291 results on '"Malarstig A"'
Search Results
2. Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases
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Carland, Corinne, Png, Grace, Malarstig, Anders, Kho, Pik Fang, Gustafsson, Stefan, Michaelsson, Karl, Lind, Lars, Tsafantakis, Emmanouil, Karaleftheri, Maria, Dedoussis, George, Ramisch, Anna, Macdonald-Dunlop, Erin, Klaric, Lucija, Joshi, Peter K., Chen, Yan, Björck, Hanna M., Eriksson, Per, Carrasco-Zanini, Julia, Wheeler, Eleanor, Suhre, Karsten, Gilly, Arthur, Zeggini, Eleftheria, Viñuela, Ana, Dermitzakis, Emmanouil T., Wilson, James F., Langenberg, Claudia, Thareja, Gaurav, Halama, Anna, Schmidt, Frank, Zanetti, Daniela, and Assimes, Themistocles
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- 2023
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3. FinnGen provides genetic insights from a well-phenotyped isolated population
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Kurki, Mitja I., Karjalainen, Juha, Palta, Priit, Sipilä, Timo P., Kristiansson, Kati, Donner, Kati M., Reeve, Mary P., Laivuori, Hannele, Aavikko, Mervi, Kaunisto, Mari A., Loukola, Anu, Lahtela, Elisa, Mattsson, Hannele, Laiho, Päivi, Della Briotta Parolo, Pietro, Lehisto, Arto A., Kanai, Masahiro, Mars, Nina, Rämö, Joel, Kiiskinen, Tuomo, Heyne, Henrike O., Veerapen, Kumar, Rüeger, Sina, Lemmelä, Susanna, Zhou, Wei, Ruotsalainen, Sanni, Pärn, Kalle, Hiekkalinna, Tero, Koskelainen, Sami, Paajanen, Teemu, Llorens, Vincent, Gracia-Tabuenca, Javier, Siirtola, Harri, Reis, Kadri, Elnahas, Abdelrahman G., Sun, Benjamin, Foley, Christopher N., Aalto-Setälä, Katriina, Alasoo, Kaur, Arvas, Mikko, Auro, Kirsi, Biswas, Shameek, Bizaki-Vallaskangas, Argyro, Carpen, Olli, Chen, Chia-Yen, Dada, Oluwaseun A., Ding, Zhihao, Ehm, Margaret G., Eklund, Kari, Färkkilä, Martti, Finucane, Hilary, Ganna, Andrea, Ghazal, Awaisa, Graham, Robert R., Green, Eric M., Hakanen, Antti, Hautalahti, Marco, Hedman, Åsa K., Hiltunen, Mikko, Hinttala, Reetta, Hovatta, Iiris, Hu, Xinli, Huertas-Vazquez, Adriana, Huilaja, Laura, Hunkapiller, Julie, Jacob, Howard, Jensen, Jan-Nygaard, Joensuu, Heikki, John, Sally, Julkunen, Valtteri, Jung, Marc, Junttila, Juhani, Kaarniranta, Kai, Kähönen, Mika, Kajanne, Risto, Kallio, Lila, Kälviäinen, Reetta, Kaprio, Jaakko, Kerimov, Nurlan, Kettunen, Johannes, Kilpeläinen, Elina, Kilpi, Terhi, Klinger, Katherine, Kosma, Veli-Matti, Kuopio, Teijo, Kurra, Venla, Laisk, Triin, Laukkanen, Jari, Lawless, Nathan, Liu, Aoxing, Longerich, Simonne, Mägi, Reedik, Mäkelä, Johanna, Mäkitie, Antti, Malarstig, Anders, Mannermaa, Arto, Maranville, Joseph, Matakidou, Athena, Meretoja, Tuomo, Mozaffari, Sahar V., Niemi, Mari E. K., Niemi, Marianna, Niiranen, Teemu, O´Donnell, Christopher J., Obeidat, Ma´en, Okafo, George, Ollila, Hanna M., Palomäki, Antti, Palotie, Tuula, Partanen, Jukka, Paul, Dirk S., Pelkonen, Margit, Pendergrass, Rion K., Petrovski, Slavé, Pitkäranta, Anne, Platt, Adam, Pulford, David, Punkka, Eero, Pussinen, Pirkko, Raghavan, Neha, Rahimov, Fedik, Rajpal, Deepak, Renaud, Nicole A., Riley-Gillis, Bridget, Rodosthenous, Rodosthenis, Saarentaus, Elmo, Salminen, Aino, Salminen, Eveliina, Salomaa, Veikko, Schleutker, Johanna, Serpi, Raisa, Shen, Huei-yi, Siegel, Richard, Silander, Kaisa, Siltanen, Sanna, Soini, Sirpa, Soininen, Hilkka, Sul, Jae Hoon, Tachmazidou, Ioanna, Tasanen, Kaisa, Tienari, Pentti, Toppila-Salmi, Sanna, Tukiainen, Taru, Tuomi, Tiinamaija, Turunen, Joni A., Ulirsch, Jacob C., Vaura, Felix, Virolainen, Petri, Waring, Jeffrey, Waterworth, Dawn, Yang, Robert, Nelis, Mari, Reigo, Anu, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Fox, Caroline, Havulinna, Aki S., Perola, Markus, Ripatti, Samuli, Jalanko, Anu, Laitinen, Tarja, Mäkelä, Tomi P., Plenge, Robert, McCarthy, Mark, Runz, Heiko, Daly, Mark J., and Palotie, Aarno
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- 2023
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4. Causal analysis of plasma IL-8 on carotid intima media thickness, a measure of subclinical atherosclerosis
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Velásquez, Ilais Moreno, Malarstig, Anders, Baldassarre, Damiano, Borne, Yan, de Faire, Ulf, Engström, Gunnar, Eriksson, Per, Giral, Philippe, Humphries, Steve E., Kurl, Sudhir, Leander, Karin, Lind, Lars, Lindén, Anders, Orsini, Nicola, Pirro, Matteo, Silveira, Angela, Smit, Andries J., Tremoli, Elena, Veglia, Fabrizio, Strawbridge, Rona J., and Gigante, Bruna
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- 2023
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5. Improving Assessment of Drug Safety Through Proteomics
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Williams, Stephen A, Murthy, Ashwin C, DeLisle, Robert K, Hyde, Craig, Malarstig, Anders, Ostroff, Rachel, Weiss, Sophie J, Segal, Mark R, and Ganz, Peter
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Aging ,Clinical Research ,Cardiovascular ,Prevention ,Patient Safety ,Heart Disease ,Good Health and Well Being ,Aged ,Aldosterone ,Anticholesteremic Agents ,Biomarkers ,Pharmacological ,Case-Control Studies ,Cholesterol Ester Transfer Proteins ,Drug-Related Side Effects and Adverse Reactions ,Early Diagnosis ,Female ,Heart Failure ,Humans ,Male ,Middle Aged ,Myocardial Infarction ,Prognosis ,Prospective Studies ,Proteomics ,Quinolines ,Stroke ,Survival Analysis ,aptamers ,biomarkers ,peptides ,precision medicine ,prescription drugs ,proteins ,proteomics ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Public Health and Health Services ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences ,Sports science and exercise - Abstract
BackgroundEarly detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.MethodsA nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.ResultsPlasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.ConclusionsHeretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.
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- 2018
6. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
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Howson, Joanna MM, Zhao, Wei, Barnes, Daniel R, Ho, Weang-Kee, Young, Robin, Paul, Dirk S, Waite, Lindsay L, Freitag, Daniel F, Fauman, Eric B, Salfati, Elias L, Sun, Benjamin B, Eicher, John D, Johnson, Andrew D, Sheu, Wayne HH, Nielsen, Sune F, Lin, Wei-Yu, Surendran, Praveen, Malarstig, Anders, Wilk, Jemma B, Tybjærg-Hansen, Anne, Rasmussen, Katrine L, Kamstrup, Pia R, Deloukas, Panos, Erdmann, Jeanette, Kathiresan, Sekar, Samani, Nilesh J, Schunkert, Heribert, Watkins, Hugh, Do, Ron, Rader, Daniel J, Johnson, Julie A, Hazen, Stanley L, Quyyumi, Arshed A, Spertus, John A, Pepine, Carl J, Franceschini, Nora, Justice, Anne, Reiner, Alex P, Buyske, Steven, Hindorff, Lucia A, Carty, Cara L, North, Kari E, Kooperberg, Charles, Boerwinkle, Eric, Young, Kristin, Graff, Mariaelisa, Peters, Ulrike, Absher, Devin, Hsiung, Chao A, Lee, Wen-Jane, Taylor, Kent D, Chen, Ying-Hsiang, Lee, I-Te, Guo, Xiuqing, Chung, Ren-Hua, Hung, Yi-Jen, Rotter, Jerome I, Juang, Jyh-Ming J, Quertermous, Thomas, Wang, Tzung-Dau, Rasheed, Asif, Frossard, Philippe, Alam, Dewan S, Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Chen, Yii-Der Ida, Nordestgaard, Børge G, Assimes, Themistocles L, Danesh, John, Butterworth, Adam S, and Saleheen, Danish
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Biological Sciences ,Genetics ,Cardiovascular ,Heart Disease ,Human Genome ,Clinical Research ,Aging ,Atherosclerosis ,Heart Disease - Coronary Heart Disease ,2.1 Biological and endogenous factors ,Arteries ,Cell Adhesion ,Chemotaxis ,Leukocyte ,Coronary Artery Disease ,Energy Metabolism ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Histone Code ,Humans ,Male ,Muscle ,Smooth ,Vascular ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Risk Factors ,CARDIoGRAMplusC4D ,EPIC-CVD ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.
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- 2017
7. Author Correction: FinnGen provides genetic insights from a well-phenotyped isolated population
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Kurki, Mitja I., Karjalainen, Juha, Palta, Priit, Sipilä, Timo P., Kristiansson, Kati, Donner, Kati M., Reeve, Mary P., Laivuori, Hannele, Aavikko, Mervi, Kaunisto, Mari A., Loukola, Anu, Lahtela, Elisa, Mattsson, Hannele, Laiho, Päivi, Della Briotta Parolo, Pietro, Lehisto, Arto A., Kanai, Masahiro, Mars, Nina, Rämö, Joel, Kiiskinen, Tuomo, Heyne, Henrike O., Veerapen, Kumar, Rüeger, Sina, Lemmelä, Susanna, Zhou, Wei, Ruotsalainen, Sanni, Pärn, Kalle, Hiekkalinna, Tero, Koskelainen, Sami, Paajanen, Teemu, Llorens, Vincent, Gracia-Tabuenca, Javier, Siirtola, Harri, Reis, Kadri, Elnahas, Abdelrahman G., Sun, Benjamin, Foley, Christopher N., Aalto-Setälä, Katriina, Alasoo, Kaur, Arvas, Mikko, Auro, Kirsi, Biswas, Shameek, Bizaki-Vallaskangas, Argyro, Carpen, Olli, Chen, Chia-Yen, Dada, Oluwaseun A., Ding, Zhihao, Ehm, Margaret G., Eklund, Kari, Färkkilä, Martti, Finucane, Hilary, Ganna, Andrea, Ghazal, Awaisa, Graham, Robert R., Green, Eric M., Hakanen, Antti, Hautalahti, Marco, Hedman, Åsa K., Hiltunen, Mikko, Hinttala, Reetta, Hovatta, Iiris, Hu, Xinli, Huertas-Vazquez, Adriana, Huilaja, Laura, Hunkapiller, Julie, Jacob, Howard, Jensen, Jan-Nygaard, Joensuu, Heikki, John, Sally, Julkunen, Valtteri, Jung, Marc, Junttila, Juhani, Kaarniranta, Kai, Kähönen, Mika, Kajanne, Risto, Kallio, Lila, Kälviäinen, Reetta, Kaprio, Jaakko, Kerimov, Nurlan, Kettunen, Johannes, Kilpeläinen, Elina, Kilpi, Terhi, Klinger, Katherine, Kosma, Veli-Matti, Kuopio, Teijo, Kurra, Venla, Laisk, Triin, Laukkanen, Jari, Lawless, Nathan, Liu, Aoxing, Longerich, Simonne, Mägi, Reedik, Mäkelä, Johanna, Mäkitie, Antti, Malarstig, Anders, Mannermaa, Arto, Maranville, Joseph, Matakidou, Athena, Meretoja, Tuomo, Mozaffari, Sahar V., Niemi, Mari E. K., Niemi, Marianna, Niiranen, Teemu, O´Donnell, Christopher J., Obeidat, Ma´en, Okafo, George, Ollila, Hanna M., Palomäki, Antti, Palotie, Tuula, Partanen, Jukka, Paul, Dirk S., Pelkonen, Margit, Pendergrass, Rion K., Petrovski, Slavé, Pitkäranta, Anne, Platt, Adam, Pulford, David, Punkka, Eero, Pussinen, Pirkko, Raghavan, Neha, Rahimov, Fedik, Rajpal, Deepak, Renaud, Nicole A., Riley-Gillis, Bridget, Rodosthenous, Rodosthenis, Saarentaus, Elmo, Salminen, Aino, Salminen, Eveliina, Salomaa, Veikko, Schleutker, Johanna, Serpi, Raisa, Shen, Huei-yi, Siegel, Richard, Silander, Kaisa, Siltanen, Sanna, Soini, Sirpa, Soininen, Hilkka, Sul, Jae Hoon, Tachmazidou, Ioanna, Tasanen, Kaisa, Tienari, Pentti, Toppila-Salmi, Sanna, Tukiainen, Taru, Tuomi, Tiinamaija, Turunen, Joni A., Ulirsch, Jacob C., Vaura, Felix, Virolainen, Petri, Waring, Jeffrey, Waterworth, Dawn, Yang, Robert, Nelis, Mari, Reigo, Anu, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Fox, Caroline, Havulinna, Aki S., Perola, Markus, Ripatti, Samuli, Jalanko, Anu, Laitinen, Tarja, Mäkelä, Tomi P., Plenge, Robert, McCarthy, Mark, Runz, Heiko, Daly, Mark J., and Palotie, Aarno
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- 2023
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8. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
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Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Rebecca Gutmann, Christopher M. Haggerty, Pim van der Harst, Craig L. Hyde, Erik Ingelsson, J. Wouter Jukema, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian’an Luan, Patrik Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify R. Mordi, Thomas Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali T. Owens, Colin N. A. Palmer, Helen M. Parry, Markus Perola, Eliana Portilla-Fernandez, Bruce M. Psaty, Regeneron Genetics Center, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari-Liis Tammesoo, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Stella Trompet, Benoit Tyl, Andre G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faiez Zannad, Jing Hua Zhao, Harry Hemingway, Nilesh J. Samani, John J. V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton-Cheh, Anders Malarstig, Hilma Holm, Steven A. Lubitz, Naveed Sattar, Michael V. Holmes, Thomas P. Cappola, Folkert W. Asselbergs, Aroon D. Hingorani, Karoline Kuchenbaecker, Patrick T. Ellinor, Chim C. Lang, Kari Stefansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, and R. Thomas Lumbers
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Science - Abstract
Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.
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- 2020
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9. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
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Surendran, Praveen, Young, Robin, Barnes, Daniel R., Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Zhao, Wei, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J.M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrières, Jean, Kee, Frank, Kuulasmaa, Kari, Müller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, EPIC-CVD Consortium, Frossard, Philippe, Nordestgaard, Børge Grønne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Howson, Joanna M.M., Erzurumluoglu, A. Mesut, Jackson, Victoria E., Melbourne, Carl A., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian’an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renström, Frida, Hallmans, Göran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Völzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D.P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N.A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Understanding Society Scientific Group, Munroe, Patricia B., Jansson, Jan-Håkan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., Wain, Louise V., Tobin, Martin D., Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valérie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Bertelsen, Sarah, Chou, Yi-Ling, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Kardia, Sharon L.R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, McGue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Weir, David R., Kaprio, Jaakko, Abecasis, Gonçalo R., Liu, Dajiang J., and Vrieze, Scott
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- 2019
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10. Experimental and Computational Analysis of Newly Identified Pathogenic Mutations in the Creatine Transporter SLC6A8
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Ferrada, Evandro, primary, Wiedmer, Tabea, additional, Wang, Wen-An, additional, Frommelt, Fabian, additional, Steurer, Barbara, additional, Klimek, Christoph, additional, Lindinger, Sabrina, additional, Osthushenrich, Tanja, additional, Garofoli, Andrea, additional, Brocchetti, Silvia, additional, Bradberry, Samuel, additional, Huang, Jiahui, additional, MacNamara, Aidan, additional, Scarabottolo, Lia, additional, Ecker, Gerhard F., additional, Malarstig, Anders, additional, and Superti-Furga, Giulio, additional
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- 2023
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11. Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease
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Christopher D. Whelan, Niklas Mattsson, Michael W. Nagle, Swetha Vijayaraghavan, Craig Hyde, Shorena Janelidze, Erik Stomrud, Julie Lee, Lori Fitz, Tarek A. Samad, Gayathri Ramaswamy, Richard A. Margolin, Anders Malarstig, and Oskar Hansson
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Alzheimer’s disease ,Mild cognitive impairment ,Biomarker ,Proteomics ,Inflammation ,Apoptosis ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract To date, the development of disease-modifying therapies for Alzheimer’s disease (AD) has largely focused on the removal of amyloid beta Aβ fragments from the CNS. Proteomic profiling of patient fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. Here, we applied the Olink™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aβ- negative cognitively normal individuals (Aβ- CN), 142 Aβ-positive CN (Aβ+ CN), 50 Aβ- mild cognitive impairment (MCI) patients, 75 Aβ+ MCI patients, and 161 Aβ+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aβ- CN, 23 Aβ- + CN, 44 Aβ- MCI and 53 Aβ+ MCI. To compare protein concentrations in patients versus controls, we applied multiple linear regressions adjusting for age, gender, medications, smoking and mean subject-level protein concentration, and corrected findings for false discovery rate (FDR, q
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- 2019
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12. New insights into the genetic etiology of Alzheimer's disease and related dementias
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Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. 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Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Broeckhoven, C, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael [0000-0001-5231-1714], Fabrizio, Tagliavini [0000-0003-1039-7315], Fladby, Tormod [0000-0002-9984-9797], Fornage, Myriam [0000-0003-0677-8158], Fox, Nick C [0000-0002-6660-657X], Bullido, María J [0000-0002-6477-1117], Froelich, Lutz [0000-0003-1494-0813], Galimberti, Daniela [0000-0002-9284-5953], García-Alberca, Jose Maria [0000-0003-2951-6644], Goate, Alison M [0000-0002-0576-2472], González-Pérez, Antonio [0000-0001-9771-5982], Green, Emma [0000-0002-8687-5590], Grünblatt, Edna [0000-0001-8505-7265], Gudnason, Vilmundur [0000-0001-5696-0084], Haapasalo, Annakaisa [0000-0003-0959-2957], Harwood, Janet [0000-0002-3225-0069], Heilmann-Heimbach, Stefanie [0000-0003-1057-465X], Herrmann, Martin J [0000-0001-9970-2122], Holstege, Henne [0000-0002-7688-3087], Biessels, Geert Jan [0000-0001-6862-2496], Jian, Xueqiu [0000-0002-0313-6494], Johansson, Charlotte [0000-0002-5351-1950], Jun, Gyungah R [0000-0002-3230-8697], Kastumata, Yuriko [0000-0002-0188-8094], Kehoe, Patrick G [0000-0002-7542-1139], Kornhuber, Johannes [0000-0002-8096-3987], Kosmidis, Mary H [0000-0001-8790-1220], Lage, Carmen [0000-0003-1703-121X], Launer, Lenore [0000-0002-3238-7612], Lee, Chien-Yueh [0000-0002-4304-974X], Lleó, Alberto [0000-0002-2568-5478], Lopez, Oscar [0000-0002-8546-8256], de Munain, Adolfo Lopez [0000-0002-9509-4032], Lunetta, Kathryn L [0000-0002-9268-810X], Ma, Yiyi [0000-0002-3609-8877], MacLeod, Catherine A [0000-0002-9314-7380], Marquié, Marta [0000-0002-0660-0950], Montes, Angel Martín [0000-0002-1694-786X], Mead, Simon [0000-0002-4326-1468], Medina, Miguel [0000-0002-7016-5340], Menéndez-González, Manuel [0000-0002-5218-0774], Mol, Merel [0000-0003-2533-2530], Morgan, Kevin [0000-0002-8217-2396], Nöthen, Markus M [0000-0002-8770-2464], Muchnik, Carolina [0000-0002-1542-3706], Nacmias, Benedetta [0000-0001-9338-9040], Nicolas, Gael [0000-0001-9391-7800], Nordestgaard, Børge G [0000-0002-1954-7220], Pasquier, Florence [0000-0001-9880-9788], Pastor, Pau [0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A [0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
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tau Proteins/genetics ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurologi ,MED/03 - GENETICA MEDICA ,45/43 ,Medizin ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,genetics [Alzheimer Disease] ,Genome-Wide Association Study ,Humans ,tau Proteins ,Alzheimer Disease ,Cognitive Dysfunction ,VARIANTS ,pathology [Alzheimer Disease] ,Tau Proteins ,Settore BIO/13 - Biologia Applicata ,Cognitive Dysfunction/psychology ,692/699/375/365/1283 ,IMPUTATION ,article ,1184 Genetics, developmental biology, physiology ,Biología y Biomedicina / Biología ,AMYLOID-BETA ,Settore MED/26 - NEUROLOGIA ,Neurology ,psychology [Cognitive Dysfunction] ,Medical Genetics ,Human ,Neuroscience(all) ,631/208/205/2138 ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,ddc:570 ,Genetics ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Medicinsk genetik ,MED/26 - NEUROLOGIA ,Alzheimer Disease/genetics ,neurology ,tau Protein ,NECROSIS-FACTOR-ALPHA ,RISK LOCI ,genetics [tau Proteins] ,PREDICTION MODELS ,Human medicine ,GENERATION ,RESPONSES - Abstract
25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
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- 2022
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13. CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers
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Ahmad, Shahzad, Milan, Marta del Campo, Hansson, Oskar, Demirkan, Ayse, Agustin, Ruiz, Sáez, Maria E., Giagtzoglou, Nikolaos, Cabrera-Socorro, Alfredo, Bakker, Margot H. M., Ramirez, Alfredo, Hankemeier, Thomas, Stomrud, Erik, Mattsson-Carlgren, Niklas, Scheltens, Philip, van der Flier, Wiesje M., Ikram, M. Arfan, Malarstig, Anders, Teunissen, Charlotte E., Amin, Najaf, and van Duijn, Cornelia M.
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- 2020
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14. Application of Machine Learning Methods to Predict Non-Alcoholic Steatohepatitis (NASH) in Non-Alcoholic Fatty Liver (NAFL) Patients.
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Suruchi Fialoke, Anders Malarstig, Melissa Miller, and Alexandra Dumitriu
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- 2018
15. Identifying therapeutic targets for cancer: 2,094 circulating proteins and risk of nine cancers
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Smith-Byrne, Karl, primary, Hedman, Asa, additional, Dimitriou, Marios, additional, Desai, Trishna, additional, Sokolov, Alexandr V., additional, Schioth, Helgi B., additional, Koprulu, Mine, additional, Pietzner, Maik, additional, Langenberg, Claudia, additional, Atkins, Joshua, additional, Cortez, Ricardo, additional, McKay, James, additional, Brennan, Paul, additional, Zhou, Sirui, additional, Richards, Brent J., additional, Yarmolinsky, James, additional, Martin, Richard M., additional, Borlido, Joana, additional, Mu, Xinmeng J., additional, Butterworth, Adam, additional, Shen, Xia, additional, Wilson, Jim, additional, Assimes, Themistocles L., additional, Hung, Rayjean J., additional, Amos, Christopher, additional, Purdue, Mark, additional, Rothman, Nathaniel, additional, Chanock, Stephen, additional, Travis, Ruth C., additional, Johansson, Mattias, additional, and Malarstig, Anders, additional
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- 2023
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16. Evaluation of Circulating Plasma Proteins in Breast Cancer: A Mendelian Randomization Analysis
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Malarstig, Anders, primary, Grassman, Felix, additional, Dahl, Leo, additional, Dimitriou, Marios, additional, Mcleod, Dianna, additional, Gabrielson, Marike, additional, Smith-Byrne, Karl, additional, Thomas, Cecilia, additional, Huang, Tzu-Hsuan, additional, Forsberg, Simon, additional, Eriksson, Per, additional, Ulfstedt, Mikael, additional, Johansson, Mattias, additional, Sokolov, Aleksandr, additional, Schioth, Helgi, additional, Hall, Per, additional, Schwenk, Jochen, additional, Czene, Kamila, additional, and Hedman, Asa, additional
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- 2023
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17. Fibroblast Growth Factor-23 and Risk of Cardiovascular Diseases A Mendelian Randomization Study
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Donovan, Killian, Herrington, William G., Pare, Guillaume, Pigeyre, Marie, Haynes, Richard, Sardell, Rebecca, Butterworth, Adam S., Folkersen, Lasse, Gustafsson, Stefan, Wang, Qin, Baigent, Colin, Malarstig, Anders, Holmes, Michael V., Staplin, Natalie, Donovan, Killian, Herrington, William G., Pare, Guillaume, Pigeyre, Marie, Haynes, Richard, Sardell, Rebecca, Butterworth, Adam S., Folkersen, Lasse, Gustafsson, Stefan, Wang, Qin, Baigent, Colin, Malarstig, Anders, Holmes, Michael V., and Staplin, Natalie
- Abstract
Background Fibroblast growth factor-23 (FGF-23) is associated with a range of cardiovascular and noncardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomization approaches can help control for such confounding.Methods SCALLOP Consortium data of 19,195 participants were used to generate an FGF-23 genetic score. Data from 337,448 UK Biobank participants were used to estimate associations between higher genetically predicted FGF-23 concentration and the odds of any atherosclerotic cardiovascular disease (n=26,266 events), nonatherosclerotic cardiovascular disease (n=12,652), and noncardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness and left ventricular mass were available in a subset. Associations with cardiovascular outcomes were also tested in three large case-control consortia: CARDIOGRAMplusC4D (coronary artery disease, n=181,249 cases), MEGASTROKE (stroke, n=34,217), and HERMES (heart failure, n=47,309).Results We identified 34 independent variants for circulating FGF-23, which formed a validated genetic score. There were no associations between genetically predicted FGF-23 and any of the cardiovascular or non cardiovascular outcomes. In UK Biobank, the odds ratio (OR) for any atherosclerotic cardiovascular disease per 1-SD higher genetically predicted logFGF-23 was 1.03 (95% confidence interval [95% CI], 0.98 to 1.08), and for any nonatherosclerotic cardiovascular disease, it was 1.01 (95% CI, 0.94 to 1.09). The ORs in the case-control consortia were 1.00 (95% CI, 0.97 to 1.03) for coronary artery disease, 1.01 (95% CI, 0.95 to 1.07) for stroke, and 1.00 (95% CI, 0.95 to 1.05) for heart failure. In those with imaging, logFGF-23 was not associated with carotid or cardiac abnormalities.Conclusions Genetically predicted FGF-23 levels are not associated with atherosclerotic and nonatherosclerotic cardiovascular diseases, suggesting no important
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- 2023
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18. Evaluation of Circulating Plasma Proteins in Breast Cancer: A Mendelian Randomization Analysis
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Anders Malarstig, Felix Grassman, Leo Dahl, Marios Dimitriou, Dianna Mcleod, Marike Gabrielson, Karl Smith-Byrne, Cecilia Thomas, Tzu-Hsuan Huang, Simon Forsberg, Per Eriksson, Mikael Ulfstedt, Mattias Johansson, Aleksandr Sokolov, Helgi Schioth, Per Hall, Jochen Schwenk, Kamila Czene, and Asa Hedman
- Abstract
The blood proteome reflects homeostatic and dynamic cellular processes across human organs. However, few blood proteomics studies of sufficient depth and size have been reported in breast cancer. To comprehensively identify circulating proteins with a causal role in breast cancer we measured 2,929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project and explored associations between proteins levels, clinical characteristics, and gene variants. The analysis revealed 812 cis-acting protein quantitative trait loci (pQTL), which were used as instruments in Mendelian randomisation (MR) analysis of breast cancer. Five proteins (P < 1.7x10-5, Bonferroni-corrected) with a potential causal role in breast cancer risk were revealed (CD160, DNPH1, LAYN, LRRC37A2 and TLR1). Confirming the MR findings in independent cohorts (FinnGen R9 and the UK Biobank), our study suggests that these proteins should be further explored as potential drug targets in breast cancer.
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- 2023
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19. Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease
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Whelan, Christopher D., Mattsson, Niklas, Nagle, Michael W., Vijayaraghavan, Swetha, Hyde, Craig, Janelidze, Shorena, Stomrud, Erik, Lee, Julie, Fitz, Lori, Samad, Tarek A., Ramaswamy, Gayathri, Margolin, Richard A., Malarstig, Anders, and Hansson, Oskar
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- 2019
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20. Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases
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Carland, Corinne, primary, Png, Grace, additional, Malarstig, Anders, additional, Kho, Pik Fang, additional, Gustafsson, Stefan, additional, Michaelsson, Karl, additional, Lind, Lars, additional, Tsafantakis, Emmanouil, additional, Karaleftheri, Maria, additional, Dedoussis, George, additional, Ramisch, Anna, additional, Macdonald-Dunlop, Erin, additional, Klaric, Lucija, additional, Joshi, Peter K., additional, Chen, Yan, additional, Björck, Hanna M., additional, Eriksson, Per, additional, Carrasco-Zanini, Julia, additional, Wheeler, Eleanor, additional, Suhre, Karsten, additional, Gilly, Arthur, additional, Zeggini, Eleftheria, additional, Viñuela, Ana, additional, Dermitzakis, Emmanouil T., additional, Wilson, James F., additional, Langenberg, Claudia, additional, Thareja, Gaurav, additional, Halama, Anna, additional, Schmidt, Frank, additional, Consortium, SCALLOP, additional, Zanetti, Daniela, additional, and Assimes, Themistocles, additional
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- 2023
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21. Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases
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Corinne Carland, Grace Png, Anders Malarstig, Pik Fang Kho, Stefan Gustafsson, Karl Michaelsson, Lars Lind, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Anna Ramisch, Erin Macdonald-Dunlop, Lucija Klaric, Peter K. Joshi, Yan Chen, Hanna M. Björck, Per Eriksson, Julia Carrasco-Zanini, Eleanor Wheeler, Karsten Suhre, Arthur Gilly, Eleftheria Zeggini, Ana Viñuela, Emmanouil T. Dermitzakis, James F. Wilson, Claudia Langenberg, Gaurav Thareja, Anna Halama, Frank Schmidt, SCALLOP Consortium, Daniela Zanetti, and Themistocles Assimes
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Background: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. Methods: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins. Results: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F). Conclusion: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.
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- 2023
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22. FinnGen provides genetic insights from a well-phenotyped isolated population
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Kurki, Mitja I, Karjalainen, Juha, Palta, Priit, Sipilä, Timo P, Kristiansson, Kati, Donner, Kati M, Reeve, Mary P, Laivuori, Hannele, Aavikko, Mervi, Kaunisto, Mari A, Loukola, Anu, Lahtela, Elisa, Mattsson, Hannele, Laiho, Päivi, Della Briotta Parolo, Pietro, Lehisto, Arto A, Kanai, Masahiro, Mars, Nina, Rämö, Joel, Kiiskinen, Tuomo, Heyne, Henrike O, Veerapen, Kumar, Rüeger, Sina, Lemmelä, Susanna, Zhou, Wei, Ruotsalainen, Sanni, Pärn, Kalle, Hiekkalinna, Tero, Koskelainen, Sami, Paajanen, Teemu, Llorens, Vincent, Gracia-Tabuenca, Javier, Siirtola, Harri, Reis, Kadri, Elnahas, Abdelrahman G, Sun, Benjamin, Foley, Christopher N, Aalto-Setälä, Katriina, Alasoo, Kaur, Arvas, Mikko, Auro, Kirsi, Biswas, Shameek, Bizaki-Vallaskangas, Argyro, Carpen, Olli, Chen, Chia-Yen, Dada, Oluwaseun A, Ding, Zhihao, Ehm, Margaret G, Eklund, Kari, Färkkilä, Martti, Finucane, Hilary, Ganna, Andrea, Ghazal, Awaisa, Graham, Robert R, Green, Eric M, Hakanen, Antti, Hautalahti, Marco, Hedman, Åsa K, Hiltunen, Mikko, Hinttala, Reetta, Hovatta, Iiris, Hu, Xinli, Huertas-Vazquez, Adriana, Huilaja, Laura, Hunkapiller, Julie, Jacob, Howard, Jensen, Jan-Nygaard, Joensuu, Heikki, John, Sally, Julkunen, Valtteri, Jung, Marc, Junttila, Juhani, Kaarniranta, Kai, Kähönen, Mika, Kajanne, Risto, Kallio, Lila, Kälviäinen, Reetta, Kaprio, Jaakko, FinnGen, Kerimov, Nurlan, Kettunen, Johannes, Kilpeläinen, Elina, Kilpi, Terhi, Klinger, Katherine, Kosma, Veli-Matti, Kuopio, Teijo, Kurra, Venla, Laisk, Triin, Laukkanen, Jari, Lawless, Nathan, Liu, Aoxing, Longerich, Simonne, Mägi, Reedik, Mäkelä, Johanna, Mäkitie, Antti, Malarstig, Anders, Mannermaa, Arto, Maranville, Joseph, Matakidou, Athena, Meretoja, Tuomo, Mozaffari, Sahar V, Niemi, Mari EK, Niemi, Marianna, Niiranen, Teemu, O Donnell, Christopher J, Obeidat, Ma En, Okafo, George, Ollila, Hanna M, Palomäki, Antti, Palotie, Tuula, Partanen, Jukka, Paul, Dirk S, Pelkonen, Margit, Pendergrass, Rion K, Petrovski, Slavé, Pitkäranta, Anne, Platt, Adam, Pulford, David, Punkka, Eero, Pussinen, Pirkko, Raghavan, Neha, Rahimov, Fedik, Rajpal, Deepak, Renaud, Nicole A, Riley-Gillis, Bridget, Rodosthenous, Rodosthenis, Saarentaus, Elmo, Salminen, Aino, Salminen, Eveliina, Salomaa, Veikko, Schleutker, Johanna, Serpi, Raisa, Shen, Huei-Yi, Siegel, Richard, Silander, Kaisa, Siltanen, Sanna, Soini, Sirpa, Soininen, Hilkka, Sul, Jae Hoon, Tachmazidou, Ioanna, Tasanen, Kaisa, Tienari, Pentti, Toppila-Salmi, Sanna, Tukiainen, Taru, Tuomi, Tiinamaija, Turunen, Joni A, Ulirsch, Jacob C, Vaura, Felix, Virolainen, Petri, Waring, Jeffrey, Waterworth, Dawn, Yang, Robert, Nelis, Mari, Reigo, Anu, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Fox, Caroline, Havulinna, Aki S, Perola, Markus, Ripatti, Samuli, Jalanko, Anu, Laitinen, Tarja, Mäkelä, Tomi P, Plenge, Robert, McCarthy, Mark, Runz, Heiko, Daly, Mark J, Palotie, Aarno, Palotie, Aarno [0000-0002-2527-5874], and Apollo - University of Cambridge Repository
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Estonia ,631/208/205/2138 ,692/308/2056 ,45/43 ,article ,Middle Aged ,United Kingdom ,White People ,631/208/457/649/2219 ,Phenotype ,Gene Frequency ,Meta-Analysis as Topic ,631/208/727/2000 ,Humans ,Disease ,Genetic Predisposition to Disease ,Finland ,Genome-Wide Association Study - Abstract
Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of
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- 2023
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23. Causal analysis of plasma IL-8 on carotid intima media thickness, a measure of subclinical atherosclerosis
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Ilais Moreno Velásquez, Anders Malarstig, Damiano Baldassarre, Yan Borne, Ulf de Faire, Gunnar Engström, Per Eriksson, Philippe Giral, Steve E. Humphries, Sudhir Kurl, Karin Leander, Lars Lind, Anders Lindén, Nicola Orsini, Matteo Pirro, Angela Silveira, Andries J. Smit, Elena Tremoli, Fabrizio Veglia, Rona J. Strawbridge, Bruna Gigante, and Groningen Kidney Center (GKC)
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Genetic association studies ,Cardiovascular and Metabolic Diseases ,Carotid intima media thickness ,Settore BIO/14 - Farmacologia ,Cohort studies ,General Medicine ,Subclinical atherosclerosis ,Chemokines ,General Biochemistry, Genetics and Molecular Biology - Abstract
Background: We investigated the causality of IL-8 on carotid intima-media thickness (c-IMT), a measure of sub-clinical atherosclerosis. Methods: The IMPROVE is a multicenter European study (n = 3,711). The association of plasma IL-8 with c-IMT (mm) was estimated by quantile regression. Genotyping was performed using the Illumina CardioMetabo and Immuno chips. Replication was attempted in three independent studies and a meta-analysis was performed using a random model. Results: In IMPROVE, each unit increase in plasma IL-8 was associated with an increase in median c-IMT measures (all p
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- 2023
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24. Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function [version 2; referees: 2 approved]
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Adeolu B. Adewoye, Nick Shrine, Linda Odenthal-Hesse, Samantha Welsh, Anders Malarstig, Scott Jelinsky, Iain Kilty, Martin D. Tobin, Edward J. Hollox, and Louise V. Wain
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Medicine ,Science - Abstract
Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5d32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5d32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.
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- 2018
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25. Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function [version 1; referees: 2 approved]
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Adeolu B. Adewoye, Nick Shrine, Linda Odenthal-Hesse, Samantha Welsh, Anders Malarstig, Scott Jelinsky, Iain Kilty, Martin D. Tobin, Edward J. Hollox, and Louise V. Wain
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Medicine ,Science - Abstract
Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5del32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.
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- 2018
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26. Genetic assessment of all SLC family members
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Anders Malarstig, Aidan MacNamara, Tanja Osthushenrich, and Evandro Ferrada
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The genetic assessment is performed both variant and gene based for all SLC family members, REsolution has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 101034439. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. This article reflects only the authors' views and neither IMI nor the European Union and EFPIA are responsible for any use that may be made of the information contained therein.
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- 2022
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27. Completion of data-mining workflow
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Anders Malarstig, Aidan MacNamara, Tanja Osthushenrich, and Evandro Ferrada
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The workflow for data mining is established and applied to all 446 SLCs, REsolution has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 101034439. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. This article reflects only the authors' views and neither IMI nor the European Union and EFPIA are responsible for any use that may be made of the information contained therein.
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- 2022
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28. Abstract 217: PCSK6 Is A Key Regulator Of Immune Status In Mice And Its Ablation Increases Atherosclerotic Plaque Burden In A Bone Marrow Transplant Model
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Bianca E Suur, Glykeria Karadimou, Mariette Lengquist, Malin Kronqvist, Anton Gisterå, Anders Malarstig, Ulf Hedin, Daniel F Ketelhuth, and Ljubica Matic
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Cardiology and Cardiovascular Medicine - Abstract
Introduction: Proprotein convertase subtilisins/kexins (PCSKs) activate cytokines and growth factors and have been implicated in various cancers. We have previously shown that PCSK6 is a key protease modulating smooth muscle cell response in atherosclerosis, but its expression also correlated positively with typical markers of T lymphocytes and macrophages in plaques and it was localised in the proximity of these cells. Here, we hypothesized that PCSK6 may be involved in modulating inflammatory responses and aimed to elucidate its role in a hyperlipidemic mice model. Methods: Detailed immunophenotyping using histology, FACS-, OLINK- and ELISA-based analyses and primary cell cultures was used to compare Pcsk6 -/- and littermate controls. Atherosclerosis was evaluated in Ldlr -/- mice upon bone marrow transplant with Pcsk6 -/- or wild-type bone-marrow. Results: At baseline Pcks6 -/- mice showed an enrichment of pro-inflammatory cytokines Ccl2, Ccl3, Ccl20, Cxcl1 and in particular Il17a and Il17f in plasma compared controls. Spleens of Pcsk6 -/- mice had an increased number of germinal centres and FACS analysis showed that they contained significantly more CD8+ T cells. Microarray analysis of spleens from Pcsk6 -/- vs. controls confirmed that T cell markers CD4, CD3E and CD3G were upregulated. In vitro , splenocytes isolated from Pcsk6 -/- mice secreted more IFN-γ, IL-2 and IL-10 than controls upon stimulation with α-CD3 and α-CD28 antibodies. Moreover, peritoneal macrophages from Pcsk6 -/- mice secreted more TNF-α, MCP-1, IL-6 and IL-10 compared to control mice upon LPS stimulation. Interestingly, bone marrow derived macrophages from Pcsk6 -/- mice were also more prone to lipid uptake. Finally, in vivo transplantation of Pcsk6 -/- bone marrow to Ldlr -/- mice led to increased atherosclerotic plaque burden compared to controls, as quantified in the aortic root. Conclusions: PCSK6 ablation led to increased number of CD8+ T cells, as well as macrophage and cytokine activation. Transplantation of Pcsk6 -/- bone marrow resulted in an increase in atherosclerotic plaque burden compared to controls. Taken together, these results indicate that PCSK6 is a key regulator of the immune system, though the exact mechanisms involved require further investigation.
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- 2022
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29. Abstract 105: Proprotein Convertase Subtilisin/kexin Type 6 (Pcsk6) Plays A Role In Angiogenesis Regulation
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Melody Chemaly, Xinran Dong, Bianca E Suur, Hong Jin, Anders Malarstig, and Ljubica Matic
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Cardiology and Cardiovascular Medicine - Abstract
Background: PCSK6 cleaves and activates growth factors involved in cell differentiation and Pcsk6-/- mice exhibit 25% embryonic lethality, while surviving offspring have blindness and cyclopia. We have shown that PCSK6 localizes to vascular smooth muscle cells of intra-plaque neovessels. We therefore hypothesize that the processes of angiogenesis, atherosclerosis and plaque neovascularisation share common molecular regulators and that PCSK6 plays a role in these processes. Methods: Association between SNPs near the PCSK6 gene and levels of 90 plasma proteins was tested using data from 30,931 individuals in the SCALLOP consortium. Associations of angiogenic factors with PCSK6 (transcriptomic and proteomic) and patient symptomatology were explored in a biobank of plaque endarterectomies (BiKE). Morpholino technology was used for Pcsk6 knockdown in zebrafish, coupled with vascular phenotype studies. Pcsk6-/- mice were used to study the expression of vasculogenesis related genes and vascular morphology at baseline (12 weeks). Results: Rs7178801 and rs11639051 in the PCSK6 gene were found to relate to plasma PDGFB and VEGFD levels. TGFB2, VEGFA, VEGFC, PDGFA and PLAUR associated with patients symptomatology in BiKE and correlated with PCSK6 levels. Gross phenotypic and histological examination of zebrafish embryos with ablated PCSK6 showed improper peripheral vascular patterning of intersegmental vessels along with cerebral and myocardial haemorrhage hemorrhage. Expression of angiogenic factors; Vegfa, Vegfb, Angpt1 and Tgfb2 were altered in the heart, liver and adipose tissue in Pcsk6-/- mice. Vessel density, length and branch numbers were reduced in the Pcsk6 -/- compared to the controls in the superficial but more significantly in the deep peripheral vessels. The smooth muscle cell coverage of the retinal vasculature was also reduced in the Pcsk6 -/- mice vs controls and Pdgfa was significantly downregulated compared to controls in mouse retinas. Conclusions: PCSK6 associates with levels of angiogenic factors on the genetic, transcriptomic and proteomic level. Lack of Pcsk6 in mice and zebrafish led to vascular patterning defects. Further planned studies will examine PCSK6 in pathological neovascularization.
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- 2022
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30. Genetic Landscape of the ACE2 Coronavirus Receptor
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Yang, Zhijian, Macdonald-Dunlop, Erin, Chen, Jiantao, Zhai, Ranran, Li, Ting, Richmond, Anne, Klaric, Lucija, Pirastu, Nicola, Ning, Zheng, Zheng, Chenqing, Wang, Yipeng, Huang, Tingting, He, Yazhou, Guo, Huiming, Ying, Kejun, Gustafsson, Stefan, Prins, Bram, Ramisch, Anna, Dermitzakis, Emmanouil T., Png, Grace, Eriksson, Niclas, Haessler, Jeffrey, Hu, Xiaowei, Zanetti, Daniela, Boutin, Thibaud, Hwang, Shih-Jen, Wheeler, Eleanor, Pietzner, Maik, Raffield, Laura M., Kalnapenkis, Anette, Peters, James E., Vinuela, Ana, Gilly, Arthur, Elmstahl, Solve, Dedoussis, George, Petrie, John R., Polasek, Ozren, Folkersen, Lasse, Chen, Yan, Yao, Chen, Vosa, Urmo, Pairo-Castineira, Erola, Clohisey, Sara, Bretherick, Andrew D., Rawlik, Konrad, Esko, Tonu, Enroth, Stefan, Johansson, Åsa, Gyllensten, Ulf B., Langenberg, Claudia, Levy, Daniel, Hayward, Caroline, Assimes, Themistocles L., Kooperberg, Charles, Manichaikul, Ani W., Siegbahn, Agneta, Wallentin, Lars, Lind, Lars, Zeggini, Eleftheria, Schwenk, Jochen M., Butterworth, Adam S., Michaëlsson, Karl, Pawitan, Yudi, Joshi, Peter K., Baillie, J. Kenneth, Malarstig, Anders, Reiner, Alexander P., Wilson, James F., Shen, Xia, Yang, Zhijian, Macdonald-Dunlop, Erin, Chen, Jiantao, Zhai, Ranran, Li, Ting, Richmond, Anne, Klaric, Lucija, Pirastu, Nicola, Ning, Zheng, Zheng, Chenqing, Wang, Yipeng, Huang, Tingting, He, Yazhou, Guo, Huiming, Ying, Kejun, Gustafsson, Stefan, Prins, Bram, Ramisch, Anna, Dermitzakis, Emmanouil T., Png, Grace, Eriksson, Niclas, Haessler, Jeffrey, Hu, Xiaowei, Zanetti, Daniela, Boutin, Thibaud, Hwang, Shih-Jen, Wheeler, Eleanor, Pietzner, Maik, Raffield, Laura M., Kalnapenkis, Anette, Peters, James E., Vinuela, Ana, Gilly, Arthur, Elmstahl, Solve, Dedoussis, George, Petrie, John R., Polasek, Ozren, Folkersen, Lasse, Chen, Yan, Yao, Chen, Vosa, Urmo, Pairo-Castineira, Erola, Clohisey, Sara, Bretherick, Andrew D., Rawlik, Konrad, Esko, Tonu, Enroth, Stefan, Johansson, Åsa, Gyllensten, Ulf B., Langenberg, Claudia, Levy, Daniel, Hayward, Caroline, Assimes, Themistocles L., Kooperberg, Charles, Manichaikul, Ani W., Siegbahn, Agneta, Wallentin, Lars, Lind, Lars, Zeggini, Eleftheria, Schwenk, Jochen M., Butterworth, Adam S., Michaëlsson, Karl, Pawitan, Yudi, Joshi, Peter K., Baillie, J. Kenneth, Malarstig, Anders, Reiner, Alexander P., Wilson, James F., and Shen, Xia
- Abstract
Background: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. Conclusions: Human plasma ACE2 shares a genetic basis with cardi
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- 2022
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31. Abstract 217: PCSK6 Is A Key Regulator Of Immune Status In Mice And Its Ablation Increases Atherosclerotic Plaque Burden In A Bone Marrow Transplant Model
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Suur, Bianca E, primary, Karadimou, Glykeria, additional, Lengquist, Mariette, additional, Kronqvist, Malin, additional, Gisterå, Anton, additional, Malarstig, Anders, additional, Hedin, Ulf, additional, Ketelhuth, Daniel F, additional, and Matic, Ljubica, additional
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- 2022
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32. Abstract 105: Proprotein Convertase Subtilisin/kexin Type 6 (Pcsk6) Plays A Role In Angiogenesis Regulation
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Chemaly, Melody, primary, Dong, Xinran, additional, Suur, Bianca E, additional, Jin, Hong, additional, Malarstig, Anders, additional, and Matic, Ljubica, additional
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- 2022
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33. The Ser82 RAGE Variant Affects Lung Function and Serum RAGE in Smokers and sRAGE Production In Vitro.
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Suzanne Miller, Amanda P Henry, Emily Hodge, Alexander K Kheirallah, Charlotte K Billington, Tracy L Rimington, Sangita K Bhaker, Ma'en Obeidat, Erik Melén, Simon K Merid, Caroline Swan, Catherine Gowland, Carl P Nelson, Ceri E Stewart, Charlotte E Bolton, Iain Kilty, Anders Malarstig, Stuart G Parker, Miriam F Moffatt, Andrew J Wardlaw, Ian P Hall, and Ian Sayers
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Medicine ,Science - Abstract
Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model.Immunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified.Immunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production.This study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism.
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- 2016
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34. FinnGen: Unique genetic insights from combining isolated population and national health register data
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Mitja I. Kurki, Juha Karjalainen, Priit Palta, Timo P. Sipilä, Kati Kristiansson, Kati Donner, Mary P. Reeve, Hannele Laivuori, Mervi Aavikko, Mari A. Kaunisto, Anu Loukola, Elisa Lahtela, Hannele Mattsson, Päivi Laiho, Pietro Della Briotta Parolo, Arto Lehisto, Masahiro Kanai, Nina Mars, Joel Rämö, Tuomo Kiiskinen, Henrike O. Heyne, Kumar Veerapen, Sina Rüeger, Susanna Lemmelä, Wei Zhou, Sanni Ruotsalainen, Kalle Pärn, Tero Hiekkalinna, Sami Koskelainen, Teemu Paajanen, Vincent Llorens, Javier Gracia-Tabuenca, Harri Siirtola, Kadri Reis, Abdelrahman G. Elnahas, Katriina Aalto-Setälä, Kaur Alasoo, Mikko Arvas, Kirsi Auro, Shameek Biswas, Argyro Bizaki-Vallaskangas, Olli Carpen, Chia-Yen Chen, Oluwaseun A. Dada, Zhihao Ding, Margaret G. Ehm, Kari Eklund, Martti Färkkilä, Hilary Finucane, Andrea Ganna, Awaisa Ghazal, Robert R. Graham, Eric Green, Antti Hakanen, Marco Hautalahti, Åsa Hedman, Mikko Hiltunen, Reetta Hinttala, Iiris Hovatta, Xinli Hu, Adriana Huertas-Vazquez, Laura Huilaja, Julie Hunkapiller, Howard Jacob, Jan-Nygaard Jensen, Heikki Joensuu, Sally John, Valtteri Julkunen, Marc Jung, Juhani Junttila, Kai Kaarniranta, Mika Kähönen, Risto M. Kajanne, Lila Kallio, Reetta Kälviäinen, Jaakko Kaprio, Nurlan Kerimov, Johannes Kettunen, Elina Kilpeläinen, Terhi Kilpi, Katherine Klinger, Veli-Matti Kosma, Teijo Kuopio, Venla Kurra, Triin Laisk, Jari Laukkanen, Nathan Lawless, Aoxing Liu, Simonne Longerich, Reedik Mägi, Johanna Mäkelä, Antti Mäkitie, Anders Malarstig, Arto Mannermaa, Joseph Maranville, Athena Matakidou, Tuomo Meretoja, Sahar V. Mozaffari, Mari EK. Niemi, Marianna Niemi, Teemu Niiranen, Christopher J. O’Donnell, Ma’en Obeidat, George Okafo, Hanna M. Ollila, Antti Palomäki, Tuula Palotie, Jukka Partanen, Dirk S. Paul, Margit Pelkonen, Rion K. Pendergrass, Slavé Petrovski, Anne Pitkäranta, Adam Platt, David Pulford, Eero Punkka, Pirkko Pussinen, Neha Raghavan, Fedik Rahimov, Deepak Rajpal, Nicole A. Renaud, Bridget Riley-Gillis, Rodosthenis Rodosthenous, Elmo Saarentaus, Aino Salminen, Eveliina Salminen, Veikko Salomaa, Johanna Schleutker, Raisa Serpi, Huei-yi Shen, Richard Siegel, Kaisa Silander, Sanna Siltanen, Sirpa Soini, Hilkka Soininen, Jae H. Sul, Ioanna Tachmazidou, Kaisa Tasanen, Pentti Tienari, Sanna Toppila-Salmi, Taru Tukiainen, Tiinamaija Tuomi, Joni A. Turunen, Jacob C. Ulirsch, Felix Vaura, Petri Virolainen, Jeffrey Waring, Dawn Waterworth, Robert Yang, Mari Nelis, Anu Reigo, Andres Metspalu, Lili Milani, Tõnu Esko, Caroline Fox, Aki S. Havulinna, Markus Perola, Samuli Ripatti, Anu Jalanko, Tarja Laitinen, Tomi Mäkelä, Robert Plenge, Mark McCarthy, Heiko Runz, Mark J. Daly, and Aarno Palotie
- Abstract
Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AFWe studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia.These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery.
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- 2022
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35. FinnGen: Unique genetic insights from combining isolated population and national health register data
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Kurki, Mitja I., primary, Karjalainen, Juha, additional, Palta, Priit, additional, Sipilä, Timo P., additional, Kristiansson, Kati, additional, Donner, Kati, additional, Reeve, Mary P., additional, Laivuori, Hannele, additional, Aavikko, Mervi, additional, Kaunisto, Mari A., additional, Loukola, Anu, additional, Lahtela, Elisa, additional, Mattsson, Hannele, additional, Laiho, Päivi, additional, Della Briotta Parolo, Pietro, additional, Lehisto, Arto, additional, Kanai, Masahiro, additional, Mars, Nina, additional, Rämö, Joel, additional, Kiiskinen, Tuomo, additional, Heyne, Henrike O., additional, Veerapen, Kumar, additional, Rüeger, Sina, additional, Lemmelä, Susanna, additional, Zhou, Wei, additional, Ruotsalainen, Sanni, additional, Pärn, Kalle, additional, Hiekkalinna, Tero, additional, Koskelainen, Sami, additional, Paajanen, Teemu, additional, Llorens, Vincent, additional, Gracia-Tabuenca, Javier, additional, Siirtola, Harri, additional, Reis, Kadri, additional, Elnahas, Abdelrahman G., additional, Aalto-Setälä, Katriina, additional, Alasoo, Kaur, additional, Arvas, Mikko, additional, Auro, Kirsi, additional, Biswas, Shameek, additional, Bizaki-Vallaskangas, Argyro, additional, Carpen, Olli, additional, Chen, Chia-Yen, additional, Dada, Oluwaseun A., additional, Ding, Zhihao, additional, Ehm, Margaret G., additional, Eklund, Kari, additional, Färkkilä, Martti, additional, Finucane, Hilary, additional, Ganna, Andrea, additional, Ghazal, Awaisa, additional, Graham, Robert R., additional, Green, Eric, additional, Hakanen, Antti, additional, Hautalahti, Marco, additional, Hedman, Åsa, additional, Hiltunen, Mikko, additional, Hinttala, Reetta, additional, Hovatta, Iiris, additional, Hu, Xinli, additional, Huertas-Vazquez, Adriana, additional, Huilaja, Laura, additional, Hunkapiller, Julie, additional, Jacob, Howard, additional, Jensen, Jan-Nygaard, additional, Joensuu, Heikki, additional, John, Sally, additional, Julkunen, Valtteri, additional, Jung, Marc, additional, Junttila, Juhani, additional, Kaarniranta, Kai, additional, Kähönen, Mika, additional, Kajanne, Risto M., additional, Kallio, Lila, additional, Kälviäinen, Reetta, additional, Kaprio, Jaakko, additional, Kerimov, Nurlan, additional, Kettunen, Johannes, additional, Kilpeläinen, Elina, additional, Kilpi, Terhi, additional, Klinger, Katherine, additional, Kosma, Veli-Matti, additional, Kuopio, Teijo, additional, Kurra, Venla, additional, Laisk, Triin, additional, Laukkanen, Jari, additional, Lawless, Nathan, additional, Liu, Aoxing, additional, Longerich, Simonne, additional, Mägi, Reedik, additional, Mäkelä, Johanna, additional, Mäkitie, Antti, additional, Malarstig, Anders, additional, Mannermaa, Arto, additional, Maranville, Joseph, additional, Matakidou, Athena, additional, Meretoja, Tuomo, additional, Mozaffari, Sahar V., additional, Niemi, Mari EK., additional, Niemi, Marianna, additional, Niiranen, Teemu, additional, O’Donnell, Christopher J., additional, Obeidat, Ma’en, additional, Okafo, George, additional, Ollila, Hanna M., additional, Palomäki, Antti, additional, Palotie, Tuula, additional, Partanen, Jukka, additional, Paul, Dirk S., additional, Pelkonen, Margit, additional, Pendergrass, Rion K., additional, Petrovski, Slavé, additional, Pitkäranta, Anne, additional, Platt, Adam, additional, Pulford, David, additional, Punkka, Eero, additional, Pussinen, Pirkko, additional, Raghavan, Neha, additional, Rahimov, Fedik, additional, Rajpal, Deepak, additional, Renaud, Nicole A., additional, Riley-Gillis, Bridget, additional, Rodosthenous, Rodosthenis, additional, Saarentaus, Elmo, additional, Salminen, Aino, additional, Salminen, Eveliina, additional, Salomaa, Veikko, additional, Schleutker, Johanna, additional, Serpi, Raisa, additional, Shen, Huei-yi, additional, Siegel, Richard, additional, Silander, Kaisa, additional, Siltanen, Sanna, additional, Soini, Sirpa, additional, Soininen, Hilkka, additional, Sul, Jae H., additional, Tachmazidou, Ioanna, additional, Tasanen, Kaisa, additional, Tienari, Pentti, additional, Toppila-Salmi, Sanna, additional, Tukiainen, Taru, additional, Tuomi, Tiinamaija, additional, Turunen, Joni A., additional, Ulirsch, Jacob C., additional, Vaura, Felix, additional, Virolainen, Petri, additional, Waring, Jeffrey, additional, Waterworth, Dawn, additional, Yang, Robert, additional, Nelis, Mari, additional, Reigo, Anu, additional, Metspalu, Andres, additional, Milani, Lili, additional, Esko, Tõnu, additional, Fox, Caroline, additional, Havulinna, Aki S., additional, Perola, Markus, additional, Ripatti, Samuli, additional, Jalanko, Anu, additional, Laitinen, Tarja, additional, Mäkelä, Tomi, additional, Plenge, Robert, additional, McCarthy, Mark, additional, Runz, Heiko, additional, Daly, Mark J., additional, and Palotie, Aarno, additional
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- 2022
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36. Abstract MP02: Proprotein Convertase Subtilisin/kexin Type 6 (PCSK6) Is Involved In Regulation Of Vasculogenesis
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Melody Chemaly, Bianca E Suur, Hong Jin, Anders Malarstig, and Ljubica Matic
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Cardiology and Cardiovascular Medicine - Abstract
Background: PCSK6 cleaves and activates growth factors involved in cell differentiation and Pcsk6-/- mice exhibit 25% embryonic lethality, while surviving offspring have blindness and cyclopia. We have shown that PCSK6 localizes to vascular smooth muscle cells of intra-plaque neovessels. Hypothesis: We hypothesize that a) the processes of vasculogenesis, atherosclerosis and plaque neovascularisation share common molecular regulators and b) that PCSK6 plays a common role in vascular remodeling. Methods: Association between SNPs near the PCSK6 gene and levels of 90 plasma proteins was tested using data from 30,931 individuals in the SCALLOP consortium. Data from the FinnGen consortium (Release 3) were queried to explore the PCSK6 SNPs associated with specific disease phenotypes. Morpholino technology was used for Pcsk6 knockdown in zebrafish, coupled with vascular phenotype studies. Pcsk6-/- mice were used to study the expression of vasculogenesis related genes as well as vascular morphology. Results: Rs7178801 and rs11639051 in the PCSK6 gene were found to relate to plasma PDGFB and VEGFD levels, while rs45482895 associated with diabetic retinopathy and disorders of the choroid and retina in humans. Gross phenotypic and histological examination of zebrafish embryos with ablated PCSK6 showed improper peripheral vascular patterning of intersegmental vessels, cerebral and myocardial haemorrhage, atrial dilatation and pericardial oedema. Gene expression levels of vasculogenesis related genes, i.e. Vegfa, Vegfb, Angpt1 and Tgfb2 were altered in the heart, liver and adipose tissue in Pcsk6-/- mice. In the retinas of Pcsk6-/- mice, Pdgfb was significantly downregulated compared to controls. Staining of the retinal vasculature showed that superficial retinal vasculature had a lower number of branching points and vessel width, while deep retinal vasculature covered a significantly smaller area in Pcsk6-/- Conclusions: Here, we show that variants in the PCSK6 gene associate with growth factors implicated in vasculogenesis and retinopathy. Lack of Pcsk6 in mice and zebrafish led to vascular patterning defects. Further studies will aim to elucidate the mechanisms by which PCSK6 regulates vasculogenesis in homeostatic and pathological conditions
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- 2021
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37. Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction.
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Louise V Wain, Ian Sayers, María Soler Artigas, Michael A Portelli, Eleftheria Zeggini, Ma'en Obeidat, Don D Sin, Yohan Bossé, David Nickle, Corry-Anke Brandsma, Anders Malarstig, Ciara Vangjeli, Scott A Jelinsky, Sally John, Iain Kilty, Tricia McKeever, Nick R G Shrine, James P Cook, Shrina Patel, Tim D Spector, Edward J Hollox, Ian P Hall, and Martin D Tobin
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Genetics ,QH426-470 - Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We hypothesised that these "resistant smokers" may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the "resistant smokers" and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34 × 10(-4)) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke.
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- 2014
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38. Abstract MP02: Proprotein Convertase Subtilisin/kexin Type 6 (PCSK6) Is Involved In Regulation Of Vasculogenesis
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Chemaly, Melody, primary, Suur, Bianca E, additional, Jin, Hong, additional, Malarstig, Anders, additional, and Matic, Ljubica, additional
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- 2021
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39. Technological readiness and implementation of genomic‐driven precision medicine for complex diseases
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Franks, P. W., primary, Melén, E., additional, Friedman, M., additional, Sundström, J., additional, Kockum, I., additional, Klareskog, L., additional, Almqvist, C., additional, Bergen, S. E., additional, Czene, K., additional, Hägg, S., additional, Hall, P., additional, Johnell, K., additional, Malarstig, A., additional, Catrina, A., additional, Hagström, H., additional, Benson, M., additional, Gustav Smith, J., additional, Gomez, M. F, additional, Orho‐Melander, M., additional, Jacobsson, B., additional, Halfvarson, J., additional, Repsilber, D., additional, Oresic, M., additional, Jern, C., additional, Melin, B., additional, Ohlsson, C., additional, Fall, T., additional, Rönnblom, L., additional, Wadelius, M., additional, Nordmark, G., additional, Johansson, Å., additional, Rosenquist, R., additional, and Sullivan, P. F., additional
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- 2021
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40. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices
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Natarajan, P. (Pradeep), Pampana, A. (Akhil), Graham, S. E. (Sarah E.), Ruotsalainen, S. E. (Sanni E.), Perry, J. A. (James A.), de Vries, P. S. (Paul S.), Broome, J. G. (Jai G.), Pirruccello, J. P. (James P.), Honigbere, M. C. (Michael C.), Aragam, K. (Krishna), Wolford, B. (Brooke), Brody, J. A. (Jennifer A.), Antonacci-Fulton, L. (Lucinda), Arden, M. (Moscati), Aslibekyan, S. (Stella), Assimes, T. L. (Themistocles L.), Ballantyne, C. M. (Christie M.), Bielak, L. F. (Lawrence F.), Bisl, J. C. (Joshua C.), Cade, B. E. (Brian E.), Do, R. (Ron), Doddapaneni, H. (Harsha), Emery, L. S. (Leslie S.), Hung, Y.-J. (Yi-Jen), Irvin, M. R. (Marguerite R.), Khan, A. T. (Alyna T.), Lange, L. (Leslie), Lee, J. (Jiwon), Lemaitre, R. N. (Rozenn N.), Martin, L. W. (Lisa W.), Metcalf, G. (Ginger), Montasser, M. E. (May E.), Moon, J.-Y. (Jee-Young), Muzny, D. (Donna), Connell, J. R. (Jeffrey R. O.), Palmer, N. D. (Nicholette D.), Peralta, J. M. (Juan M.), Peyser, P. A. (Patricia A.), Stilp, A. M. (Adrienne M.), Tsai, M. (Michael), Wang, F. F. (Fei Fei), Weeks, D. E. (Daniel E.), Yanek, L. R. (Lisa R.), Wilson, J. G. (James G.), Abecasis, G. (Goncalo), Arnett, D. K. (Donna K.), Becker, L. C. (Lewis C.), Blangercy, J. (John), Boerwinkle, E. (Eric), Bowden, D. W. (Donald W.), Chang, Y.-C. (Yi-Cheng), Chen, Y. I. (Yii-Der, I), Choi, W. J. (Won Jung), Correa, A. (Adolfo), Curran, J. E. (Joanne E.), Daly, M. J. (Mark J.), DutcherE, S. K. (Susan K.), Ellinor, P. T. (Patrick T.), Fornage, M. (Myriam), Freedman, B. I. (Barry, I), Gabriel, S. (Stacey), Germer, S. (Soren), Gibbs, R. A. (Richard A.), He, J. (Jiang), Hveem, K. (Kristian), Jarvik, G. P. (Gail P.), Kaplan, R. C. (Robert C.), Kardia, S. L. (Sharon L. R.), Kennyn, E. (Eimear), Kim, R. W. (Ryan W.), Kooperberg, C. (Charles), Laurie, C. C. (Cathy C.), Lee, S. (Seonwook), Lloyd-Jones, D. M. (Don M.), Loos, R. J. (Ruth J. F.), Lubitz, S. A. (Steven A.), Mathias, R. A. (Rasika A.), Martinez, K. A. (Karine A. Viaud), McGarvey, S. T. (Stephen T.), Mitche, B. D. (Braxton D.), Nickerson, D. A. (Deborah A.), North, K. E. (Kari E.), Palotie, A. (Aarno), Park, C. J. (Cheol Joo), Psat, B. M. (Bruce M. Y.), Rao, D. C. (D. C.), Redline, S. (Susan), Reiner, A. P. (Alexander P.), Seo, D. (Daekwan), Seo, J.-S. (Jeong-Sun), Smith, A. V. (Albert, V), Tracy, R. P. (Russell P.), Kathiresan, S. (Sekar), Cupples, L. A. (L. Adrienne), Rotten, J. I. (Jerome, I), Morrison, A. C. (Alanna C.), Rich, S. S. (Stephen S.), Ripatti, S. (Samuli), Wilier, C. (Cristen), Peloso, G. M. (Gina M.), Vasan, R. S. (Ramachandran S.), Abe, N. (Namiko), Albert, C. (Christine), Almasy, L. (Laura), Alonso, A. (Alvaro), Ament, S. (Seth), Anderson, P. (Peter), Applebaum-Bowden, D. (Deborah), Arking, D. (Dan), Ashley-Koch, A. (Allison), Auer, P. (Paul), Avramopoulos, D. (Dimitrios), Barnard, J. (John), Barnes, K. (Kathleen), Barr, R. G. (R. Graham), Barron-Casella, E. (Emily), Beaty, T. (Terri), Becker, D. (Diane), Beer, R. (Rebecca), Begum, F. (Ferdouse), Beitelshees, A. (Amber), Benjamin, E. (Emelia), Bezerra, M. (Marcos), Bielak, L. (Larry), Blackwel, T. (Thomas), Bowler, R. (Russell), Broecke, U. (Ulrich), Bunting, K. (Karen), Burchard, E. (Esteban), Buth, E. (Erin), Cardwel, J. (Jonathan), Carty, C. (Cara), Casaburi, R. (Richard), Casella, J. (James), Chaffin, M. (Mark), Chang, C. (Christy), Chasman, D. (Daniel), Chavan, S. (Sameer), Chen, B.-J. (Bo-Juen), Chen, W.-M. (Wei-Min), Chol, M. (Michael), Choi, S. H. (Seung Hoan), Chuang, L.-M. (Lee-Ming), Chung, M. (Mina), Conomos, M. P. (Matthew P.), Cornell, E. (Elaine), Crapo, J. (James), Curtis, J. (Jeffrey), Custer, B. (Brian), Damcott, C. (Coleen), Darbar, D. (Dawood), Das, S. (Sayantan), David, S. (Sean), Davis, C. (Colleen), Daya, M. (Michelle), de Andrade, M. (Mariza), DeBaunuo, M. (Michael), Duan, Q. (Qing), Devine, R. D. (Ranjan Deka Dawn DeMeo Scott), Duggirala, Q. R. (Qing Ravi), Durda, J. P. (Jon Peter), Dutcher, S. (Susan), Eaton, C. (Charles), Ekunwe, L. (Lynette), Farber, C. (Charles), Farnaml, L. (Leanna), Fingerlin, T. (Tasha), Flickinger, M. (Matthew), Franceschini, N. (Nora), Fu, M. (Mao), Fullerton, S. M. (Stephanie M.), Fulton, L. (Lucinda), Gan, W. (Weiniu), Gao, Y. (Yan), Gass, M. (Margery), Ge, B. (Bruce), Geng, X. P. (Xiaoqi Priscilla), Gignoux, C. (Chris), Gladwin, M. (Mark), Glahn, D. (David), Gogarten, S. (Stephanie), Gong, D.-W. (Da-Wei), Goring, H. (Harald), Gu, C. C. (C. Charles), Guan, Y. (Yue), Guo, X. (Xiuqing), Haessler, J. (Jeff), Hall, M. (Michael), Harris, D. (Daniel), Hawle, N. Y. (Nicola Y.), Heavner, B. (Ben), Heckbert, S. (Susan), Hernandez, R. (Ryan), Herrington, D. (David), Hersh, C. (Craig), Hidalgo, B. (Bertha), Hixson, J. (James), Hokanson, J. (John), Hong, E. (Elliott), Hoth, K. (Karin), Hsiung, C. A. (Chao Agnes), Huston, H. (Haley), Hwu, C. M. (Chii Min), Jackson, R. (Rebecca), Jain, D. (Deepti), Jaquish, C. (Cashell), Jhun, M. A. (Min A.), Johnsen, J. (Jill), Johnson, A. (Andrew), Johnson, C. (Craig), Johnston, R. (Rich), Jones, K. (Kimberly), Kang, H. M. (Hyun Min), Kaufman, L. (Laura), Kell, S. Y. (Shannon Y.), Kessler, M. (Michael), Kinney, G. (Greg), Konkle, B. (Barbara), Kramer, H. (Holly), Krauter, S. (Stephanie), Lange, C. (Christoph), Lange, E. (Ethan), Laurie, C. (Cecelia), LeBoff, M. (Meryl), Lee, S. S. (Seunggeun Shawn), Lee, W.-J. (Wen-Jane), LeFaive, J. (Jonathon), Levine, D. (David), Levy, D. (Dan), Lewis, J. (Joshua), Li, Y. (Yun), Lin, H. (Honghuang), Lin, K. H. (Keng Han), Lin, X. (Xihong), Liu, S. (Simin), Liu, Y. (Yongmei), Lunetta, K. (Kathryn), Luo, J. (James), Mahaney, M. (Michael), Make, B. (Barry), Manichaikul, A. (Ani), Mansonl, J. (JoAnn), Margolin, L. (Lauren), Mathai, S. (Susan), McArdle, P. (Patrick), Mcdonald, M.-L. (Merry-Lynn), McFarland, S. (Sean), McHugh, C. (Caitlin), Mei, H. (Hao), Meyers, D. A. (Deborah A.), Mikulla, J. (Julie), Min, N. (Nancy), Minear, M. (Mollie), Minster, R. L. (Ryan L.), Musani, S. (Solomon), Mwasongwe, S. (Stanford), Mychaleckyj, J. C. (Josyf C.), Nadkarni, G. (Girish), Naik, R. (Rakhi), Naseri, T. (Take), Nekhai, S. (Sergei), Nelson, S. C. (Sarah C.), Nickerson, D. (Deborah), Connell, J. O. (Jeff O.), Connor, T. O. (Tim O.), Ochs-Balcom, H. (Heather), Pankow, J. (James), Papanicolaou, G. (George), Parkerl, M. (Margaret), Parsa, A. (Afshin), Penchey, S. (Sara), Perez, M. (Marco), Peters, U. (Ulrike), Phillips, L. S. (Lawrence S.), Phillips, S. (Sam), Pollin, T. (Toni), Post, W. (Wendy), Becker, J. P. (Julia Powers), Boorgula, M. P. (Meher Preethi), Preuss, M. (Michael), Prokopenko, D. (Dmitry), Qasba, P. (Pankaj), Qiao, D. (Dandi), Rafaels, N. (Nicholas), Raffield, L. (Laura), Rasmussen-Torvik, L. (Laura), Ratan, A. (Aakrosh), Reed, R. (Robert), Reganl, E. (Elizabeth), Reupena, M. S. (Muagututi Sefuiva), Rice, K. (Ken), Roden, D. (Dan), Roselli, C. (Carolina), Ruczinski, I. (Ingo), Russel, P. (Pamela), Ruuska, S. (Sarah), Ryan, K. (Kathleen), Sabino, E. C. (Ester Cerdeira), Sakornsakolpatl, P. (Phuwanat), Salzberg, S. (Steven), Sandow, K. (Kevin), Sankaran, V. G. (Vijay G.), Scheller, C. (Christopher), Schmidt, E. (Ellen), Schwander, K. (Karen), Schwartz, D. (David), Sciurba, F. (Frank), Seidman, C. (Christine), Seidman, J. (Jonathan), Sheehan, V. (Vivien), Shetty, A. (Amol), Shetty, A. (Aniket), Sheu, W. H. (Wayne Hui-Heng), Shoemaker, M. B. (M. Benjamin), Silver, B. (Brian), Silvermanl, E. (Edwin), Smith, J. (Jennifer), Smith, J. (Josh), Smith, N. (Nicholas), Smith, T. (Tanja), Smoller, S. (Sylvia), Snively, B. (Beverly), Soferlm, T. (Tamar), Streeten, E. (Elizabeth), Su, J. L. (Jessica Lasky), Sung, Y. J. (Yun Ju), Sylvia, J. (Jody), Sztalryd, C. (Carole), Taliun, D. (Daniel), Tang, H. (Hua), Taub, M. (Margaret), Taylor, K. D. (Kent D.), Taylor, S. (Simeon), Telen, M. (Marilyn), Thornton, T. A. (Timothy A.), Tinker, L. (Lesley), Tirschwel, D. (David), Tiwari, H. (Hemant), Vaidya, D. (Dhananjay), VandeHaar, P. (Peter), Vrieze, S. (Scott), Walker, T. (Tarik), Wallace, R. (Robert), Waits, A. (Avram), Wan, E. (Emily), Wang, H. (Heming), Watson, K. (Karol), Weir, B. (Bruce), Weiss, S. (Scott), Weng, L.-C. (Lu-Chen), Williams, K. (Kayleen), Williams, L. K. (L. Keoki), Wilson, C. (Carla), Wong, Q. (Quenna), Xu, H. (Huichun), Yang, I. (Ivana), Yang, R. (Rongze), Zaghlou, N. (Norann), Zekavat, M. (Maryam), Zhang, Y. (Yingze), Zhao, S. X. (Snow Xueyan), Zhao, W. (Wei), Zni, D. (Degui), Zhou, X. (Xiang), Zhu, X. (Xiaofeng), Zody, M. (Michael), Zoellner, S. (Sebastian), Daly, M. (Mark), Jacob, H. (Howard), Matakidou, A. (Athena), Runz, H. (Heiko), John, S. (Sally), Plenge, R. (Robert), McCarthy, M. (Mark), Hunkapiller, J. (Julie), Ehm, M. (Meg), Waterworth, D. (Dawn), Fox, C. (Caroline), Malarstig, A. (Anders), Klinger, K. (Kathy), Call, K. (Kathy), Mkel, T. (Tomi), Kaprio, J. (Jaakko), Virolainen, P. (Petri), Pulkki, K. (Kari), Kilpi, T. (Terhi), Perola, M. (Markus), Partanen, J. (Jukka), Pitkranta, A. (Anne), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Savinainen, K. (Kimmo), Kosma, V.-M. (Veli-Matti), Kujala, U. (Urho), Tuovila, O. (Outi), Hendolin, M. (Minna), Pakkanen, R. (Raimo), Waring, J. (Jeff), Riley-Gillis, B. (Bridget), Liu, J. (Jimmy), Biswas, S. (Shameek), Diogo, D. (Dorothee), Marshall, C. (Catherine), Hu, X. (Xinli), Gossel, M. (Matthias), Schleutker, J. (Johanna), Arvas, M. (Mikko), Hinttala, R. (Reetta), Kettunen, J. (Johannes), Laaksonen, R. (Reijo), Mannermaa, A. (Arto), Paloneva, J. (Juha), Soininen, H. (Hilkka), Julkunen, V. (Valtteri), Remes, A. (Anne), Klviinen, R. (Reetta), Hiltunen, M. (Mikko), Peltola, J. (Jukka), Tienari, P. (Pentti), Rinne, J. (Juha), Ziemann, A. (Adam), Waring, J. (Jeffrey), Esmaeeli, S. (Sahar), Smaoui, N. (Nizar), Lehtonen, A. (Anne), Eaton, S. (Susan), Landenper, S. (Sanni), Michon, J. (John), Kerchner, G. (Geoff), Bowers, N. (Natalie), Teng, E. (Edmond), Eicher, J. (John), Mehta, V. (Vinay), Gormle, P. Y. (Padhraig Y.), Linden, K. (Kari), Whelan, C. (Christopher), Xu, F. (Fanli), Pulford, D. (David), Frkkil, M. (Martti), Pikkarainen, S. (Sampsa), Jussila, A. (Airi), Blomster, T. (Timo), Kiviniemi, M. (Mikko), Voutilainen, M. (Markku), Georgantas, B. (Bob), Heap, G. (Graham), Rahimov, F. (Fedik), Usiskin, K. (Keith), Maranville, J. (Joseph), Lu, T. (Tim), Oh, D. (Danny), Kalpala, K. (Kirsi), Miller, M. (Melissa), McCarthy, L. (Linda), Eklund, K. (Kari), Palomki, A. (Antti), Isomki, P. (Pia), Piri, L. (Laura), Kaipiainen-Seppnen, O. (Oili), Lertratanaku, A. (Apinya), Bing, D. C. (David Close Marla Hochfeld Nan), Gordillo, J. E. (Jorge Esparza), Mars, N. (Nina), Laitinen, T. (Tarja), Pelkonen, M. (Margit), Kauppi, P. (Paula), Kankaanranta, H. (Hannu), Harju, T. (Terttu), Greenberg, S. (Steven), Chen, H. (Hubert), Betts, J. (Jo), Ghosh, S. (Soumitra), Salomaa, V. (Veikko), Niiranen, T. (Teemu), Juonala, M. (Markus), Metsrinne, K. (Kaj), Khnen, M. (Mika), Junttila, J. (Juhani), Laakso, M. (Markku), Pihlajamki, J. (Jussi), Sinisalo, J. (Juha), Taskinen, M.-R. (Marja-Riitta), Tuomi, T. (Tiinamaija), Laukkanen, J. (Jari), Challis, B. (Ben), Peterson, A. (Andrew), Chu, A. (Audrey), Parkkinen, J. (Jaakko), Muslin, A. (Anthony), Joensuu, H. (Heikki), Meretoja, T. (Tuomo), Aaltonen, L. (Lauri), Auranen, A. (Annika), Karihtala, P. (Peeter), Kauppila, S. (Saila), Auvinen, P. (Pivi), Elenius, K. (Klaus), Popovic, R. (Relja), Schutzman, J. (Jennifer), Loboda, A. (Andrey), Chhibber, A. (Aparna), Lehtonen, H. (Heli), McDonough, S. (Stefan), Crohns, M. (Marika), Kulkarni, D. (Diptee), Kaarniranta, K. (Kai), Turunen, J. (Joni), Ollila, T. (Terhi), Seitsonen, S. (Sanna), Uusitalo, H. (Hannu), Aaltonen, V. (Vesa), Uusitalo-Jrvinen, H. (Hannele), Luodonp, M. (Marja), Hautala, N. (Nina), Strauss, E. (Erich), Chen, H. (Hao), Podgornaia, A. (Anna), Hoffman, J. (Joshua), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Hannula-Jouppi, K. (Katariina), Salmi, T. (Teea), Peltonen, S. (Sirkku), Koulu, L. (Leena), Harvima, I. (Ilkka), Wu, Y. (Ying), Choy, D. (David), Jalanko, A. (Anu), Kajanne, R. (Risto), Lyhs, U. (Ulrike), Kaunisto, M. (Mari), Davis, J. W. (Justin Wade), Quarless, D. (Danjuma), Petrovski, S. (Slav), Chen, C.-Y. (Chia-Yen), Bronson, P. (Paola), Yang, R. (Robert), Chang, D. (Diana), Bhangale, T. (Tushar), Holzinger, E. (Emily), Wang, X. (Xulong), Chen, X. (Xing), Auro, K. (Kirsi), Wang, C. (Clarence), Xu, E. (Ethan), Auge, F. (Franck), Chatelain, C. (Clement), Kurki, M. (Mitja), Karjalainen, J. (Juha), Havulinna, A. (Aki), Palin, K. (Kimmo), Palta, P. (Priit), Parolo, P. D. (Pietro Della Briotta), Zhou, W. (Wei), Lemmel, S. (Susanna), Rivas, M. (Manuel), Harju, J. (Jarmo), Lehisto, A. (Arto), Ganna, A. (Andrea), Llorens, V. (Vincent), Karlsson, A. (Antti), Kristiansson, K. (Kati), Hyvrinen, K. (Kati), Ritari, J. (Jarmo), Wahlfors, T. (Tiina), Koskinen, M. (Miika), Pylkäs, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Mantere, T. (Tuomo), Kangasniemi, E. (Eeva), Heikkinen, S. (Sami), Laakkonen, E. (Eija), Kononen, J. (Juha), Loukola, A. (Anu), Laiho, P. (Pivi), Sistonen, T. (Tuuli), Kaiharju, E. (Essi), Laukkanen, M. (Markku), Jrvensivu, E. (Elina), Lhteenmki, S. (Sini), Mnnikk, L. (Lotta), Wong, R. (Regis), Mattsson, H. (Hannele), Hiekkalinna, T. (Tero), Jimnez, M. G. (Manuel Gonzlez), Donner, K. (Kati), Prn, K. (KaIle), Nunez-Fontarnau, J. (Javier), Kilpelinen, E. (Elina), Sipi, T. P. (Timo P.), Brein, G. (Georg), Dada, A. (Alexander), Awaisa, G. (Ghazal), Shcherban, A. (Anastasia), Sipil, T. (Tuomas), Laivuori, H. (Hannele), Kiiskinen, T. (Tuomo), Siirtola, H. (Harri), Tabuenca, J. G. (Javier Gracia), Kallio, L. (Lila), Soini, S. (Sirpa), Pitknen, K. (Kimmo), and Kuopio, T. (Teijo)
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Cardiovascular genetics ,Genome-wide association studies - Abstract
Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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- 2021
41. Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes : Meta-Analyses and Mendelian Randomization Analyses
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Lind, L., Gigante, B., Borné, Y., Rudholm Feldreich, Tobias, Leppert, J., Hedberg, P., Ostgren, C. J., Nystrom, F. H., Ärnlöv, Johan, Malarstig, A., Lind, L., Gigante, B., Borné, Y., Rudholm Feldreich, Tobias, Leppert, J., Hedberg, P., Ostgren, C. J., Nystrom, F. H., Ärnlöv, Johan, and Malarstig, A.
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- 2021
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42. Technological readiness and implementation of genomic-driven precision medicine for complex diseases
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Franks, P. W., Melén, E., Friedman, M., Sundström, J., Kockum, I., Klareskog, L., Almqvist, C., Bergen, S. E., Czene, K., Hägg, S., Hall, P., Johnell, K., Malarstig, A., Catrina, A., Hagström, H., Benson, M., Gustav Smith, J., Gomez, M. F., Orho-Melander, M., Jacobsson, B., Halfvarson, Jonas, Repsilber, Dirk, Oresic, Matej, Jern, C., Melin, B., Ohlsson, C., Fall, T., Rönnblom, L., Wadelius, M., Nordmark, G., Johansson, Å., Rosenquist, R., Sullivan, P. F., Franks, P. W., Melén, E., Friedman, M., Sundström, J., Kockum, I., Klareskog, L., Almqvist, C., Bergen, S. E., Czene, K., Hägg, S., Hall, P., Johnell, K., Malarstig, A., Catrina, A., Hagström, H., Benson, M., Gustav Smith, J., Gomez, M. F., Orho-Melander, M., Jacobsson, B., Halfvarson, Jonas, Repsilber, Dirk, Oresic, Matej, Jern, C., Melin, B., Ohlsson, C., Fall, T., Rönnblom, L., Wadelius, M., Nordmark, G., Johansson, Å., Rosenquist, R., and Sullivan, P. F.
- Abstract
The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data., Funding Agencies:SciLifeLab United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH)MH077139 MH1095320European Commission 610307 733161 825843European Research Council (ERC)European Commission CoG-2015_681742_NASCENTStrategic Research Area Epidemiology at Karolinska Institutet Vth 80-year Foundation Clinical Research Support (Avtal om Läkarutbildning och Forskning) Swedish government County councils ALF-agreement IMI2 Joint Undertaking 115974European Federation of Pharmaceutical Industries and Associations with JDRF H2020 Program ERA PerMed JTC 2018 Call (VR) 2018-05619
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- 2021
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43. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.
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Ricardo C Ferreira, Daniel F Freitag, Antony J Cutler, Joanna M M Howson, Daniel B Rainbow, Deborah J Smyth, Stephen Kaptoge, Pamela Clarke, Charlotte Boreham, Richard M Coulson, Marcin L Pekalski, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich, Adam S Butterworth, Anders Malarstig, John Danesh, and John A Todd
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Genetics ,QH426-470 - Abstract
Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10⁻²²) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10⁻²²). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10⁻⁷). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.
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- 2013
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44. Genetic variants associated with Lp(a) lipoprotein level and coronary disease
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Clarke, Robert, Peden, John F., Hopewell, Jemma C., Kyriakou, Theodosios, Goel, Anuj, Heath, Simon C., Parish, Sarah, Barlera, Simona, Franzosi, Maria Grazia, Rust, Stephan, Bennett, Derrick, Silveira, Angela, Malarstig, Anders, Green, Fiona R., Lathrop, Mark, Gigante, Bruna, Leander, Karin, de Faire, Ulf, Seedorf, Udo, Hamsten, Anders, Collins, Rory, Watkins, Hugh, and Farrall, Martin
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Coronary heart disease -- Physiological aspects ,Lipoprotein A -- Genetic aspects - Abstract
Several experimental studies are conducted to explain the genetic determinants that are associated with the Lp(a) lipoprotein level and the coronary disease in patients. The Lp(a) lipoprotein is shown to exhibit a significant role in the onset of the coronary disease.
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- 2009
45. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
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Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjornsson, Gardar, Fatemifar, Ghazaleh, Hedman, Asa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Arnlov, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Doerr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engstrom, Gunnar, Esko, Tonu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Gudbjartsson, Daniel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Kober, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, Maerz, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Voelker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, Lumbers, R Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M, Habegger, Lukas, Hahn, Young, Hawes, Alicia, van Hout, Cristopher, Jones, Marcus B, Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K, McCarthy, Shane, Mitnaul, Lyndon J, O'Dushlaine, Colm, Overton, John D, Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G, Schleicher, Thomas D, Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C, Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H, Widom, Louis, Wolf, Sarah E, Yadav, Ashish, Ye, Bin, Ctr, Regeneron Genetics, Shah, Sonia [0000-0001-5860-4526], Henry, Albert [0000-0001-7422-2288], Roselli, Carolina [0000-0001-5267-6756], Lin, Honghuang [0000-0003-3043-3942], Chaffin, Mark D. [0000-0002-1234-5562], Helgadottir, Anna [0000-0002-1806-2467], Verweij, Niek [0000-0002-4303-7685], Almgren, Peter [0000-0002-0473-0241], Chen, Xu [0000-0002-7299-3238], Ghanbari, Mohsen [0000-0002-9476-7143], Giedraitis, Vilmantas [0000-0003-3423-2021], Gross, Stefan [0000-0003-4121-7161], Guðbjartsson, Daníel F. [0000-0002-5222-9857], Hyde, Craig L. [0000-0002-6939-287X], Ingelsson, Erik [0000-0003-2256-6972], Jukema, J. Wouter [0000-0002-3246-8359], Kleber, Marcus E. [0000-0003-0663-7275], Koekemoer, Andrea [0000-0001-8222-3547], Langenberg, Claudia [0000-0002-5017-7344], Lindgren, Cecilia M. [0000-0002-4903-9374], Lovering, Ruth C. [0000-0002-9791-0064], Luan, Jian’an [0000-0003-3137-6337], Magnusson, Patrik [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mordi, Ify R. [0000-0002-2686-729X], Morris, Andrew D. [0000-0002-1766-0473], Nagle, Michael W. [0000-0002-4677-7582], Nelson, Christopher P. [0000-0001-8025-2897], Palmer, Colin N. A. [0000-0002-6415-6560], Rice, Kenneth M. [0000-0002-3071-7278], Rotter, Jerome I. [0000-0001-7191-1723], Salomaa, Veikko [0000-0001-7563-5324], van Setten, Jessica [0000-0002-4934-7510], Svensson, Per [0000-0003-0372-6272], Taylor, Kent D. [0000-0002-2756-4370], Teder-Laving, Maris [0000-0002-5872-1850], Teumer, Alexander [0000-0002-8309-094X], Tyl, Benoit [0000-0001-5297-8412], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Wiggins, Kerri L. [0000-0003-2749-1279], Hemingway, Harry [0000-0003-2279-0624], Yang, Jian [0000-0003-2001-2474], Visscher, Peter M. [0000-0002-2143-8760], Lubitz, Steven A. [0000-0002-9599-4866], Sattar, Naveed [0000-0002-1604-2593], Cappola, Thomas P. [0000-0002-9630-7204], Asselbergs, Folkert W. [0000-0002-1692-8669], Kuchenbaecker, Karoline [0000-0001-9726-603X], Ellinor, Patrick T. [0000-0002-2067-0533], Vasan, Ramachandran S. [0000-0001-7357-5970], Lumbers, R. Thomas [0000-0002-9077-4741], Apollo - University of Cambridge Repository, Chaffin, Mark D [0000-0002-1234-5562], Guðbjartsson, Daníel F [0000-0002-5222-9857], Hyde, Craig L [0000-0002-6939-287X], Jukema, J Wouter [0000-0002-3246-8359], Kleber, Marcus E [0000-0003-0663-7275], Lindgren, Cecilia M [0000-0002-4903-9374], Lovering, Ruth C [0000-0002-9791-0064], Luan, Jian'an [0000-0003-3137-6337], Mordi, Ify R [0000-0002-2686-729X], Morris, Andrew D [0000-0002-1766-0473], Nagle, Michael W [0000-0002-4677-7582], Nelson, Christopher P [0000-0001-8025-2897], Palmer, Colin NA [0000-0002-6415-6560], Rice, Kenneth M [0000-0002-3071-7278], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, Andre G [0000-0002-7276-3387], Wiggins, Kerri L [0000-0003-2749-1279], Visscher, Peter M [0000-0002-2143-8760], Lubitz, Steven A [0000-0002-9599-4866], Cappola, Thomas P [0000-0002-9630-7204], Asselbergs, Folkert W [0000-0002-1692-8669], Ellinor, Patrick T [0000-0002-2067-0533], Vasan, Ramachandran S [0000-0001-7357-5970], Lumbers, R Thomas [0000-0002-9077-4741], Palmer, Colin N A [0000-0002-6415-6560], Cardiovascular Centre (CVC), University of Queensland [Brisbane], University College of London [London] (UCL), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University Medical Center Groningen [Groningen] (UMCG), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), deCODE genetics [Reykjavik], Karolinska Institutet [Stockholm], Pfizer, University of Pennsylvania [Philadelphia], University of Groningen [Groningen], Imperial College London, Lund University [Lund], Herlev and Gentofte Hospital, Massachusetts General Hospital [Boston], Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden] (Division of Family Medicine), Dalarna University, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, Department of Biostatistics, University of Washington [Seattle], Emory University School of Medicine, Emory University [Atlanta, GA], The University of Texas Medical School at Houston, Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, Novartis Institutes for BioMedical Research (NIBR), University of Liverpool, Universität Heidelberg [Heidelberg], Medizinische Fakultät Mannheim, The Alan Turing Institute, Ninewells Hospital and Medical School [Dundee], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Minnesota System, Regeneron Pharmaceuticals [Tarrytown], Department of Clinical Sciences, Cardiovascular Epidemiology, Skane University Hospital [Lund], Institute of Genomics [Tartu, Estonia], University of Tartu, Robertson Centre for Biostatistics, University of Glasgow, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Uppsala University, Brigham & Women’s Hospital [Boston] (BWH), University of Maryland School of Medicine, University of Maryland System, School of Science and Engineering (Reykjavik University), Carver College of Medicine, University of Iowa, Geisinger Health System [Danville, PA, USA], Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, Uppsala Universitet [Uppsala], Leiden University Medical Center (LUMC), Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Glenfield Hospital, University Hospitals Leicester, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Big Data Institute, University of Oxford [Oxford], University of Iowa [Iowa City], The Wellcome Trust Centre for Human Genetics [Oxford], Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Medical University Graz, Skane University Hospital [Malmo], Vanderbilt University School of Medicine [Nashville], University of Edinburgh, Université médicale de Vienne, Autriche, National Institute for Health and Welfare [Helsinki], University of Turku, Birmingham Women's and Children's NHS Foundation Trust, Kaiser Permanente, Harbor UCLA Medical Center [Torrance, Ca.], Los Angeles Biomedical Research Institute (LA BioMed), University Medical Center [Utrecht], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Seattle Epidemiologic Research and Information Center [Seattle], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Cardiology, Södersjukhuset, Stockholm, Estonian Genome and Medicine, Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], Aalborg University [Denmark] (AAU), Institut de Recherches SERVIER (IRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, GlaxoSmithKline, Glaxo Smith Kline, Northeastern Ohio Medical University (NEOMED), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Department of Cardiovascular Sciences [Leicester], University of Leicester, Queensland Brain Institute, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, University of Dundee, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Atherosclerosis Risk in Communities Study (ARIC)The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694 and RC2 HL102419, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT- CHF)This project was funded by a grant from the European Commission (FP7‐242209‐ BIOSTAT‐CHF, EudraCT 2010–020808–29). Cardiovascular Health Study (CHS) This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Heart Failure Study (deCODE) We at deCODE thank the women and men of Iceland that have participated in our studies and our colleagues that contributed to data collection and processing. DiscovEHR We acknowledge and thank all participants in Geisinger’s MyCode Community Health Initiative for their support and permission to use their health and genomic information in the DiscovEHR collaboration. This work was supported by the Regeneron Genetics Center and Geisinger. Estonian Genome Center at the University of Tartu (EGCUT) This study was supported by Estonian Research Council Grant IUT20-60, EU, H2020 grant 692145, European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) GENTRANSMED. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) The EPHESUS was supported by Pfizer, Inc. The European Prospective Investigation of Cancer, Norfolk study (EPIC-Norfolk) The EPIC-Norfolk Study is supported by programme grants from the Medical Research Council UK (G1000143) and Cancer Research UK (C864/A14136) and with additional support from the European Union, Stroke Association, British Heart Foundation, Research into Ageing, Department of Health, The Wellcome Trust and the Food Standards Agency. NJW and CL also acknowledge support from the Medical Research Council, UK (MC_UU_12015/1, MC_PC_13048). We thank all EPIC participants and staff for their contribution to the study, and thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the Medical Research Council Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data handling work. Framingham Heart Study (FHS) This work was conducted using data and resources from the Framingham Heart Study (FHS) of the National Heart Lung and Blood Institute and Boston University School of Medicine. The study was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No.N02-HL-6-4278). The work was also supported by R01 HL093328, R01 HL105993, and R01 HL71039 (PI: Ramachandran). FINRISK V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Genetics of Diabetes Audit and Research Tayside Scotland GoDARTS) The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. We acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The Genetic Risk Assessment of Defibrillator Events (GRADE) NIH-NHLBI R01 HL77398 (Genetic Modulators of Sudden Death). S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study We extend our appreciation to the participants of the LURIC study, without their collaboration, this article would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC has received funding from the 7th Framework Program (RiskyCAD, grant agreement number 305739 and Atheroremo, grant agreement number 201668) of the European Union. Malmö Diet and Cancer Study (MDCS) J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016- 0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15- 0067) to the Lund University Diabetes Center. The Malmo Diet and Cancer Study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Malmo city council. Penn Heart Failure Study (PHFS) The study was supported by NIH grants (NIH R01L088577 and NIH R01H105993). Prevention of REnal and Vascular ENd-stage Disease (PREVEND) The Prevention of Renal and Vascular Endstage Disease Study (PREVEND) genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), the Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Niek Verweij was supported by NWO VENI grant 016.186.125. PROspective Study of Pravastatin in the Elderly at Risk for vascular disease (PROSPER)The PROSPER study was supported by an investigator-initiated grant obtained from Bristol- Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Study of Health in Pomerania (SHIP) SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID)SOLID-TIMI 52 was funded by GlaxoSmithKline. TwinGene (TwinGene) TwinGene received funding from the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254, QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation no. 20070481. TwinGene is part of the Swedish Twin Registry which is managed by Karolinska Institutet and receives funding through the Swedish Research Council (2017–00641). UK Biobank (UKBiobank) This research has been conducted using the UK Biobank Resource under Application Number 15422. This work was supported in part by grants to R.T.L. from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, MRC Proximity to Discovery Award Scheme, the American Heart Association Institute for Precision Mecidine, Pfizer Ltd, the University College London British Heart Foundation Research Accelerator (AA/18/6/34223), and was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A. H. is supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship. R.T.L is supported by a UK Research and Innovation Rutherford Fellowship and was previously supported by a National Institutes of Health Research Clinical Lectureship. Uppsala Longitudinal Study of Adult Men (ULSAM) J.Ä. is supported by the Swedish Research Council and the Swedish Heart Lung foundation. C.M.L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138- 27). Women’s Genome Health Study (WGHS) The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467, HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen., Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
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0301 basic medicine ,Dánartíðni ,Epidemiology ,LOCI ,45/43 ,General Physics and Astronomy ,Muscle Proteins ,Genome-wide association study ,Disease ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,Genome-wide association studies ,DISEASE ,Ventricular Function, Left ,Coronary artery disease ,0302 clinical medicine ,Risk Factors ,Atrial Fibrillation ,IMPUTATION ,Medicine ,Blóðrásarsjúkdómar ,692/308/174 ,lcsh:Science ,2. Zero hunger ,RISK ,Multidisciplinary ,Microfilament Proteins ,article ,Atrial fibrillation ,Mendelian Randomization Analysis ,CATALOG ,3. Good health ,OBESITY ,Erfðarannsóknir ,Cardiomyopathies ,Medical Genetics ,Cyclin-Dependent Kinase Inhibitor p21 ,Science ,631/208/205/2138 ,Heart failure ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,631/443/592/2727 ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,RESOURCE ,Humans ,Mortality ,METAANALYSIS ,Genetic association ,Medicinsk genetik ,Adaptor Proteins, Signal Transducing ,Heart Failure ,HYPERTENSION ,business.industry ,Case-control study ,Klinisk medicin ,692/699/75/230 ,General Chemistry ,Cardiovascular genetics ,medicine.disease ,R1 ,030104 developmental biology ,Case-Control Studies ,lcsh:Q ,Morbidity ,Clinical Medicine ,business ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Genome-Wide Association Study - Abstract
Publisher's version (útgefin grein), Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies., We acknowledge the contribution from the EchoGen Consortium.
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- 2020
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46. Genes contributing to pain sensitivity in the normal population: an exome sequencing study.
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Frances M K Williams, Serena Scollen, Dandan Cao, Yasin Memari, Craig L Hyde, Baohong Zhang, Benjamin Sidders, Daniel Ziemek, Yujian Shi, Juliette Harris, Ian Harrow, Brian Dougherty, Anders Malarstig, Robert McEwen, Joel C Stephens, Ketan Patel, Cristina Menni, So-Youn Shin, Dylan Hodgkiss, Gabriela Surdulescu, Wen He, Xin Jin, Stephen B McMahon, Nicole Soranzo, Sally John, Jun Wang, and Tim D Spector
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Genetics ,QH426-470 - Abstract
Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF
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- 2012
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47. CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE epsilon 4 carriers
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Ahmad, Shahzad, Milan, Marta del Campo, Hansson, Oskar, Demirkan, Ayse, Agustin, Ruiz, Saez, Maria E., Giagtzoglou, Nikolaos, Cabrera-Socorro, Alfredo, Bakker, Margot H. M., Ramirez, Alfredo, Hankemeier, Thomas, Stomrud, Erik, Mattsson-Carlgren, Niklas, Scheltens, Philip, van der Flier, Wiesje M., Ikram, M. Arfan, Malarstig, Anders, Teunissen, Charlotte E., Amin, Najaf, van Duijn, Cornelia M., Ahmad, Shahzad, Milan, Marta del Campo, Hansson, Oskar, Demirkan, Ayse, Agustin, Ruiz, Saez, Maria E., Giagtzoglou, Nikolaos, Cabrera-Socorro, Alfredo, Bakker, Margot H. M., Ramirez, Alfredo, Hankemeier, Thomas, Stomrud, Erik, Mattsson-Carlgren, Niklas, Scheltens, Philip, van der Flier, Wiesje M., Ikram, M. Arfan, Malarstig, Anders, Teunissen, Charlotte E., Amin, Najaf, and van Duijn, Cornelia M.
- Abstract
Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD=161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (A beta) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N=441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (beta =0.638, P=3.33x10(-4)) and HAGH (beta =0.481, P=7.20x10(-4)), were significantly elevated in APOE epsilon 4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (beta =1.365, P=3.97x10(-3)) and HAGH proteins (beta =0.506, P=9.31x10(-7)) when comparing cases and controls in APOE epsilon 4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE epsilon 4 stratum (P<1x10(-3)). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P=1.92x10(-9)). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
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- 2020
48. Using Mendelian randomization to assess and develop clinical interventions: limitations and benefits
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Burgess, Stephen and Malarstig, Anders
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- 2013
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49. Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization.
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Henry, Albert, Gordillo-Maranon, Maria, Finan, Chris, Schmidt, Amand F., Ferreira, Joao Pedro, Karra, Ravi MHS, Sundstrom, Johan, Lind, Lars, Arnlov, Johan, Zannad, Faiez, Malarstig, Anders, Hingorani, Aroon D., Lumbers, R. Thomas BChir,, HERMES, Consortia, SCALLOP, Gordillo-Marañón, María, Ferreira, João Pedro, Karra, Ravi, Sundström, Johan, and Ärnlöv, Johan
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- 2022
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50. Use of Mendelian randomisation to assess potential benefit of clinical intervention
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Burgess, Stephen, Butterworth, Adam, Malarstig, Anders, and Thompson, Simon G
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- 2012
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