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1. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, de Vries, Paul S, Prins, Bram P, Van der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian’an, Bak, Tom, Schork, Nicholas, Del Greco M., Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Johan, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, Hollander, Wouter den, Ahluwalia, Tarunveer Singh, Zhao, Jing, Draisma, Harmen HM, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O’Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik KE, Ballantyne, Christie M, and Hottenga, Jouke Jan

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Good Health and Well Being, Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Bipolar Disorder, Body Mass Index, C-Reactive Protein, Child, Female, Genetic Loci, Genome-Wide Association Study, Humans, Inflammation, Liver, Male, Mendelian Randomization Analysis, Metabolic Networks and Pathways, Middle Aged, Schizophrenia, Young Adult, LifeLines Cohort Study, CHARGE Inflammation Working Group, C-reactive protein, DEPICT, Mendelian randomization, coronary artery disease, genome-wide association study, inflammation, inflammatory disorders, schizophrenia, system biology, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

Published
2018

6. Study protocol for a randomized controlled trial to explore the effects of personalized lifestyle advices and tandem skydives on pleasure in anhedonic young adults

Author

van Roekel, G.H., Masselink, Maurits, Vrijen, Charlotte, Heininga, Vera E., Bak, Tom, Oldehinkel, Albertine J., Nederhof, Esther, van Roekel, G.H., Masselink, Maurits, Vrijen, Charlotte, Heininga, Vera E., Bak, Tom, Oldehinkel, Albertine J., and Nederhof, Esther

Abstract

Background: Anhedonia is generally defined as the inability to feel pleasure in response to experiences that are usually enjoyable. Anhedonia is one of the two core symptoms of depression and is a major public health concern. Anhedonia has proven particularly difficult to counteract and predicts poor treatment response generally. It has often been hypothesized that anhedonia can be deterred by a healthy lifestyle. However, it is quite unlikely that a one-size-fits-all approach will be effective for everyone. In this study the effects of personalized lifestyle advice based on observed individual patterns of lifestyle behaviors and experienced pleasure will be examined. Further, we will explore whether a tandem skydive following the personalized lifestyle advice positively influences anhedonic young adults' abilities to carry out the recommended lifestyle changes, and whether this ultimately improves their self-reported pleasure.Methods: Our study design is an exploratory intervention study, preceded by a cross-sectional survey as a screening instrument. For the survey, 2000 young adults (18-24 years old) will be selected from the general population. Based on survey outcomes, 72 individuals (36 males and 36 females) with persistent anhedonia (i.e., more than two months) and 60 individuals (30 males and 30 females) without anhedonia (non-anhedonic control group) will be selected for the intervention study. The non-anhedonic control group will fill out momentary assessments of pleasure and lifestyle behaviors three times a day, for one month. The anhedonic individuals will fill out momentary assessments for three consecutive months. After the first month, the anhedonic individuals will be randomly assigned to (1) no intervention, (2) lifestyle advice only, (3) lifestyle advice plus tandem skydive. The personalized lifestyle advice is based on patterns observed in the first month.Discussion: The present study is the first to examine

Published
2016

10. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, De Vries, Paul S, Prins, Bram P, Van Der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian'an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, Den Hollander, Wouter, Ahluwalia, Tarunveer S, Zhao, Jing, Draisma, Harmen H M, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O'Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K E, Ballantyne, Christie M, Hottenga, Jouke Jan, Montgomery, Grant W, Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J, Menni, Cristina, Frånberg, Mattias, St Pourcain, Beate, Felix, Stephan B, Pers, Tune H, Bakker, Stephan J L, Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H, Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R, Holliday, Elizabeth G, Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M, Chen, Yii-Der I, James, Alan L, Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A, Smith, Erin N, Berenson, Gerald S, Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M T, Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R, Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A, Pennell, Craig E, Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes De Leon, Carlos F, Bottinger, Erwin P, Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A W, Willemsen, Gonneke, Evans, David M, Madden, Pamela A F, Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B, Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B, Raitakari, Olli T, Attia, John R, Van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A, Hicks, Andrew A, Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M, Starr, John M, Karlsson, Magnus, Lind, Lars, Li, Jun Z, Chambers, John C, Mori, Trevor A, De Geus, Eco J C N, Heath, Andrew C, Martin, Nicholas G, Auvinen, Juha, Buckley, Brendan M, De Craen, Anton J M, Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J, McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M, Mohlke, Karen L, Pedersen, Nancy L, Morrison, Alanna C, Boomsma, Dorret I, Whitfield, John B, Strachan, David P, Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Spector, Tim D, Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G, Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B, Rotter, Jerome I, März, Winfried, Wild, Philipp S, Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G, Wilson, James F, Penninx, Brenda W J H, Becker, Diane M, Worrall, Bradford B, Gibson, Greg, Krauss, Ronald M, Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J, Oldehinkel, Albertine J, Palmer, Lyle J, Murray, Sarah S, Pramstaller, Peter P, Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J, Mägi, Reedik, Vandenput, Liesbeth, Van Der Harst, Pim, Desch, Karl C, Kooner, Jaspal S, Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R, Arnett, Donna K, Beilin, Lawrence J, Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J F, Evans, Denis A, Schmidt, Helena, Smith, George Davey, Slagboom, P Eline, Eiriksdottir, Gudny, Morris, Andrew P, Psaty, Bruce M, Tracy, Russell P, Nolte, Ilja M, Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P, Gross, Myron, Bis, Joshua C, Franke, Lude, Franco, Oscar H, Benjamin, Emelia J, Chasman, Daniel I, Dupuis, Josée, Snieder, Harold, Dehghan, Abbas, and Alizadeh, Behrooz Z

Subjects
2. Zero hunger, 610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

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