra, Agarwal, Manu, Jagannath, Arun, Gupta, Ramneek, and Kumar, Amar

Subjects
SOUTHERN root-knot nematode, TOMATO diseases & pests, HOST plants, GENE expression in plants, CELLULAR signal transduction
Abstract

Summary: Root‐knot nematodes (RKNs, Meloidogyne incognita) are economically important endoparasites with a wide host range. We used a comprehensive transcriptomic approach to investigate the expression of both tomato and RKN genes in tomato roots at five infection time intervals from susceptible plants and two infection time intervals from resistant plants, grown under soil conditions. Differentially expressed genes during susceptible (1827, tomato; 462, RKN) and resistance (25, tomato; 160, RKN) interactions were identified. In susceptible responses, tomato genes involved in cell wall structure, development, primary and secondary metabolite, and defence signalling pathways, together with RKN genes involved in host parasitism, development and defence, are discussed. In resistance responses, tomato genes involved in secondary metabolite and hormone‐mediated defence responses, together with RKN genes involved in starvation stress‐induced apoptosis, are discussed. In addition, 40 novel differentially expressed RKN genes encoding secretory proteins were identified. Our findings provide novel insights into the temporal regulation of genes involved in various biological processes from tomato and RKN simultaneously during susceptible and resistance responses, and reveal the involvement of a complex network of biosynthetic pathways during disease development. [ABSTRACT FROM AUTHOR]

Published
2018
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