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1. Novel loci and biomedical consequences of iron homoeostasis variation

Author: Allara, Elias, Bell, Steven, Smith, Rebecca, Keene, Spencer J., Gill, Dipender, Gaziano, Liam, Morselli Gysi, Deisy, Wang, Feiyi, Tragante, Vinicius, Mason, Amy, Karthikeyan, Savita, Lumbers, R. Thomas, Bonglack, Emmanuela, Ouwehand, Willem, Roberts, David J., Dowsett, Joseph, Ostrowski, Sisse Rye, Larsen, Margit Hørup, Ullum, Henrik, Pedersen, Ole Birger, Brunak, Søren, Banasik, Karina, Erikstrup, Christian, Mitchell, Jonathan, Fuchsberger, Christian, Pattaro, Cristian, Pramstaller, Peter P., Girelli, Domenico, Arvas, Mikko, Toivonen, Jarkko, Molnos, Sophie, Peters, Annette, Polasek, Ozren, Rudan, Igor, Hayward, Caroline, McDonnell, Ciara, Pirastu, Nicola, Wilson, James F., van den Hurk, Katja, Quee, Franke, Ferrucci, Luigi, Bandinelli, Stefania, Tanaka, Toshiko, Girotto, Giorgia, Concas, Maria Pina, Pecori, Alessandro, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi J., Kiemeney, Lambertus A., Sweep, Fred C., Galesloot, Tessel E., Sulem, Patrick, Gudbjartsson, Daniel, Ferkingstad, Egil, Djousse, Luc, Cho, Kelly, Inouye, Michael, Burgess, Stephen, Benyamin, Beben, Oexle, Konrad, Swinkels, Dorine, Stefansson, Kari, Magnusson, Magnus, Ganna, Andrea, Gaziano, Michael, Ivey, Kerry, Danesh, John, Pereira, Alexandre, Wood, Angela M., Butterworth, Adam S., and Di Angelantonio, Emanuele
Published: 2024
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2. Lifestyle and demographic associations with 47 inflammatory and vascular stress biomarkers in 9876 blood donors

Author: Kjerulff, Bertram, Dowsett, Joseph, Jacobsen, Rikke Louise, Gladov, Josephine, Larsen, Margit Hørup, Lundgaard, Agnete Troen, Banasik, Karina, Westergaard, David, Mikkelsen, Susan, Dinh, Khoa Manh, Hindhede, Lotte, Kaspersen, Kathrine Agergård, Schwinn, Michael, Juul, Anders, Poulsen, Betina, Lindegaard, Birgitte, Pedersen, Carsten Bøcker, Sabel, Clive Eric, Bundgaard, Henning, Nielsen, Henriette Svarre, Møller, Janne Amstrup, Boldsen, Jens Kjærgaard, Burgdorf, Kristoffer Sølvsten, Kessing, Lars Vedel, Handgaard, Linda Jenny, Thørner, Lise Wegner, Didriksen, Maria, Nyegaard, Mette, Grarup, Niels, Ødum, Niels, Johansson, Pär I., Jennum, Poul, Frikke-Schmidt, Ruth, Berger, Sanne Schou, Brunak, Søren, Jacobsen, Søren, Hansen, Thomas Folkmann, Lundquist, Tine Kirkeskov, Hansen, Torben, Sørensen, Torben Lykke, Sigsgaard, Torben, Nielsen, Kaspar René, Bruun, Mie Topholm, Hjalgrim, Henrik, Ullum, Henrik, Rostgaard, Klaus, Sørensen, Erik, Pedersen, Ole Birger, Ostrowski, Sisse Rye, and Erikstrup, Christian
Published: 2024
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3. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction

Author: Schormair, Barbara, Zhao, Chen, Bell, Steven, Didriksen, Maria, Nawaz, Muhammad S., Schandra, Nathalie, Stefani, Ambra, Högl, Birgit, Dauvilliers, Yves, Bachmann, Cornelius G., Kemlink, David, Sonka, Karel, Paulus, Walter, Trenkwalder, Claudia, Oertel, Wolfgang H., Hornyak, Magdolna, Teder-Laving, Maris, Metspalu, Andres, Hadjigeorgiou, Georgios M., Polo, Olli, Fietze, Ingo, Ross, Owen A., Wszolek, Zbigniew K., Ibrahim, Abubaker, Bergmann, Melanie, Kittke, Volker, Harrer, Philip, Dowsett, Joseph, Chenini, Sofiene, Ostrowski, Sisse Rye, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole B., Topholm Bruun, Mie, Nielsen, Kaspar R., Butterworth, Adam S., Soranzo, Nicole, Ouwehand, Willem H., Roberts, David J., Danesh, John, Burchell, Brendan, Furlotte, Nicholas A., Nandakumar, Priyanka, Earley, Christopher J., Ondo, William G., Xiong, Lan, Desautels, Alex, Perola, Markus, Vodicka, Pavel, Dina, Christian, Stoll, Monika, Franke, Andre, Lieb, Wolfgang, Stewart, Alexandre F. R., Shah, Svati H., Gieger, Christian, Peters, Annette, Rye, David B., Rouleau, Guy A., Berger, Klaus, Stefansson, Hreinn, Ullum, Henrik, Stefansson, Kari, Hinds, David A., Di Angelantonio, Emanuele, Oexle, Konrad, and Winkelmann, Juliane
Published: 2024
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4. Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

Author: Chen, Hao Yu, Dina, Christian, Small, Aeron M, Shaffer, Christian M, Levinson, Rebecca T, Helgadóttir, Anna, Capoulade, Romain, Munter, Hans Markus, Martinsson, Andreas, Cairns, Benjamin J, Trudsø, Linea C, Hoekstra, Mary, Burr, Hannah A, Marsh, Thomas W, Damrauer, Scott M, Dufresne, Line, Le Scouarnec, Solena, Messika-Zeitoun, David, Ranatunga, Dilrini K, Whitmer, Rachel A, Bonnefond, Amélie, Sveinbjornsson, Garðar, Daníelsen, Ragnar, Arnar, David O, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Gudbjartsson, Daníel F, Hólm, Hilma, Ghouse, Jonas, Olesen, Morten Salling, Christensen, Alex H, Mikkelsen, Susan, Jacobsen, Rikke Louise, Dowsett, Joseph, Pedersen, Ole Birger Vesterager, Erikstrup, Christian, Ostrowski, Sisse R, Center, Regeneron Genetics, O’Donnell, Christopher J, Budoff, Matthew J, Gudnason, Vilmundur, Post, Wendy S, Rotter, Jerome I, Lathrop, Mark, Bundgaard, Henning, Johansson, Bengt, Ljungberg, Johan, Näslund, Ulf, Le Tourneau, Thierry, Smith, J Gustav, Wells, Quinn S, Söderberg, Stefan, Stefánsson, Kári, Schott, Jean-Jacques, Rader, Daniel J, Clarke, Robert, Engert, James C, and Thanassoulis, George
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Prevention, Heart Disease - Coronary Heart Disease, Atherosclerosis, Genetics, Human Genome, Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Humans, Genome-Wide Association Study, Adiposity, Genetic Predisposition to Disease, Aortic Valve Stenosis, Obesity, Risk Factors, Inflammation, Dyslipidemias, Apolipoproteins, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Aortic stenosis, Genome-wide association study, Mendelian randomization, Phenome-wide association study, Gene expression, Genetic risk score, Regeneron Genetics Center, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract: AimsAlthough highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS.Methods and resultsA genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.ConclusionDyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.
Published: 2023

5. Developmental language disorder – heritability and genetic correlations with other disorders affecting language

Author: Banasik, Karina, Bay, Jakob, Kjærgaard Boldsen, Jens, Brodersen, Thorsten, Brunak, Søren, Demur, Alfonso Buil, Nordahl Christoffersen, Lea Arregui, Didriksen, Maria, Dinh, Khoa Manh, Dowsett, Joseph, Erikstrup, Christian, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hansen, Thomas Folkmann, Mikkelsen, Dorte Helenius, Hindhede, Lotte, Hjalgrim, Henrik, von Stemann, Jakob Hjorth, Jensen, Bitten Aagaard, Schork, Andrew Joseph, Kaspersen, Kathrine, Kjerulff, Bertram Dalskov, Kongstad, Mette, Mikkelsen, Susan, Mikkelsen, Christina, Nissen, Janna, Nyegaard, Mette, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Elgaard Quinn, Liam James, Rafnar, Þórunn, Rohde, Palle Duun, Rostgaard, Klaus, Schwinn, Michael, Sørensen, Erik, Stefansson, Kari, Stefánsson, Hreinn, Thørner, Lise Wegner, Þorsteinsdóttir, Unnur, Bruun, Mie Topholm, Ullum, Henrik, Werge, Thomas, Westergaard, David, Nudel, Ron, Chrsitensen, Rikke Vang, Kalnak, Nelli, Lundberg, Mischa, Christoffersen, Lea Arregui Nordahl, Burgdorf, Kristoffer Sølvsten, Pedersen, Ole Birger Vesterager, Gísladóttir, Rósa S., and Walters, G. Bragi
Published: 2024
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6. Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies

Author: Adams, Mark J., Streit, Fabian, Meng, Xiangrui, Awasthi, Swapnil, Adey, Brett N., Choi, Karmel W., Chundru, V. Kartik, Coleman, Jonathan R.I., Ferwerda, Bart, Foo, Jerome C., Gerring, Zachary F., Giannakopoulou, Olga, Gupta, Priya, Hall, Alisha S.M., Harder, Arvid, Howard, David M., Hübel, Christopher, Kwong, Alex S.F., Levey, Daniel F., Mitchell, Brittany L., Ni, Guiyan, Ota, Vanessa K., Pain, Oliver, Pathak, Gita A., Schulte, Eva C., Shen, Xueyi, Thorp, Jackson G., Walker, Alicia, Yao, Shuyang, Zeng, Jian, Zvrskovec, Johan, Aarsland, Dag, Actkins, Ky'Era V., Adli, Mazda, Agerbo, Esben, Aichholzer, Mareike, Aiello, Allison, Air, Tracy M., Als, Thomas D., Andersson, Evelyn, Andlauer, Till F.M., Arolt, Volker, Ask, Helga, Bäckman, Julia, Badola, Sunita, Ballard, Clive, Banasik, Karina, Bass, Nicholas J., Beekman, Aartjan T.F., Belangero, Sintia, Bigdeli, Tim B., Binder, Elisabeth B., Bjerkeset, Ottar, Bjornsdottir, Gyda, Børte, Sigrid, Bränn, Emma, Braun, Alice, Brodersen, Thorsten, Brückl, Tanja M., Brunak, Søren, Bruun, Mie T., Burmeister, Margit, Buspavanich, Pichit, Bybjerg-Grauholm, Jonas, Byrne, Enda M., Cai, Jianwen, Campbell, Archie, Campbell, Megan L., Campos, Adrian I., Castelao, Enrique, Cervilla, Jorge, Chaumette, Boris, Chen, Chia-Yen, Chen, Hsi-Chung, Chen, Zhengming, Cichon, Sven, Colodro-Conde, Lucía, Corbett, Anne, Corfield, Elizabeth C., Couvy-Duchesne, Baptiste, Craddock, Nick, Dannlowski, Udo, Davies, Gail, de Geus, E.J.C., Deary, Ian J., Degenhardt, Franziska, Dehghan, Abbas, DePaulo, J. Raymond, Deuschle, Michael, Didriksen, Maria, Dinh, Khoa Manh, Direk, Nese, Djurovic, Srdjan, Docherty, Anna R., Domschke, Katharina, Dowsett, Joseph, Drange, Ole Kristian, Dunn, Erin C., Eaton, William, Einarsson, Gudmundur, Eley, Thalia C., Elsheikh, Samar S.M., Engelmann, Jan, Benros, Michael E., Erikstrup, Christian, Escott-Price, Valentina, Fabbri, Chiara, Fang, Yu, Finer, Sarah, Frank, Josef, Free, Robert C., Gallo, Linda, Gao, He, Gill, Michael, Gilles, Maria, Goes, Fernando S., Gordon, Scott Douglas, Grove, Jakob, Gudbjartsson, Daniel F., Gutierrez, Blanca, Hahn, Tim, Hall, Lynsey S., Hansen, Thomas F., Haraldsson, Magnus, Hartman, Catharina A., Havdahl, Alexandra, Hayward, Caroline, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hickie, Ian B., Hjalgrim, Henrik, Hjerling-Leffler, Jens, Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Hovatta, Iiris, Huang, Qin Qin, Hucks, Donald, Huider, Floris, Hunt, Karen A., Ialongo, Nicholas S., Ising, Marcus, Isometsä, Erkki, Jansen, Rick, Jiang, Yunxuan, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kanai, Masahiro, Karlsson, Robert, Kasper, Siegfried, Kendler, Kenneth S., Kessler, Ronald C., Kloiber, Stefan, Knowles, James A., Koen, Nastassja, Kraft, Julia, Kranzler, Henry R., Krebs, Kristi, Kallak, Theodora Kunovac, Kutalik, Zoltán, Lahtela, Elisa, Lake, Marilyn, Larsen, Margit Hørup, Lenze, Eric J., Lewins, Melissa, Lewis, Glyn, Li, Liming, Lin, Bochao Danae, Lin, Kuang, Lind, Penelope A., Liu, Yu-Li, MacIntyre, Donald J., MacKinnon, Dean F., Maher, Brion S., Maier, Wolfgang, Marshe, Victoria S., Martinez-Levy, Gabriela A., Matsuda, Koichi, Mbarek, Hamdi, McGuffin, Peter, Medland, Sarah E., Meinert, Susanne, Mikkelsen, Christina, Mikkelsen, Susan, Milaneschi, Yuri, Millwood, Iona Y., Molina, Esther, Mondimore, Francis M., Mortensen, Preben Bo, Mulsant, Benoit H., Naamanka, Joonas, Najman, Jake M., Nauck, Matthias, Nenadić, Igor, Nielsen, Kasper R., Nolt, Ilja M., Nordentoft, Merete, Nöthen, Markus M., Nyegaard, Mette, O'Donovan, Michael C., Oddsson, Asmundur, Oliveira, Adrielle M., Olsen, Catherine M., Oskarsson, Hogni, Ostrowski, Sisse Rye, Owen, Michael J., Packer, Richard, Palviainen, Teemu, Pan, Pedro M., Pato, Carlos N., Pato, Michele T., Pedersen, Nancy L., Pedersen, Ole Birger, Peyrot, Wouter J., Potash, James B., Preisig, Martin, Preuss, Michael H., Quiroz, Jorge A., Renteria, Miguel E., Reynolds III, Charles F., Rice, John P., Sakaue, Saori, Santoro, Marcos L., Schoevers, Robert A., Schork, Andrew, Schulze, Thomas G., Send, Tabea S., Shi, Jianxin, Sigurdsson, Engilbert, Singh, Kritika, Sinnamon, Grant C.B., Sirignano, Lea, Smeland, Olav B., Smith, Daniel J., Sofer, Tamar, Sørensen, Erik, Srinivasan, Sundararajan, Stefansson, Hreinn, Stefansson, Kari, Straub, Peter, Su, Mei-Hsin, Tadic, André, Teismann, Henning, Teumer, Alexander, Thapar, Anita, Thomson, Pippa A., Thørner, Lise Wegner, Topaloudi, Apostolia, Tsai, Shih-Jen, Tzoulaki, Ioanna, Uhl, George, Uitterlinden, André G., Ullum, Henrik, Umbricht, Daniel, Ursano, Robert J., Van der Auwera, Sandra, van Hemert, Albert M., Veluchamy, Abirami, Viktorin, Alexander, Völzke, Henry, Walters, G. Bragi, Wang, Xiaotong, Wani, Agaz, Weissman, Myrna M., Wellmann, Jürgen, Whiteman, David C., Wildman, Derek, Willemsen, Gonneke, Williams, Alexander T., Winsvold, Bendik S., Witt, Stephanie H., Xiong, Ying, Zillich, Lea, Zwart, John-Anker, Twenty-Three and Me Research Team, China Kadoorie Biobank Collaborative Group, Estonian Biobank Research Team, Genes & Health Research Team, HUNT All-In Psychiatry, The BioBank Japan Project, VA Million Veteran Program, Andreassen, Ole A., Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Børglum, Anders D., Breen, Gerome, Cai, Na, Coon, Hilary, Copeland, William E., Creese, Byron, Cruz-Fuentes, Carlos S., Czamara, Darina, Davis, Lea K., Derks, Eske M., Domenici, Enrico, Elliott, Paul, Forstner, Andreas J., Gawlik, Micha, Gelernter, Joel, Grabe, Hans J., Hamilton, Steven P., Hveem, Kristian, John, Catherine, Kaprio, Jaakko, Kircher, Tilo, Krebs, Marie-Odile, Kuo, Po-Hsiu, Landén, Mikael, Lehto, Kelli, Levinson, Douglas F., Li, Qingqin S., Lieb, Klaus, Loos, Ruth J.F., Lu, Yi, Lucae, Susanne, Luykx, Jurjen J., Maes, Hermine H.M., Magnusson, Patrik K., Martin, Hilary C., Martin, Nicholas G., McQuillin, Andrew, Middeldorp, Christel M., Milani, Lili, Mors, Ole, Müller, Daniel J., Müller-Myhsok, Bertram, Okada, Yukinori, Oldehinkel, Albertine J., Paciga, Sara A., Palmer, Colin N.A., Paschou, Peristera, Penninx, Brenda W.J.H., Perlis, Roy H., Peterson, Roseann E., Pistis, Giorgio, Polimanti, Renato, Porteous, David J., Posthuma, Danielle, Rabinowitz, Jill A., Reichborn-Kjennerud, Ted, Reif, Andreas, Rice, Frances, Ricken, Roland, Rietschel, Marcella, Rivera, Margarita, Rück, Christian, Salum, Giovanni A., Schaefer, Catherine, Sen, Srijan, Serretti, Alessandro, Skalkidou, Alkistis, Smoller, Jordan W., Stein, Dan J., Stein, Frederike, Stein, Murray B., Sullivan, Patrick F., Tesli, Martin, Thorgeirsson, Thorgeir E., Tiemeier, Henning, Timpson, Nicholas J., Uddin, Monica, Uher, Rudolf, van Heel, David A., Verweij, Karin J.H., Walters, Robin G., Wassertheil-Smoller, Sylvia, Wendland, Jens R., Werge, Thomas, Zwinderman, Aeilko H., Kuchenbaecker, Karoline, Wray, Naomi R., Ripke, Stephan, Lewis, Cathryn M., and McIntosh, Andrew M.
Published: 2024
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7. Chronic inflammation markers and cytokine-specific autoantibodies in Danish blood donors with restless legs syndrome

Author: Dowsett, Joseph, Didriksen, Maria, von Stemann, Jakob Hjorth, Larsen, Margit Hørup, Thørner, Lise Wegner, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole Birger, Hansen, Morten Bagge, Eugen-Olsen, Jesper, Banasik, Karina, and Ostrowski, Sisse Rye
Published: 2022
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8. No association between plasma hepcidin levels and restless legs syndrome - results from the Danish Blood Donor Study

Author: Dowsett, Joseph, Didriksen, Maria, Larsen, Margit Hørup, Burgdorf, Kristoffer Sølvsten, Thørner, Lise Wegner, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole Birger, Ostrowski, Sisse Rye, and Ullum, Henrik
Published: 2021
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9. Genome-wide association analysis of cognitive function in Danish long-lived individuals

Author: Nygaard, Marianne, Dowsett, Joseph, McGue, Matt, Christensen, Kaare, Christiansen, Lene, Tan, Qihua, and Mengel-From, Jonas
Published: 2021
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10. A deep learning approach to prediction of blood group antigens from genomic data.

Author: Moslemi, Camous, Sækmose, Susanne, Larsen, Rune, Brodersen, Thorsten, Bay, Jakob T., Didriksen, Maria, Nielsen, Kaspar R., Bruun, Mie T., Dowsett, Joseph, Dinh, Khoa M., Mikkelsen, Christina, Hyvärinen, Kati, Ritari, Jarmo, Partanen, Jukka, Ullum, Henrik, Erikstrup, Christian, Ostrowski, Sisse R., Olsson, Martin L., and Pedersen, Ole B.
Subjects: BLOOD group antigens, CONVOLUTIONAL neural networks, BLOOD grouping & crossmatching, BLOOD groups, DEEP learning
Abstract: Background: Deep learning methods are revolutionizing natural science. In this study, we aim to apply such techniques to develop blood type prediction models based on cheap to analyze and easily scalable screening array genotyping platforms. Methods: Combining existing blood types from blood banks and imputed screening array genotypes for ~111,000 Danish and 1168 Finnish blood donors, we used deep learning techniques to train and validate blood type prediction models for 36 antigens in 15 blood group systems. To account for missing genotypes a denoising autoencoder initial step was utilized, followed by a convolutional neural network blood type classifier. Results: Two thirds of the trained blood type prediction models demonstrated an F1‐accuracy above 99%. Models for antigens with low or high frequencies like, for example, Cw, low training cohorts like, for example, Cob, or very complicated genetic underpinning like, for example, RhD, proved to be more challenging for high accuracy (>99%) DL modeling. However, in the Danish cohort only 4 out of 36 models (Cob, Cw, D‐weak, Kpa) failed to achieve a prediction F1‐accuracy above 97%. This high predictive performance was replicated in the Finnish cohort. Discussion: High accuracy in a variety of blood groups proves viability of deep learning‐based blood type prediction using array chip genotypes, even in blood groups with nontrivial genetic underpinnings. These techniques are suitable for aiding in identifying blood donors with rare blood types by greatly narrowing down the potential pool of candidate donors before clinical grade confirmation. [ABSTRACT FROM AUTHOR]
Published: 2024
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11. Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis

Author: Hindy, George, Tyrrell, Daniel J., Vasbinder, Alexi, Wei, Changli, Presswalla, Feriel, Wang, Hui, Blakely, Pennelope, Ozel, Ayse Bilge, Graham, Sarah, Holton, Grace H., Dowsett, Joseph, Fahed, Akl C., Amadi, Kingsley-Michael, Erne, Grace K., Tekmulla, Annika, Ismail, Anis, Launius, Christopher, Sotoodehnia, Nona, Pankow, James S., Thorner, Lise Wegner, Erikstrup, Christian, Pedersen, Ole Birger, Banasik, Karina, Brunak, Soren, Ullum, Henrik, Eugen-Olsen, Jesper, Ostrowski, Sisse Rye, Haas, Mary E., Nielsen, Jonas B., Lotta, Luca A., Engstrom, Gunnar, Melander, Olle, Orho-Melander, Marju, Zhao, Lili, Murthy, Venkatesh L., Pinsky, David J., Willer, Cristen J., Heckbert, Susan R., Reiser, Jochen, Goldstein, Daniel R., Desch, Karl C., and Hayek, Salim S.
Subjects: Immune response -- Genetic aspects, Cell receptors -- Health aspects, Atherosclerosis -- Genetic aspects -- Development and progression -- Care and treatment, Health care industry
Abstract: People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR ([suPAR.sup.Tg]) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of [suPAR.sup.Tg] mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating [suPAR.sup.Tg] monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function., Introduction People with chronic kidney disease (CKD) are disproportionately affected by cardiovascular disease (CVD), with two-thirds of patients having at least one form of CVD, atherosclerosis being the most common [...]
Published: 2022
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12. A genome-wide association study of social trust in 33,882 Danish blood donors

Author: Sequeros, Celia Burgos, Hansen, Thomas Folkmann, Westergaard, David, Louloudis, Ioannis, Kalamajski, Sebastian, Röder, Timo, Rohde, Palle Duun, Schwinn, Michael, Clemmensen, Line Harder, Didriksen, Maria, Nyegaard, Mette, Hjalgrim, Henrik, Nielsen, Kaspar René, Bruun, Mie Topholm, Ostrowski, Sisse Rye, Erikstrup, Christian, Mikkelsen, Susan, Sørensen, Erik, Banasik, Karina, Bay, Jakob, Boldsen, Jens Kjærgaard, Brodersen, Thorsten, Brunak, Søren, Burgdorf, Kristoffer, Chalmer, Mona Ameri, Dinh, Khoa Manh, Dowsett, Joseph, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hindhede, Lotte, Jacobsen, Rikke Louise, Jemec, Gregor, Jensen, Bitten Aagaard, Kaspersen, Katrine, Kjerulff, Bertram Dalskov, Kogelman, Lisette, Larsen, Margit Anita Hørup, Lundgaard, Agnete, Mikkelsen, Christina, Nissen, Ioanna, Pedersen, Ole Birger Vestager, Pil Henriksen, Alexander, Rostgaard, Klaus, Stefansson, Kari, Stefánsson, Hreinn, Thorsteinsdóttir, Unnur, Thørner, Lise Wegner, Topholm Bruun, Mie, Ullum, Henrik, Werge, Thomas, Giordano, Giuseppe Nicola, Sequeros, Celia Burgos, Hansen, Thomas Folkmann, Westergaard, David, Louloudis, Ioannis, Kalamajski, Sebastian, Röder, Timo, Rohde, Palle Duun, Schwinn, Michael, Clemmensen, Line Harder, Didriksen, Maria, Nyegaard, Mette, Hjalgrim, Henrik, Nielsen, Kaspar René, Bruun, Mie Topholm, Ostrowski, Sisse Rye, Erikstrup, Christian, Mikkelsen, Susan, Sørensen, Erik, Banasik, Karina, Bay, Jakob, Boldsen, Jens Kjærgaard, Brodersen, Thorsten, Brunak, Søren, Burgdorf, Kristoffer, Chalmer, Mona Ameri, Dinh, Khoa Manh, Dowsett, Joseph, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hindhede, Lotte, Jacobsen, Rikke Louise, Jemec, Gregor, Jensen, Bitten Aagaard, Kaspersen, Katrine, Kjerulff, Bertram Dalskov, Kogelman, Lisette, Larsen, Margit Anita Hørup, Lundgaard, Agnete, Mikkelsen, Christina, Nissen, Ioanna, Pedersen, Ole Birger Vestager, Pil Henriksen, Alexander, Rostgaard, Klaus, Stefansson, Kari, Stefánsson, Hreinn, Thorsteinsdóttir, Unnur, Thørner, Lise Wegner, Topholm Bruun, Mie, Ullum, Henrik, Werge, Thomas, and Giordano, Giuseppe Nicola
Abstract: Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n = 33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes and estimated the single nucleotide polymorphism-based heritability of trust to be 6% (95% confidence interval = (2.1, 9.9)). In our discovery cohort (n = 25,819), we identified one significantly associated locus (lead variant: rs12776883) in an intronic enhancer region of PLPP4, a gene highly expressed in brain, kidneys, and testes. However, we could not replicate the signal in an independent set of donors who were phenotyped a year later (n = 8063). In the subsequent meta-analysis, we found a second significantly associated variant (rs71543507) in an intergenic enhancer region. Overall, our work confirms that social trust is heritable, and provides an initial look into the genetic factors that influence it.
Published: 2024

13. SMIM1 absence is associated with reduced energy expenditure and excess weight

Author: Banasik, Karina, Bay, Jakob, Boldsen, Jens Kjærgaard, Brodersen, Thorsten, Brunak, Søren, Burgdorf, Kristoffer, Chalmer, Mona Ameri, Didriksen, Maria, Dinh, Khoa Manh, Dowsett, Joseph, Erikstrup, Christian, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hansen, Thomas Folkmann, Hindhede, Lotte, Hjalgrim, Henrik, Jacobsen, Rikke Louise, Jemec, Gregor, Jensen, Bitten Aagaard, Kaspersen, Katrine, Kjerulff, Bertram Dalskov, Kogelman, Lisette, Hørup Larsen, Margit Anita, Louloudis, Ioannis, Lundgaard, Agnete, Susan, Mikkelsen, Christina, Nissen, Ioanna, Nyegaard, Mette, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Henriksen, Alexander Pil, Rohde, Palle Duun, Rostgaard, Klaus, Schwinn, Michael, Stefansson, Kari, Stefánsson, Hreinn, Sørensen, Erik, þorsteinsdóttir, Unnur, Thørner, Lise Wegner, Bruun, Mie Topholm, Ullum, Henrik, Werge, Thomas, Westergaard, David, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian’an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Katie Chan, Kei Hang, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Loz, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V.R., Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P., Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Southam, Lorraine, Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J.L., Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J.C., Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M. Arfan, Johnson, W. Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R.H.J., Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, Van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Goncalo R., Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Ida Chen, Yii-Der, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, Janaka de Silva, H., Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J. Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L.R., Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J.F., Magnusson, Patrik K.E., Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N.A., Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P. Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I.A., Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E. Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G.M., Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C.J., Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., Barroso, Inês, Stefanucci, Luca, Moslemi, Camous, Tomé, Ana R., Virtue, Samuel, Bidault, Guillaume, Gleadall, Nicholas S., Watson, Laura P.E., Kwa, Jing E., Burden, Frances, Farrow, Samantha, Võsa, Urmo, Burling, Keith, Walker, Lindsay, Ord, John, Barker, Peter, Warner, James, Frary, Amy, Renhstrom, Karola, Ashford, Sofie E., Piper, Jo, Biggs, Gail, Erber, Wendy N., Hoffman, Gary J., Schoenmakers, Nadia, Rieneck, Klaus, Dziegiel, Morten H., Azzu, Vian, Vacca, Michele, Aparicio, Hugo Javier, Hui, Qin, Cho, Kelly, Sun, Yan V., Wilson, Peter W., Bayraktar, Omer A., Vidal-Puig, Antonio, Ostrowski, Sisse R., Astle, William J., Olsson, Martin L., Storry, Jill R., Pedersen, Ole B., Ouwehand, Willem H., Chatterjee, Krishna, Vuckovic, Dragana, and Frontini, Mattia
Published: 2024
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14. Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Author: Didriksen, Maria, Nawaz, Muhammad Sulaman, Dowsett, Joseph, Bell, Steven, Erikstrup, Christian, Pedersen, Ole B., Sørensen, Erik, Jennum, Poul J., Burgdorf, Kristoffer S., Burchell, Brendan, Butterworth, Adam S., Soranzo, Nicole, Rye, David B., Trotti, Lynn Marie, Saini, Prabhjyot, Stefansdottir, Lilja, Magnusson, Sigurdur H., Thorleifsson, Gudmar, Sigmundsson, Thordur, Sigurdsson, Albert P., Van Den Hurk, Katja, Quee, Franke, Tanck, Michael W. T., Ouwehand, Willem H., Roberts, David J., Earley, Eric J., Busch, Michael P., Mast, Alan E., Page, Grier P., Danesh, John, Di Angelantonio, Emanuele, Stefansson, Hreinn, Ullum, Henrik, and Stefansson, Kari
Published: 2020
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15. Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement

Author: Henkel, Cecilie, Styrkársdóttir, Unnur, Thorleifsson, Gudmar, Stefánsdóttir, Lilja, Björnsdóttir, Gyda, Banasik, Karina, Brunak, Søren, Erikstrup, Christian, Dinh, Khoa Manh, Hansen, Thomas Folkmann, Nielsen, Kaspar René, Bruun, Mie Topholm, Dowsett, Joseph, Brodersen, Thorsten, Thorgeirsson, Thorgeir E, Gromov, Kirill, Boesen, Mikael Ploug, Ullum, Henrik, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Stefánsson, Kári, Troelsen, Anders, and Nyegaard, Mette
Subjects: Polymorphism, Genetic, Rheumatology, Osteoarthritis, Immunology, Immunology and Allergy, Orthopedic Procedures, Osteoarthritis, Knee, General Biochemistry, Genetics and Molecular Biology
Abstract: ObjectivesOsteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement.MethodsWe included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain.ResultsWe identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 inATG7) and mechanotransduction (rs202127176 inPIEZO1). One variant, rs13107325 inSLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups.ConclusionsOur results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.
Published: 2022
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16. Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

Author: Yu Chen, Hao, Dina, Christian, Small, Aeron M, Shaffer, Christian M, Levinson, Rebecca T, Helgadóttir, Anna, Capoulade, Romain, Munter, Hans Markus, Martinsson, Andreas, Cairns, Benjamin J, Trudsø, Linea C, Hoekstra, Mary, Burr, Hannah A, Marsh, Thomas W, Damrauer, Scott M, Dufresne, Line, Le Scouarnec, Solena, Messika-Zeitoun, David, Ranatunga, Dilrini K, Whitmer, Rachel A, Bonnefond, Amélie, Sveinbjornsson, Garðar, Daníelsen, Ragnar, Arnar, David O, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Gudbjartsson, Daníel F, Hólm, Hilma, Ghouse, Jonas, Olesen, Morten Salling, Christensen, Alex H, Mikkelsen, Susan, Jacobsen, Rikke Louise, Dowsett, Joseph, Pedersen, Ole Birger Vesterager, Erikstrup, Christian, Ostrowski, Sisse R, Regeneron Genetics Center, O'Donnell, Christopher J, Budoff, Matthew J, Gudnason, Vilmundur, Post, Wendy S, Rotter, Jerome I, Lathrop, Mark, Bundgaard, Henning, Johansson, Bengt, Ljungberg, Johan, Näslund, Ulf, Le Tourneau, Thierry, Smith, J Gustav, Wells, Quinn S, Söderberg, Stefan, Stefánsson, Kári, Schott, Jean-Jacques, Rader, Daniel J, Clarke, Robert, Engert, James C, and Thanassoulis, George
Subjects: Genome-wide association study, Phenome-wide association study, Clinical Sciences, Cardiorespiratory Medicine and Haematology, Cardiovascular, Risk Factors, Mendelian randomization, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Obesity, Polymorphism, Aetiology, Adiposity, Dyslipidemias, Inflammation, Aortic stenosis, Prevention, Human Genome, Aortic Valve Stenosis, Single Nucleotide, Mendelian Randomization Analysis, Regeneron Genetics Center, Genetic risk score, Apolipoproteins, Heart Disease, Cardiovascular System & Hematology, Gene expression, Genome-Wide Association Study
Abstract: AimsAlthough highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS.Methods and resultsA genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.ConclusionDyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.
Published: 2023

17. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Author: Bjornsdottir, Gyda, Chalmer, Mona A., Stefansdottir, Lilja, Skuladottir, Astros Th, Einarsson, Gudmundur, Andresdottir, Margret, Beyter, Doruk, Ferkingstad, Egil, Gretarsdottir, Solveig, Halldorsson, Bjarni V., Halldorsson, Gisli H., Helgadottir, Anna, Helgason, Hannes, Hjorleifsson Eldjarn, Grimur, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Jonsdottir, Ingileif, Knowlton, Kirk U., Nadauld, Lincoln D., Lund, Sigrun H., Magnusson, Olafur Th, Melsted, Pall, Moore, Kristjan H.S., Oddsson, Asmundur, Olason, Pall I., Sigurdsson, Asgeir, Banasik, Karina, Brunak, Søren, Didriksen, Maria, Kogelman, Lisette J.A., Nielsen, Kaspar R., Sørensen, Erik, Pedersen, Ole B., Ullum, Henrik, Bay, Jakob, Burgdorf, Kristoffer, Dowsett, Joseph, Hjalgrim, Henrik, Jacobsen, Rikke L., Louloudis, Ioannis, Lundgaard, Agnete, Mikkelsen, Christina, Nyegaard, Mette, Henriksen, Alexander P., Werge, Thomas, Westergaard, David, Olesen, Jes, Ostrowski, Sisse R., Hansen, Thomas F., Bjornsdottir, Gyda, Chalmer, Mona A., Stefansdottir, Lilja, Skuladottir, Astros Th, Einarsson, Gudmundur, Andresdottir, Margret, Beyter, Doruk, Ferkingstad, Egil, Gretarsdottir, Solveig, Halldorsson, Bjarni V., Halldorsson, Gisli H., Helgadottir, Anna, Helgason, Hannes, Hjorleifsson Eldjarn, Grimur, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Jonsdottir, Ingileif, Knowlton, Kirk U., Nadauld, Lincoln D., Lund, Sigrun H., Magnusson, Olafur Th, Melsted, Pall, Moore, Kristjan H.S., Oddsson, Asmundur, Olason, Pall I., Sigurdsson, Asgeir, Banasik, Karina, Brunak, Søren, Didriksen, Maria, Kogelman, Lisette J.A., Nielsen, Kaspar R., Sørensen, Erik, Pedersen, Ole B., Ullum, Henrik, Bay, Jakob, Burgdorf, Kristoffer, Dowsett, Joseph, Hjalgrim, Henrik, Jacobsen, Rikke L., Louloudis, Ioannis, Lundgaard, Agnete, Mikkelsen, Christina, Nyegaard, Mette, Henriksen, Alexander P., Werge, Thomas, Westergaard, David, Olesen, Jes, Ostrowski, Sisse R., and Hansen, Thomas F.
Abstract: Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.
Published: 2023

18. Cohort Profile:The Danish Blood Donor Study

Author: Erikstrup, Christian, Sørensen, Erik, Nielsen, Kaspar R, Bruun, Mie T, Petersen, Mikkel S, Rostgaard, Klaus, Thørner, Lise W, Larsen, Margit, Mikkelsen, Susan, Dinh, Khoa M, Schwinn, Michael, Rigas, Andreas S, Didriksen, Maria, Dowsett, Joseph, von Stemann, Jakob H, Brodersen, Thorsten, Paulsen, Isabella W, Hindhede, Lotte, Sækmose, Susanne G, Kaspersen, Kathrine A, Boldsen, Jens K, Kjerulff, Bertram, Werge, Thomas, Brunak, Søren, Banasik, Karina, Hansen, Thomas F, Ullum, Henrik, Hjalgrim, Henrik, Ostrowski, Sisse R, Pedersen, Ole B, Erikstrup, Christian, Sørensen, Erik, Nielsen, Kaspar R, Bruun, Mie T, Petersen, Mikkel S, Rostgaard, Klaus, Thørner, Lise W, Larsen, Margit, Mikkelsen, Susan, Dinh, Khoa M, Schwinn, Michael, Rigas, Andreas S, Didriksen, Maria, Dowsett, Joseph, von Stemann, Jakob H, Brodersen, Thorsten, Paulsen, Isabella W, Hindhede, Lotte, Sækmose, Susanne G, Kaspersen, Kathrine A, Boldsen, Jens K, Kjerulff, Bertram, Werge, Thomas, Brunak, Søren, Banasik, Karina, Hansen, Thomas F, Ullum, Henrik, Hjalgrim, Henrik, Ostrowski, Sisse R, and Pedersen, Ole B
Published: 2023

19. Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement

Author: Henkel, Cecilie, Styrkársdóttir, Unnur, Thorleifsson, Gudmar, Stefánsdóttir, Lilja, Björnsdóttir, Gyda, Banasik, Karina, Brunak, Søren, Erikstrup, Christian, Dinh, Khoa Manh, Hansen, Thomas Folkmann, Nielsen, Kaspar René, Bruun, Mie Topholm, Dowsett, Joseph, Brodersen, Thorsten, Thorgeirsson, Thorgeir E, Gromov, Kirill, Boesen, Mikael Ploug, Ullum, Henrik, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Stefánsson, Kári, Troelsen, Anders, Henkel, Cecilie, Styrkársdóttir, Unnur, Thorleifsson, Gudmar, Stefánsdóttir, Lilja, Björnsdóttir, Gyda, Banasik, Karina, Brunak, Søren, Erikstrup, Christian, Dinh, Khoa Manh, Hansen, Thomas Folkmann, Nielsen, Kaspar René, Bruun, Mie Topholm, Dowsett, Joseph, Brodersen, Thorsten, Thorgeirsson, Thorgeir E, Gromov, Kirill, Boesen, Mikael Ploug, Ullum, Henrik, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Stefánsson, Kári, and Troelsen, Anders
Abstract: OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement.METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain.RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups.CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.
Published: 2023

20. A large cohort study of the effects of Lewis, ABO, 13 other blood groups, and secretor status on COVID-19 susceptibility, severity, and long COVID-19

Author: Moslemi, Camous, Saekmose, Susanne, Larsen, Rune, Brodersen, Thorsten, Didriksen, Maria, Hjalgrim, Henrik, Banasik, Karina, Nielsen, Kaspar R, Bruun, Mie T., Dowsett, Joseph, Kasperen, Kathrine A, Mikkelsen, Susan, Hansen, Thomas F, Ullum, Henrik, Erikstrup, Christian, Olsson, Martin L, Ostrowski, Sisse R, Pedersen, Ole B, Moslemi, Camous, Saekmose, Susanne, Larsen, Rune, Brodersen, Thorsten, Didriksen, Maria, Hjalgrim, Henrik, Banasik, Karina, Nielsen, Kaspar R, Bruun, Mie T., Dowsett, Joseph, Kasperen, Kathrine A, Mikkelsen, Susan, Hansen, Thomas F, Ullum, Henrik, Erikstrup, Christian, Olsson, Martin L, Ostrowski, Sisse R, and Pedersen, Ole B
Abstract: BACKGROUND: Previous studies have reported Blood type O to confer a lower risk of SARS-CoV-2 infection, while secretor status and other blood groups have been suspected to have a similar effect as well.STUDY DESIGN AND METHODS: To determine whether any other blood groups influence testing positive for SARS-CoV-2, COVID-19 severity, or prolonged COVID-19, we used a large cohort of 650,156 Danish blood donors with varying available data for secretor status and blood groups ABO, Rh, Colton, Duffy, Diego, Dombrock, Kell, Kidd, Knops, Lewis, Lutheran, MNS, P1PK, Vel, and Yt. Of these, 36,068 tested positive for SARS-CoV-2 whereas 614,088 tested negative between 2020-02-17 and 2021-08-04. Associations between infection and blood groups were assessed using logistic regression models with sex and age as covariates.RESULTS: The Lewis blood group antigen Lea displayed strongly reduced SARS-CoV-2 susceptibility OR 0.85 CI[0.79-0.93] p < .001. Compared to blood type O, the blood types B, A, and AB were found more susceptible toward infection with ORs 1.1 CI[1.06-1.14] p < .001, 1.17 CI[1.14-1.2] p < .001, and 1.2 CI[1.14-1.26] p < .001, respectively. No susceptibility associations were found for the other 13 blood groups investigated. There was no association between any blood groups and COVID-19 hospitalization or long COVID-19. No secretor status associations were found.DISCUSSION: This study uncovers a new association to reduced SARS-CoV-2 susceptibility for Lewis type Lea and confirms the previous link to blood group O. The new association to Lea could be explained by a link between mucosal microbiome and SARS-CoV-2.
Published: 2023

21. Genetic prediction of 33 blood group phenotypes using an existing genotype dataset

Author: Moslemi, Camous, Sækmose, Susanne G., Larsen, Rune, Bay, Jakob T., Brodersen, Thorsten, Didriksen, Maria, Hjalgrim, Henrik, Banasik, Karina, Nielsen, Kaspar R., Bruun, Mie T., Dowsett, Joseph, Dinh, Khoa M., Mikkelsen, Susan, Mikkelsen, Christina, Hansen, Thomas F., Ullum, Henrik, Erikstrup, Christian, Brunak, Søren, Krogfelt, Karen Angeliki, Storry, Jill R., Ostrowski, Sisse R., Olsson, Martin L., Pedersen, Ole B., Moslemi, Camous, Sækmose, Susanne G., Larsen, Rune, Bay, Jakob T., Brodersen, Thorsten, Didriksen, Maria, Hjalgrim, Henrik, Banasik, Karina, Nielsen, Kaspar R., Bruun, Mie T., Dowsett, Joseph, Dinh, Khoa M., Mikkelsen, Susan, Mikkelsen, Christina, Hansen, Thomas F., Ullum, Henrik, Erikstrup, Christian, Brunak, Søren, Krogfelt, Karen Angeliki, Storry, Jill R., Ostrowski, Sisse R., Olsson, Martin L., and Pedersen, Ole B.
Abstract: Background: Accurate blood type data are essential for blood bank management, but due to costs, few of 43 blood group systems are routinely determined in Danish blood banks. However, a more comprehensive dataset of blood types is useful in scenarios such as rare blood type allocation. We aimed to investigate the viability and accuracy of predicting blood types by leveraging an existing dataset of imputed genotypes for two cohorts of approximately 90,000 each (Danish Blood Donor Study and Copenhagen Biobank) and present a more comprehensive overview of blood types for our Danish donor cohort. Study Design and Methods: Blood types were predicted from genome array data using known variant determinants. Prediction accuracy was confirmed by comparing with preexisting serological blood types. The Vel blood group was used to test the viability of using genetic prediction to narrow down the list of candidate donors with rare blood types. Results: Predicted phenotypes showed a high balanced accuracy >99.5% in most cases: A, B, C/c, Coa/Cob, Doa/Dob, E/e, Jka/Jkb, Kna/Knb, Kpa/Kpb, M/N, S/s, Sda, Se, and Yta/Ytb, while some performed slightly worse: Fya/Fyb, K/k, Lua/Lub, and Vel ~99%–98% and CW and P1 ~96%. Genetic prediction identified 70 potential Vel negatives in our cohort, 64 of whom were confirmed correct using polymerase chain reaction (negative predictive value: 91.5%). Discussion: High genetic prediction accuracy in most blood groups demonstrated the viability of generating blood types using preexisting genotype data at no cost and successfully narrowed the pool of potential individuals with the rare Vel-negative phenotype from 180,000 to 70.
Published: 2023

22. GWAS Summary Statistics from a Global Meta-Analysis of Aortic Stenosis

Author: Chen, Hao Yu, PhD, Dina, Christian, PhD, Small, Aeron M., MD, Shaffer, Christian M., Levinson, Rebecca T., PhD, Helgadóttir, Anna, MD, PhD, Capoulade, Romain, PhD, Munter, Hans Markus, PhD, Martinsson, Andreas, MD, Cairns, Benjamin J., PhD, Trudsø, Linea C., Hoekstra, Mary, Burr, Hannah A., Marsh, Thomas W., Damrauer, Scott M., MD, Dufresne, Line, Scouarnec, Solena Le, PhD, Messika-Zeitoun, David, MD, PhD, Ranatunga, Dilrini K., Whitmer, Rachel A., PhD, Bonnefond, Amélie, PhD, Sveinbjornsson, Garðar, Daníelsen, Ragnar, MD, PhD, Arnar, David O., MD, PhD, Thorgeirsson, Gudmundur, MD, PhD, Thorsteinsdottir, Unnur, PhD, Gudbjartsson, Daníel F., PhD, Hólm, Hilma, MD, Ghouse, Jonas, MD, Olesen, Morten Salling, PhD, Christensen, Alex H., MD, Mikkelsen, Susan, MD, Jacobsen, Rikke Louise, Dowsett, Joseph, Pedersen, Ole Birger Vesterager, MD, Erikstrup, Christian, MD, Ostrowski, Sisse R., Regeneron Genetics Center, O'Donnell, Christopher J., MD, Budoff, Matthew J., MD, Gudnason, Vilmundur, MD, Post, Wendy S., MD, Rotter, Jerome I., MD, Lathrop, Mark, PhD, Bundgaard, Henning, Johansson, Bengt, MD, PhD, Ljungberg, Johan, MD, PhD, Näslund, Ulf, MD, PhD, Tourneau, Thierry Le, MD, PhD, Smith, J. Gustav, MD, Wells, Quinn S., MD, Söderberg, Stefan, MD, PhD, Stefánsson, Kári, MD, PhD, Schott, Jean-Jacques, PhD, Rader, Daniel J., MD, Clarke, Robert, MD, Engert, James C., PhD, and Thanassoulis, George
Abstract: GWAS Summary Statistics for a Global Meta-Analysis of Aortic Stenosis in the TARGET Consortium 10.5281/zenodo.7630002 This dataset contains the genome-wide association summary statistics for a Global Meta-Analysis of Aortic Stenosis. For the analysis description and included cohorts, please see Chen et al., the European Heart Journal (2023). The data are provided on an "AS-IS" basis, without warranty of any type, expressed or implied, including but not limited to any warranty as to their performance, merchantability, or fitness for any particular purpose. If investigators use these data, any and all consequences are entirely their responsibility. By downloading and using these data, you agree that you will cite the appropriate publication in any communications or publications arising directly or indirectly from these data. When using this data, please cite the paper and this repository: Chenet al., GWAS Summary Statistics for a Global Meta-Analysis of Aortic Stenosis,the European Heart Journal (2023). Zenodo.10.5281/zenodo.7630002 Column headers: CHR: Chromosome code. Not present with 'no-map' modifier. BP: Base-pair coordinate. Not present with 'no-map' modifier. SNP: Variant identifier A1: Effect Allele A2: Other Allele N_cohort: Number of valid studies for variant P: Fixed-effects meta-analysis p-value P.R.: Random-effects meta-analysis p-value OR: Fixed-effects BETA/OR estimate OR.R.: Random-effects BETA/OR estimate Q: p-value for Cochran's Q statistic I: I2 heterogeneity index (0-100 scale) N_ind: Number of individuals Fundings: Fundings for this study were obtained from the following (listed in alphabetical order): ALFEDIAM Ardix Medical Assistance Publique - Hôpitaux de Paris Association Diabète Risque Vasculaire Bayer Diagnostics Becton Dickinson British Heart Foundation British Heart Foundation Oxford Centre Canadian Institutes for Health Research Capital Regions Research Council Cardionics, Merck Santé, Novo Nordisk CNAMTS, Lilly, Novartis Pharma Cohortes Santé TGIR County Council of Västerbotten Crafoord Foundation Ellison Medical Foundation European Research Council Fédération Française de Cardiologie Fédération Française de Cardiologie, a Fondation Coeur et Recherche Fonds de Recherche du Québec - Santé. French Regional Council of Pays-de-la-Loire (VaCaRMe program) Heart and Stroke Foundation of Canada Heart Foundation of Northern Sweden. Kaiser Permanente Knut and Alice Wallenberg foundation to the Wallenberg Center La Fondation de France Medical Research Council and the University of Oxford National Center for Advancing Translational Sciences (CTSI) National Heart, Lung, and Blood Institute (NHLBI) National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) National Institutes of Health Novo Nordisk Foundation ONIVINS Robert Wood Johnson Foundation Sanofi-Aventis; by INSERM (Réseaux en Santé Publique, Interactions entre les déterminants de la santé) Skåne University Hospital Société francophone du diabète Swedish Foundation for Strategic Research Swedish Heart–Lung Foundation Swedish National Health Service Swedish Research Council The Innovation Fund Denmark Umeå University U.S. Department of Veteran Affairs Vanderbilt University Medical Center’s institutional funding Wayne and Gladys Valley Foundation &nbsp
Published: 2023
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23. Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles:A Mendelian randomization analysis

Author: Helgadottir, Anna, Thorleifsson, Gudmar, Snaebjarnarson, Audunn, Stefansdottir, Lilja, Sveinbjornsson, Gardar, Tragante, Vinicius, Björnsson, Eyþór, Steinthorsdottir, Valgerdur, Gretarsdottir, Solveig, Helgason, Hannes, Saemundsdottir, Jona, Olafsson, Isleifur, Thune, Jens Jakob, Axelsson Raja, Anna, Ghouse, Jonas, Olesen, Morten Salling, Christensen, Alex, Jacobsen, Rikke Louise, Dowsett, Joseph, Bruun, Mie Topholm, Nielsen, Kaspar, Knowlton, Kirk, Nadauld, Lincoln, Benediktsson, Rafn, Erikstrup, Christian, Pedersen, Ole B., Banasik, Karina, Brunak, Søren, Bundgaard, Henning, Ostrowski, Sisse R., Sulem, Patrick, Arnar, David O., Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F., Stefansson, Kari, Holm, Hilma, and Nyegaard, Mette
Subjects: Epidemiology, Apolipoproteins B/genetics, Coronary Artery Disease/genetics, Lipoproteins, Cholesterol, HDL, Non-HDL cholesterol, Coronary Artery Disease, Cholesterol, LDL, Mendelian Randomization Analysis, Atherosclerosis, Apolipoprotein, Cholesterol, Apolipoprotein B-100/genetics, Risk Factors, Apolipoprotein B-100, Mendelian randomization, Humans, Cardiology and Cardiovascular Medicine, Apolipoprotein B, Apolipoproteins B
Abstract: Background and aims:The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration.Method and results:We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N = 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses.In univariate MR analysis, both exposures associated with CAD (βnon-HDL-C = 0.40, P = 2.8 × 10−48 and βapoB = 0.38, P = 1.3 × 10−44). Adding effects on non-HDL-C into a model that already included those on apoB significantly improved the genetically predicted CAD effects (P = 3.9 × 10−5), while adding apoB into the model including non-HDL-C did not (P = 0.69). Thirty-five per cent (82/235) of the variants used as genetic instruments had discordant effects on the exposures, associating with non-HDL-C/apoB ratio at P Conclusion:Many sequence variants have discordant effects on non-HDL-C and apoB. These variants allowed us to show that the causal mechanism underlying the relationship between apolipoprotein B particles and CAD is more associated with non-HDL-C than apoB particle concentration.
Published: 2022
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24. A large cohort study of the effects of Lewis, ABO , 13 other blood groups, and secretor status on COVID ‐19 susceptibility, severity, and long COVID ‐19

Author: Moslemi, Camous, primary, Sækmose, Susanne, additional, Larsen, Rune, additional, Brodersen, Thorsten, additional, Didriksen, Maria, additional, Hjalgrim, Henrik, additional, Banasik, Karina, additional, Nielsen, Kaspar R., additional, Bruun, Mie T., additional, Dowsett, Joseph, additional, Kasperen, Kathrine A., additional, Mikkelsen, Susan, additional, Hansen, Thomas F., additional, Ullum, Henrik, additional, Erikstrup, Christian, additional, Olsson, Martin L., additional, Ostrowski, Sisse R., additional, and Pedersen, Ole B., additional
Published: 2022
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25. Cohort Profile: The Danish Blood Donor Study

Author: Erikstrup, Christian, primary, Sørensen, Erik, additional, Nielsen, Kaspar R, additional, Bruun, Mie T, additional, Petersen, Mikkel S, additional, Rostgaard, Klaus, additional, Thørner, Lise W, additional, Larsen, Margit, additional, Mikkelsen, Susan, additional, Dinh, Khoa M, additional, Schwinn, Michael, additional, Rigas, Andreas S, additional, Didriksen, Maria, additional, Dowsett, Joseph, additional, von Stemann, Jakob H, additional, Brodersen, Thorsten, additional, Paulsen, Isabella W, additional, Hindhede, Lotte, additional, Sækmose, Susanne G, additional, Kaspersen, Kathrine A, additional, Boldsen, Jens K, additional, Kjerulff, Bertram, additional, Werge, Thomas, additional, Brunak, Søren, additional, Banasik, Karina, additional, Hansen, Thomas F, additional, Ullum, Henrik, additional, Hjalgrim, Henrik, additional, Ostrowski, Sisse R, additional, and Pedersen, Ole B, additional
Published: 2022
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26. Cohort Profile: The Danish Blood Donor Study.

Author: Erikstrup, Christian, Sørensen, Erik, Nielsen, Kaspar R, Bruun, Mie T, Petersen, Mikkel S, Rostgaard, Klaus, Thørner, Lise W, Larsen, Margit, Mikkelsen, Susan, Dinh, Khoa M, Schwinn, Michael, Rigas, Andreas S, Didriksen, Maria, Dowsett, Joseph, Stemann, Jakob H von, Brodersen, Thorsten, Paulsen, Isabella W, Hindhede, Lotte, Sækmose, Susanne G, and Kaspersen, Kathrine A
Subjects: IRON supplements, SUMATRIPTAN, BLOOD donors, FERRITIN, SARS-CoV-2
Abstract: Key Features The Danish Blood Donor Study (DBDS) was established to study the impact of blood donation on the health of blood donors and to answer broader health-related research questions. Google Scholar Crossref Search ADS PubMed WorldCat 4 Atsma F, Veldhuizen I, Verbeek A, de Kort W, de Vegt F. Healthy donor effect: its magnitude in health research among blood donors. Donor health Briefly, we have confirmed iron deficiency as a major health issue among blood donors and that sex, age and donation frequency are by far the most important predictors of iron deficiency. Acknowledgements We thank the Danish blood donors for their valuable participation in the Danish Blood Donor Study, and the staff at the blood centres for making this study possible. [Extracted from the article]
Published: 2023
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27. IL-6 Autoantibodies Predict Lower Platelet Counts and Altered Plasma Cytokine Profiles in Healthy Blood Donors: Results From the Danish Blood Donor Study

Author: von Stemann, Jakob Hjorth, primary, Pedersen, Ole Birger Vesterager, additional, Hjalgrim, Henrik, additional, Erikstrup, Christian, additional, Ullum, Henrik, additional, Dowsett, Joseph, additional, Thørner, Lise Wegner, additional, Larsen, Margit Anita Hørup, additional, Sørensen, Erik, additional, Hansen, Morten Bagge, additional, and Ostrowski, Sisse Rye, additional
Published: 2022
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28. Clinical, genetic, and experimental increase in soluble urokinase plasminogen activator receptor levels promotes atherosclerosis

Author: Hindy, George, Tyrrell, Daniel J, Vasbinder, Alexi, Wei, Changli, Presswalla, Feriel, Wang, Hui, Blakely, Pennelope K, Ozel, Ayse Bilge, Graham, Sarah E, Holton, Grace H, Dowsett, Joseph, Fahed, Akl C, Amadi, Kingsley-Michael, Erne, Grace K, Tekumulla, Annika, Ismail, Anis, Launius, Christopher, Sotoodehnia, Nona, Pankow, James S, Thørner, Lise Wegner, Erikstrup, Christian, Pedersen, Ole Birger, Banasik, Karina, Brunak, Søren, Ullum, Henrik, Eugen-Olsen, Jesper, Ostrowski, Sisse Rye, Haas, Mary E, Nielsen, Jonas B, Lotta, Luca A, Engström, Gunnar, Melander, Olle, Orho-Melander, Marju, Zhao, Lili, Murthy, Venkatesh L, Pinsky, David J, Willer, Cristen J, Heckbert, Susan R, Reiser, Jochen, Goldstein, Daniel R, Desch, Karl C, Hayek, Salim S, Hindy, George, Tyrrell, Daniel J, Vasbinder, Alexi, Wei, Changli, Presswalla, Feriel, Wang, Hui, Blakely, Pennelope K, Ozel, Ayse Bilge, Graham, Sarah E, Holton, Grace H, Dowsett, Joseph, Fahed, Akl C, Amadi, Kingsley-Michael, Erne, Grace K, Tekumulla, Annika, Ismail, Anis, Launius, Christopher, Sotoodehnia, Nona, Pankow, James S, Thørner, Lise Wegner, Erikstrup, Christian, Pedersen, Ole Birger, Banasik, Karina, Brunak, Søren, Ullum, Henrik, Eugen-Olsen, Jesper, Ostrowski, Sisse Rye, Haas, Mary E, Nielsen, Jonas B, Lotta, Luca A, Engström, Gunnar, Melander, Olle, Orho-Melander, Marju, Zhao, Lili, Murthy, Venkatesh L, Pinsky, David J, Willer, Cristen J, Heckbert, Susan R, Reiser, Jochen, Goldstein, Daniel R, Desch, Karl C, and Hayek, Salim S
Abstract: People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the PLAUR gene (rs4760) confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, Pcsk9 transfection in mice over-expressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared to wild-type mice, despite similar cholesterol levels. Pre-atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared to wild-type aortas. Aortic and circulating suPARTg monocytes exhibited a pro-inflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.
Published: 2022

29. Investigating the inflammation marker neutrophil-to-lymphocyte ratio in Danish blood donors with restless legs syndrome

Author: Dowsett, Joseph, primary, Didriksen, Maria, additional, Larsen, Margit Hørup, additional, Dinh, Khoa Manh, additional, Kaspersen, Kathrine Agergård, additional, Mikkelsen, Susan, additional, Thørner, Lise Wegner, additional, Sørensen, Erik, additional, Erikstrup, Christian, additional, Pedersen, Ole Birger, additional, Eugen-Olsen, Jesper, additional, Banasik, Karina, additional, and Ostrowski, Sisse Rye, additional
Published: 2021
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30. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Fatality Rate among Elderly Danes:A Cross-sectional Study on Retired Blood Donors

Author: Pedersen, Ole Birger, Nissen, Janna, Dinh, Khoa Manh, Schwinn, Michael, Kaspersen, Kathrine Agergård, Boldsen, Jens Kjærgaard, Didriksen, Maria, Dowsett, Joseph, Sørensen, Erik, Thørner, Lise Wegner, Larsen, Margit Anita Hørup, Grum-Schwensen, Birgitte, Sækmose, Susanne, Paulsen, Isabella Worlewenut, Frisk, Nanna Lond Skov, Brodersen, Thorsten, Vestergaard, Lasse Skafte, Rostgaard, Klaus, Mølbak, Kåre, Skov, Robert Leo, Erikstrup, Christian, Ullum, Henrik, Hjalgrim, Henrik, Pedersen, Ole Birger, Nissen, Janna, Dinh, Khoa Manh, Schwinn, Michael, Kaspersen, Kathrine Agergård, Boldsen, Jens Kjærgaard, Didriksen, Maria, Dowsett, Joseph, Sørensen, Erik, Thørner, Lise Wegner, Larsen, Margit Anita Hørup, Grum-Schwensen, Birgitte, Sækmose, Susanne, Paulsen, Isabella Worlewenut, Frisk, Nanna Lond Skov, Brodersen, Thorsten, Vestergaard, Lasse Skafte, Rostgaard, Klaus, Mølbak, Kåre, Skov, Robert Leo, Erikstrup, Christian, Ullum, Henrik, and Hjalgrim, Henrik
Abstract: Background: Although the vast majority of individuals succumbing to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are elderly, infection fatality rate (IFR) estimates for the age group ≥70 years are still scarce. To this end, we assessed SARS-CoV-2 seroprevalence among retired blood donors and combined it with national coronavirus disease 2019 (COVID-19) survey data to provide reliable population-based IFR estimates for this age group. Methods: We identified 60â-926 retired blood donors aged ≥70 years in the rosters of 3 regionwide Danish blood banks and invited them to fill in a questionnaire on COVID-19-related symptoms and behaviors. Among 24â-861 (40.8%) responders, we invited a random sample of 3200 individuals for blood testing. Overall, 1201 (37.5%) individuals were tested for SARS-CoV-2 antibodies (Wantai) and compared with 1110 active blood donors aged 17-69 years. Seroprevalence 95% confidence intervals (CIs) were adjusted for assay sensitivity and specificity. Results: Among retired (aged ≥70 years) and active (aged 17-69 years) blood donors, adjusted seroprevalences were 1.4% (95% CI,. 3-2.5%) and 2.5% (95% CI, 1.3-3.8%), respectively. Using available population data on COVID-19-related fatalities, IFRs for patients aged ≥70 years and for 17-69 years were estimated at 5.4% (95% CI, 2.7-6.4%) and. 083% (95% CI,. 054-.18%), respectively. Only 52.4% of SARS-CoV-2-seropositive retired blood donors reported having been sick since the start of the pandemic. Conclusions: COVID-19 IFR in the age group >69 years is estimated to be 65 times the IFR for people aged 18-69 years.
Published: 2021

31. Investigating the inflammation marker neutrophil-to-lymphocyte ratio in Danish blood donors with restless legs syndrome

Author: Dowsett, Joseph, Didriksen, Maria, Larsen, Margit Hørup, Dinh, Khoa Manh, Kaspersen, Kathrine Agergård, Mikkelsen, Susan, Thørner, Lise Wegner, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole Birger, Eugen-Olsen, Jesper, Banasik, Karina, Ostrowski, Sisse Rye, Dowsett, Joseph, Didriksen, Maria, Larsen, Margit Hørup, Dinh, Khoa Manh, Kaspersen, Kathrine Agergård, Mikkelsen, Susan, Thørner, Lise Wegner, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole Birger, Eugen-Olsen, Jesper, Banasik, Karina, and Ostrowski, Sisse Rye
Abstract: Background Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder that occurs in the evening and night, thereby impacting quality of sleep in sufferers. The pathophysiology of RLS is poorly understood but inflammation has been proposed as possibly being involved. The neutrophil-to-lymphocyte ratio (NLR) can be used as an inflammation marker but results from small studies have been inconclusive in determining whether NLR is associated with RLS. We aimed to assess whether an association between NLR and RLS exists in a large cohort of healthy individuals. Methods Neutrophils and lymphocytes were measured in blood samples of 13,055 individuals from the Danish Blood Donor Study, all of whom completed the validated Cambridge-Hopkins RLS-questionnaire for RLS assessment. Results In the sample, 661 individuals were determined as current RLS cases (5.1%). A higher proportion of individuals with RLS were females (62.5% vs 47.5%; P<0.001) and RLS cases were older than controls (P<0.001), but no differences in body mass index (BMI), smoking or alcohol consumption were found between the two groups. An increased NLR was observed in RLS cases compared to controls (median NLR: 1.80 vs 1.72; P = 0.033). In an unadjusted logistic regression model, increased NLR was associated with RLS (OR = 1.10 per NLR unit increase [95%CI:1.01–1.20]; P = 0.032); however, the association was not significant in multivariate models adjusting for sex and age (P = 0.094) or sex, age, alcohol consumption, smoking status and BMI (P = 0.107). Conclusion We found no association between RLS and NLR among Danish blood donors after adjusting for sex, age, alcohol consumption, smoking status and BMI. Further studies are needed to determine whether inflammation is a risk factor for RLS.
Published: 2021

32. Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor

Author: Dowsett, Joseph, Ferkingstad, Egil, Rasmussen, Line Jee Hartmann, Thørner, Lise Wegner, Magnússon, Magnús K, Sugden, Karen, Thorleifsson, Gudmar, Frigge, Mike, Burgdorf, Kristoffer Sølvsten, Ostrowski, Sisse Rye, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole Birger, Hansen, Thomas Folkmann, Banasik, Karina, Brunak, Søren, Tragante, Vinicius, Lund, Sigrun Helga, Stefansdottir, Lilja, Gunnarson, Bjarni, Poulton, Richie, Arseneault, Louise, Caspi, Avshalom, Moffitt, Terrie E, Gudbjartsson, Daníel, Eugen-Olsen, Jesper, Stefánsson, Hreinn, Stefánsson, Kári, Ullum, Henrik, Dowsett, Joseph, Ferkingstad, Egil, Rasmussen, Line Jee Hartmann, Thørner, Lise Wegner, Magnússon, Magnús K, Sugden, Karen, Thorleifsson, Gudmar, Frigge, Mike, Burgdorf, Kristoffer Sølvsten, Ostrowski, Sisse Rye, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole Birger, Hansen, Thomas Folkmann, Banasik, Karina, Brunak, Søren, Tragante, Vinicius, Lund, Sigrun Helga, Stefansdottir, Lilja, Gunnarson, Bjarni, Poulton, Richie, Arseneault, Louise, Caspi, Avshalom, Moffitt, Terrie E, Gudbjartsson, Daníel, Eugen-Olsen, Jesper, Stefánsson, Hreinn, Stefánsson, Kári, and Ullum, Henrik
Abstract: Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR's potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation.
Published: 2021

33. Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles: a Mendelian randomization analysis

Author: Helgadottir, Anna, Thorleifsson, Gudmar, Snaebjarnarson, Audunn, Stefansdottir, Lilja, Sveinbjornsson, Gardar, Tragante, Vinicius, Björnsson, Eyþór, Steinthorsdottir, Valgerdur, Gretarsdottir, Solveig, Helgason, Hannes, Saemundsdottir, Jona, Olafsson, Isleifur, Thune, Jens Jakob, Raja, Anna Axelsson, Ghouse, Jonas, Olesen, Morten Salling, Christensen, Alex, Jacobsen, Rikke Louise, Dowsett, Joseph, Bruun, Mie Topholm, Nielsen, Kaspar, Knowlton, Kirk, Nadauld, Lincoln, Benediktsson, Rafn, Erikstrup, Christian, Pedersen, Ole B, Banasik, Karina, Brunak, Søren, Bundgaard, Henning, Ostrowski, Sisse R, Sulem, Patrick, Arnar, David O, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F, Stefansson, Kari, and Holm, Hilma
Abstract: Graphical Abstract
Published: 2022
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34. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Fatality Rate Among Elderly Danes: A Cross-sectional Study on Retired Blood Donors

Author: Pedersen, Ole Birger, primary, Nissen, Janna, additional, Dinh, Khoa Manh, additional, Schwinn, Michael, additional, Kaspersen, Kathrine Agergård, additional, Boldsen, Jens Kjærgaard, additional, Didriksen, Maria, additional, Dowsett, Joseph, additional, Sørensen, Erik, additional, Thørner, Lise Wegner, additional, Larsen, Margit Anita Hørup, additional, Grum-Schwensen, Birgitte, additional, Sækmose, Susanne, additional, Paulsen, Isabella Worlewenut, additional, Frisk, Nanna Lond Skov, additional, Brodersen, Thorsten, additional, Vestergaard, Lasse Skafte, additional, Rostgaard, Klaus, additional, Mølbak, Kåre, additional, Skov, Robert Leo, additional, Erikstrup, Christian, additional, Ullum, Henrik, additional, and Hjalgrim, Henrik, additional
Published: 2020
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35. Dowsett, Joseph

Author: Dowsett, Joseph and Dowsett, Joseph
Published: 2020

36. SMIM1absence is associated with reduced energy expenditure and excess weight

Author: Stefanucci, Luca, Moslemi, Camous, Tomé, Ana R., Virtue, Samuel, Bidault, Guillaume, Gleadall, Nicholas S., Watson, Laura P.E., Kwa, Jing E., Burden, Frances, Farrow, Samantha, Banasik, Karina, Bay, Jakob, Boldsen, Jens Kjærgaard, Brodersen, Thorsten, Brunak, Søren, Burgdorf, Kristoffer, Chalmer, Mona Ameri, Didriksen, Maria, Dinh, Khoa Manh, Dowsett, Joseph, Erikstrup, Christian, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hansen, Thomas Folkmann, Hindhede, Lotte, Hjalgrim, Henrik, Jacobsen, Rikke Louise, Jemec, Gregor, Jensen, Bitten Aagaard, Kaspersen, Katrine, Kjerulff, Bertram Dalskov, Kogelman, Lisette, Hørup Larsen, Margit Anita, Louloudis, Ioannis, Lundgaard, Agnete, Susan, Mikkelsen, Christina, Nissen, Ioanna, Nyegaard, Mette, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Henriksen, Alexander Pil, Rohde, Palle Duun, Rostgaard, Klaus, Schwinn, Michael, Stefansson, Kari, Stefánsson, Hreinn, Sørensen, Erik, þorsteinsdóttir, Unnur, Thørner, Lise Wegner, Bruun, Mie Topholm, Ullum, Henrik, Werge, Thomas, Westergaard, David, Chen, Ji, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian’an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Katie Chan, Kei Hang, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Loz, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V.R., Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P., Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Southam, Lorraine, Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J.L., Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J.C., Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M. Arfan, Johnson, W. Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R.H.J., Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, Van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Goncalo R., Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Ida Chen, Yii-Der, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, Janaka de Silva, H., Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J. Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L.R., Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J.F., Magnusson, Patrik K.E., Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N.A., Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P. Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I.A., Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E. Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G.M., Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C.J., Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., Barroso, Inês, Võsa, Urmo, Burling, Keith, Walker, Lindsay, Ord, John, Barker, Peter, Warner, James, Frary, Amy, Renhstrom, Karola, Ashford, Sofie E., Piper, Jo, Biggs, Gail, Erber, Wendy N., Hoffman, Gary J., Schoenmakers, Nadia, Erikstrup, Christian, Rieneck, Klaus, Dziegiel, Morten H., Ullum, Henrik, Azzu, Vian, Vacca, Michele, Aparicio, Hugo Javier, Hui, Qin, Cho, Kelly, Sun, Yan V., Wilson, Peter W., Bayraktar, Omer A., Vidal-Puig, Antonio, Ostrowski, Sisse R., Astle, William J., Olsson, Martin L., Storry, Jill R., Pedersen, Ole B., Ouwehand, Willem H., Chatterjee, Krishna, Vuckovic, Dragana, and Frontini, Mattia
Abstract: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.
Published: 2024
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37. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Fatality Rate Among Elderly Danes: A Cross-sectional Study on Retired Blood Donors.

Author: Pedersen, Ole Birger, Nissen, Janna, Dinh, Khoa Manh, Schwinn, Michael, Kaspersen, Kathrine Agergård, Boldsen, Jens Kjærgaard, Didriksen, Maria, Dowsett, Joseph, Sørensen, Erik, Thørner, Lise Wegner, Larsen, Margit Anita Hørup, Grum-Schwensen, Birgitte, Sækmose, Susanne, Paulsen, Isabella Worlewenut, Frisk, Nanna Lond Skov, Brodersen, Thorsten, Vestergaard, Lasse Skafte, Rostgaard, Klaus, Mølbak, Kåre, and Skov, Robert Leo
Subjects: RESEARCH, SEROPREVALENCE, COVID-19, DANES, CONFIDENCE intervals, IMMUNOGLOBULINS, CROSS-sectional method, SURVEYS, QUESTIONNAIRES, DESCRIPTIVE statistics, STATISTICAL sampling, SENSITIVITY & specificity (Statistics), OLD age
Abstract: Background Although the vast majority of individuals succumbing to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are elderly, infection fatality rate (IFR) estimates for the age group ≥70 years are still scarce. To this end, we assessed SARS-CoV-2 seroprevalence among retired blood donors and combined it with national coronavirus disease 2019 (COVID-19) survey data to provide reliable population-based IFR estimates for this age group. Methods We identified 60 926 retired blood donors aged ≥70 years in the rosters of 3 regionwide Danish blood banks and invited them to fill in a questionnaire on COVID-19–related symptoms and behaviors. Among 24 861 (40.8%) responders, we invited a random sample of 3200 individuals for blood testing. Overall, 1201 (37.5%) individuals were tested for SARS-CoV-2 antibodies (Wantai) and compared with 1110 active blood donors aged 17–69 years. Seroprevalence 95% confidence intervals (CIs) were adjusted for assay sensitivity and specificity. Results Among retired (aged ≥70 years) and active (aged 17–69 years) blood donors, adjusted seroprevalences were 1.4% (95% CI,.3–2.5%) and 2.5% (95% CI, 1.3–3.8%), respectively. Using available population data on COVID-19–related fatalities, IFRs for patients aged ≥70 years and for 17–69 years were estimated at 5.4% (95% CI, 2.7–6.4%) and.083% (95% CI,.054–.18%), respectively. Only 52.4% of SARS-CoV-2–seropositive retired blood donors reported having been sick since the start of the pandemic. Conclusions COVID-19 IFR in the age group >69 years is estimated to be 65 times the IFR for people aged 18–69 years. [ABSTRACT FROM AUTHOR]
Published: 2021
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38. Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma : a randomized trial

Author: Malmström, Annika, Poulsen, Hans Skovgaard, Grønberg, Bjørn Henning, Stragliotto, Giuseppe, Hansen, Steinbjørn, Asklund, Thomas, Holmlund, Birgitta, Lysiak, Malgorzata, Dowsett, Joseph, Kristensen, Bjarne Winther, Söderkvist, Peter, Rosell, Johan, Henriksson, Roger, Malmström, Annika, Poulsen, Hans Skovgaard, Grønberg, Bjørn Henning, Stragliotto, Giuseppe, Hansen, Steinbjørn, Asklund, Thomas, Holmlund, Birgitta, Lysiak, Malgorzata, Dowsett, Joseph, Kristensen, Bjarne Winther, Söderkvist, Peter, Rosell, Johan, and Henriksson, Roger
Abstract: Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.Patients and methods: Patients, after surgery for GBM or AA, age 60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200mg/m(2) days 1-5 every 28 days, followed by RT 60Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75mg/m(2) was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p=.76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p=.022). For patients with GBM, no difference in survival was observed (p=.10). MGMT and IDH status affected outcome.Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.
Published: 2017
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39. Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma:a randomized trial

Author: Malmström, Annika, Poulsen, Hans Skovgaard, Grønberg, Bjørn Henning, Stragliotto, Giuseppe, Hansen, Steinbjørn, Asklund, Thomas, Holmlund, Birgitta, Łysiak, Małgorzata, Dowsett, Joseph, Kristensen, Bjarne Winther, Söderkvist, Peter, Rosell, Johan, Henriksson, Roger, Malmström, Annika, Poulsen, Hans Skovgaard, Grønberg, Bjørn Henning, Stragliotto, Giuseppe, Hansen, Steinbjørn, Asklund, Thomas, Holmlund, Birgitta, Łysiak, Małgorzata, Dowsett, Joseph, Kristensen, Bjarne Winther, Söderkvist, Peter, Rosell, Johan, and Henriksson, Roger
Abstract: INTRODUCTION: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.PATIENTS AND METHODS: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200 mg/m2days 1-5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m2was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.RESULTS: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome.CONCLUSIONS: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.
Published: 2017

40. Iron deficiency and infection risk in Danish blood donors.

Author: Brøns N, Kaspersen KA, Bay JT, Dowsett J, Erikstrup C, Hjalgrim H, Aagaard B, Mikkelsen C, Mikkelsen S, Pedersen OB, Rostgaard K, Schwinn M, Sørensen E, Rigas AS, Glenthøj A, and Ostrowski SR
Abstract: Background: We aimed to investigate if iron deficiency was associated with infection susceptibility in a large cohort of healthy individuals., Study Design and Methods: The Danish Blood Donor Study is a national ongoing prospective study of blood donors. We included 94,628 donors with 338,290 ferritin measurements from March 2010 to October 2022. We performed sex-stratified multivariable Cox regression to estimate the risk of infection for iron-deficient donors compared with iron-replete donors. Infection was defined as either a filled prescription of antibiotics registered in the Danish National Prescription Registry (NPR), or a hospital contact with infection registered in the Danish National Patient Registry (DNPR)., Results: Iron deficiency was associated with an overall increased risk of infection (defined as prescriptions of antibiotics) for women (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.02-1.15). Subgroup analyses showed an increased risk of respiratory tract infections (HR 1.16, 95% CI 1.05-1.28) and urinary tract infections (HR 1.16, 95% CI 1.04-1.29). Iron deficiency was not associated with overall risk of infection for men (HR 1.02, 95% CI 0.82-1.28). For both men and women, no association was found between iron deficiency and hospital contacts for infections., Conclusion: Iron deficiency was associated with an increased risk of infection in female blood donors. However, effect sizes were small, and there was no association between iron deficiency and hospital contacts for infection. Consequently, risk of infection should not be considered an apprehension regarding blood donation. These findings support the role of iron in immune function and monitorization of iron stores in female blood donors., (© 2025 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)
Published: 2025
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41. Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

Author: Yu Chen H, Dina C, Small AM, Shaffer CM, Levinson RT, Helgadóttir A, Capoulade R, Munter HM, Martinsson A, Cairns BJ, Trudsø LC, Hoekstra M, Burr HA, Marsh TW, Damrauer SM, Dufresne L, Le Scouarnec S, Messika-Zeitoun D, Ranatunga DK, Whitmer RA, Bonnefond A, Sveinbjornsson G, Daníelsen R, Arnar DO, Thorgeirsson G, Thorsteinsdottir U, Gudbjartsson DF, Hólm H, Ghouse J, Olesen MS, Christensen AH, Mikkelsen S, Jacobsen RL, Dowsett J, Pedersen OBV, Erikstrup C, Ostrowski SR, O'Donnell CJ, Budoff MJ, Gudnason V, Post WS, Rotter JI, Lathrop M, Bundgaard H, Johansson B, Ljungberg J, Näslund U, Le Tourneau T, Smith JG, Wells QS, Söderberg S, Stefánsson K, Schott JJ, Rader DJ, Clarke R, Engert JC, and Thanassoulis G
Subjects: Humans, Genome-Wide Association Study methods, Adiposity genetics, Genetic Predisposition to Disease, Obesity, Risk Factors, Inflammation, Apolipoproteins genetics, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide genetics, Aortic Valve Stenosis genetics, Dyslipidemias complications, Dyslipidemias genetics
Abstract: Aims: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS., Methods and Results: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS., Conclusion: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies., Competing Interests: Conflict of interest Scott M. Damrauer receives research support (to the University of Pennsylvania) from RenalytixAI and personal fees from Caico Ibs, both outside the scope of the present work. SMD is also named as a co-inventor on a government-owned US Patent application related to the use of genetic risk prediction for venous thromboembolic disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. SMD is named as a co-inventor on a Government-owned US Patent application related to the use of PDE3B inhibition for preventing cardiovascular disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. Stefan Söderberg has received speaker honoraria and consulting fees from Actelion Ltd. George Thanassoulis has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen, Sanofi, Novartis, HLS Therapeutics and Silence. Morten Salling Olesen has received 5.000.000 dkrfra Sundhedsdonationer.Journalnr. 2022-0243. David O. Arnar has received travel support from Pfizer to attend the ESC 2022 Scientific Meeting in Barcelona and has stock options in Sidekick Health Digital Therapeutics. Henning Bundgaard has received lecture fees from Amgen, MSD, Sanofi-Avensis, BMS and grants from NordForsk, Innovation Fond, Denmark, The Capital Regions Research Foundation. Alex Hoerby Christensen—Novo Nordisk Foundation NNF20OC0065799. Romaine Capoulade has received an Honorarium for one lecture from Novartis. Robert Clarke has received support from BAYER (China Kadoorie Biobank). Unnur Thorsteinsdottir’s research is funded by deCODE genetics/Amgen. Daniel F. Gudbjartsson receives funds from deCODE Genetics/Amgen. Until 1 June 2022, Gudmundur Thorgeirsson was a part time employee of deCode Genetics that is owned by Amgen. Hilma Holm is an employee of deCODE genetics/Amgen Inc. Anna Helgadottir is an employee of deCODE genetics/Amgen Inc., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Published: 2023
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42. Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial.

Author: Malmström A, Poulsen HS, Grønberg BH, Stragliotto G, Hansen S, Asklund T, Holmlund B, Łysiak M, Dowsett J, Kristensen BW, Söderkvist P, Rosell J, and Henriksson R
Subjects: Adult, Astrocytoma genetics, Brain Neoplasms genetics, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Dacarbazine therapeutic use, Female, Glioblastoma genetics, Humans, Isocitrate Dehydrogenase genetics, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Mutation, Pilot Projects, Prognosis, Promoter Regions, Genetic, Survival Rate, Temozolomide, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins genetics, X-linked Nuclear Protein genetics, Young Adult, Antineoplastic Agents, Alkylating therapeutic use, Astrocytoma therapy, Brain Neoplasms therapy, Chemoradiotherapy, Adjuvant methods, Dacarbazine analogs & derivatives, Glioblastoma therapy, Neurosurgical Procedures, Radiotherapy, Adjuvant methods
Abstract: Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ., Patients and Methods: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200 mg/m 2 days 1-5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m 2 was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety., Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome., Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.
Published: 2017
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