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1. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Author

Ashley Budu-Aggrey, Anna Kilanowski, Maria K. Sobczyk, andMe Research Team, Suyash S. Shringarpure, Ruth Mitchell, Kadri Reis, Anu Reigo, Estonian Biobank Research Team, Reedik Mägi, Mari Nelis, Nao Tanaka, Ben M. Brumpton, Laurent F. Thomas, Pol Sole-Navais, Christopher Flatley, Antonio Espuela-Ortiz, Esther Herrera-Luis, Jesus V. T. Lominchar, Jette Bork-Jensen, Ingo Marenholz, Aleix Arnau-Soler, Ayoung Jeong, Katherine A. Fawcett, Hansjorg Baurecht, Elke Rodriguez, Alexessander Couto Alves, Ashish Kumar, Patrick M. Sleiman, Xiao Chang, Carolina Medina-Gomez, Chen Hu, Cheng-jian Xu, Cancan Qi, Sarah El-Heis, Philip Titcombe, Elie Antoun, João Fadista, Carol A. Wang, Elisabeth Thiering, Baojun Wu, Sara Kress, Dilini M. Kothalawala, Latha Kadalayil, Jiasong Duan, Hongmei Zhang, Sabelo Hadebe, Thomas Hoffmann, Eric Jorgenson, Hélène Choquet, Neil Risch, Pål Njølstad, Ole A. Andreassen, Stefan Johansson, Catarina Almqvist, Tong Gong, Vilhelmina Ullemar, Robert Karlsson, Patrik K. E. Magnusson, Agnieszka Szwajda, Esteban G. Burchard, Jacob P. Thyssen, Torben Hansen, Line L. Kårhus, Thomas M. Dantoft, Alexander C.S.N. Jeanrenaud, Ahla Ghauri, Andreas Arnold, Georg Homuth, Susanne Lau, Markus M. Nöthen, Norbert Hübner, Medea Imboden, Alessia Visconti, Mario Falchi, Veronique Bataille, Pirro Hysi, Natalia Ballardini, Dorret I. Boomsma, Jouke J. Hottenga, Martina Müller-Nurasyid, Tarunveer S. Ahluwalia, Jakob Stokholm, Bo Chawes, Ann-Marie M. Schoos, Ana Esplugues, Mariona Bustamante, Benjamin Raby, Syed Arshad, Chris German, Tõnu Esko, Lili A. Milani, Andres Metspalu, Chikashi Terao, Katrina Abuabara, Mari Løset, Kristian Hveem, Bo Jacobsson, Maria Pino-Yanes, David P. Strachan, Niels Grarup, Allan Linneberg, Young-Ae Lee, Nicole Probst-Hensch, Stephan Weidinger, Marjo-Riitta Jarvelin, Erik Melén, Hakon Hakonarson, Alan D. Irvine, Deborah Jarvis, Tamar Nijsten, Liesbeth Duijts, Judith M. Vonk, Gerard H. Koppelmann, Keith M. Godfrey, Sheila J. Barton, Bjarke Feenstra, Craig E. Pennell, Peter D. Sly, Patrick G. Holt, L. Keoki Williams, Hans Bisgaard, Klaus Bønnelykke, John Curtin, Angela Simpson, Clare Murray, Tamara Schikowski, Supinda Bunyavanich, Scott T. Weiss, John W. Holloway, Josine L. Min, Sara J. Brown, Marie Standl, and Lavinia Paternoster

Subjects
Science
Abstract

Abstract Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Published
2023
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2. Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Author

Ferreira, Manuel AR, Vonk, Judith M, Baurecht, Hansjörg, Marenholz, Ingo, Tian, Chao, Hoffman, Joshua D, Helmer, Quinta, Tillander, Annika, Ullemar, Vilhelmina, Lu, Yi, Grosche, Sarah, Rüschendorf, Franz, Granell, Raquel, Brumpton, Ben M, Fritsche, Lars G, Bhatta, Laxmi, Gabrielsen, Maiken E, Nielsen, Jonas B, Zhou, Wei, Hveem, Kristian, Langhammer, Arnulf, Holmen, Oddgeir L, Løset, Mari, Abecasis, Gonçalo R, Willer, Cristen J, Emami, Nima C, Cavazos, Taylor B, Witte, John S, Szwajda, Agnieszka, 23andMe Research Team, collaborators of the SHARE study, Hinds, David A, Hübner, Norbert, Weidinger, Stephan, Magnusson, Patrik Ke, Jorgenson, Eric, Karlsson, Robert, Paternoster, Lavinia, Boomsma, Dorret I, Almqvist, Catarina, Lee, Young-Ae, and Koppelman, Gerard H

Subjects
23andMe Research Team, collaborators of the SHARE study, Humans, Asthma, Eczema, Age of Onset, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Middle Aged, Child, Female, Rhinitis, Allergic, Seasonal, Male, Genome-Wide Association Study, Genetic Loci, Polymorphism, Single Nucleotide, Rhinitis, Allergic, Seasonal, Developmental Biology, Genetics
Abstract

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P

Published
2020

3. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Sarah Grosche, Ingo Marenholz, Jorge Esparza-Gordillo, Aleix Arnau-Soler, Erola Pairo-Castineira, Franz Rüschendorf, Tarunveer S. Ahluwalia, Catarina Almqvist, Andreas Arnold, Australian Asthma Genetics Consortium (AAGC), Hansjörg Baurecht, Hans Bisgaard, Klaus Bønnelykke, Sara J. Brown, Mariona Bustamante, John A. Curtin, Adnan Custovic, Shyamali C. Dharmage, Ana Esplugues, Mario Falchi, Dietmar Fernandez-Orth, Manuel A. R. Ferreira, Andre Franke, Sascha Gerdes, Christian Gieger, Hakon Hakonarson, Patrick G. Holt, Georg Homuth, Norbert Hubner, Pirro G. Hysi, Marjo-Riitta Jarvelin, Robert Karlsson, Gerard H. Koppelman, Susanne Lau, Manuel Lutz, Patrik K. E. Magnusson, Guy B. Marks, Martina Müller-Nurasyid, Markus M. Nöthen, Lavinia Paternoster, Craig E. Pennell, Annette Peters, Konrad Rawlik, Colin F. Robertson, Elke Rodriguez, Sylvain Sebert, Angela Simpson, Patrick M. A. Sleiman, Marie Standl, Dora Stölzl, Konstantin Strauch, Agnieszka Szwajda, Albert Tenesa, Philip J. Thompson, Vilhelmina Ullemar, Alessia Visconti, Judith M. Vonk, Carol A. Wang, Stephan Weidinger, Matthias Wielscher, Catherine L. Worth, Chen-Jian Xu, and Young-Ae Lee

Subjects
Science
Abstract

Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Published
2021
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4. Taking the LEAP: study protocol for a randomized, multicentre, naturalistic, efficacy trial of the compuLsive Exercise Activity theraPy (LEAP) - a cognitive behavioral program specifically targeting compulsive exercise in patients with eating disorders

Author

Elin Monell, Caroline Meyer, Agnieszka Szwajda, and Emma Forsén Mantilla

Subjects
Compulsive exercise, Eating disorders, Treatment, Efficacy trial, Psychiatry, RC435-571
Abstract

Abstract Background About half of Swedish eating disorder patients report exercising compulsively and compulsive exercise (CE) is prevalent in all diagnoses and both genders. Yet there are no systematic treatments targeting CE in specialist care. This study aims to evaluate the effects of The CompuLsive Exercise Activity TheraPy (LEAP) - a promising group treatment targeting compulsive exercise, in Swedish eating disorder patients. Method One hundred twenty-eight adult females and males suffering from anorexia nervosa, bulimia nervosa or other specified feeding and eating disorders (type 1, 2, or 4) with CE will be recruited via four specialist eating disorder treatment units. Participants will be randomized to receive treatment as usual (control group) or treatment as usual plus LEAP (intervention group). The groups will be assessed on key variables (e.g., BMI, eating disorder symptoms, exercise cognitions and behaviors) at three occasions: initially, after 3 months and after 6 months. Discussion The project takes place in a clinical setting, including both male and female patients with different eating disorder diagnoses with CE, enabling a good indication of the efficacy of LEAP. If our results are positive, LEAP has the potential of benefiting about half of the eating disorder population, with remission and recovery hopefully improving as a result. Trial registration The trial is registered with the ISRCTN registry (registration date 2020-03-25), trial ID: ISRCTN80711391 .

Published
2021
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6. Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

Author

Aldi, Silvia, Matic, Ljubica Perisic, Hamm, Gregory, van Keulen, Daniëlle, Tempel, Dennie, Holmstrøm, Kim, Szwajda, Agnieszka, Nielsen, Boye Schnack, Emilsson, Valur, Ait-Belkacem, Rima, Lengquist, Mariette, Paulsson-Berne, Gabrielle, Eriksson, Per, Lindeman, Jan H.N., Gool, Alain J., Stauber, Jonathan, Hedin, Ulf, and Hurt-Camejo, Eva

Published
2018
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7. Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Author

Manuel A R Ferreira, Judith M Vonk, Hansjörg Baurecht, Ingo Marenholz, Chao Tian, Joshua D Hoffman, Quinta Helmer, Annika Tillander, Vilhelmina Ullemar, Yi Lu, Sarah Grosche, Franz Rüschendorf, Raquel Granell, Ben M Brumpton, Lars G Fritsche, Laxmi Bhatta, Maiken E Gabrielsen, Jonas B Nielsen, Wei Zhou, Kristian Hveem, Arnulf Langhammer, Oddgeir L Holmen, Mari Løset, Gonçalo R Abecasis, Cristen J Willer, Nima C Emami, Taylor B Cavazos, John S Witte, Agnieszka Szwajda, andMe Research Team, collaborators of the SHARE study, David A Hinds, Norbert Hübner, Stephan Weidinger, Patrik Ke Magnusson, Eric Jorgenson, Robert Karlsson, Lavinia Paternoster, Dorret I Boomsma, Catarina Almqvist, Young-Ae Lee, and Gerard H Koppelman

Subjects
Genetics, QH426-470
Abstract

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P

Published
2020
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9. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Author

Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, Paternoster, Lavinia, Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, and Paternoster, Lavinia

Abstract

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Published
2023

10. Data from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Pemovska, Tea, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Edgren, Henrik, primary, Eldfors, Samuli, primary, Szwajda, Agnieszka, primary, Almusa, Henrikki, primary, Bespalov, Maxim M., primary, Ellonen, Pekka, primary, Elonen, Erkki, primary, Gjertsen, Bjørn T., primary, Karjalainen, Riikka, primary, Kulesskiy, Evgeny, primary, Lagström, Sonja, primary, Lehto, Anna, primary, Lepistö, Maija, primary, Lundán, Tuija, primary, Majumder, Muntasir Mamun, primary, Marti, Jesus M. Lopez, primary, Mattila, Pirkko, primary, Murumägi, Astrid, primary, Mustjoki, Satu, primary, Palva, Aino, primary, Parsons, Alun, primary, Pirttinen, Tero, primary, Rämet, Maria E., primary, Suvela, Minna, primary, Turunen, Laura, primary, Västrik, Imre, primary, Wolf, Maija, primary, Knowles, Jonathan, primary, Aittokallio, Tero, primary, Heckman, Caroline A., primary, Porkka, Kimmo, primary, Kallioniemi, Olli, primary, and Wennerberg, Krister, primary

Published
2023
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11. Supplementary Table S2 from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Pemovska, Tea, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Edgren, Henrik, primary, Eldfors, Samuli, primary, Szwajda, Agnieszka, primary, Almusa, Henrikki, primary, Bespalov, Maxim M., primary, Ellonen, Pekka, primary, Elonen, Erkki, primary, Gjertsen, Bjørn T., primary, Karjalainen, Riikka, primary, Kulesskiy, Evgeny, primary, Lagström, Sonja, primary, Lehto, Anna, primary, Lepistö, Maija, primary, Lundán, Tuija, primary, Majumder, Muntasir Mamun, primary, Marti, Jesus M. Lopez, primary, Mattila, Pirkko, primary, Murumägi, Astrid, primary, Mustjoki, Satu, primary, Palva, Aino, primary, Parsons, Alun, primary, Pirttinen, Tero, primary, Rämet, Maria E., primary, Suvela, Minna, primary, Turunen, Laura, primary, Västrik, Imre, primary, Wolf, Maija, primary, Knowles, Jonathan, primary, Aittokallio, Tero, primary, Heckman, Caroline A., primary, Porkka, Kimmo, primary, Kallioniemi, Olli, primary, and Wennerberg, Krister, primary

Published
2023
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12. Supplementary Figures, Tables and Methods from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Pemovska, Tea, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Edgren, Henrik, primary, Eldfors, Samuli, primary, Szwajda, Agnieszka, primary, Almusa, Henrikki, primary, Bespalov, Maxim M., primary, Ellonen, Pekka, primary, Elonen, Erkki, primary, Gjertsen, Bjørn T., primary, Karjalainen, Riikka, primary, Kulesskiy, Evgeny, primary, Lagström, Sonja, primary, Lehto, Anna, primary, Lepistö, Maija, primary, Lundán, Tuija, primary, Majumder, Muntasir Mamun, primary, Marti, Jesus M. Lopez, primary, Mattila, Pirkko, primary, Murumägi, Astrid, primary, Mustjoki, Satu, primary, Palva, Aino, primary, Parsons, Alun, primary, Pirttinen, Tero, primary, Rämet, Maria E., primary, Suvela, Minna, primary, Turunen, Laura, primary, Västrik, Imre, primary, Wolf, Maija, primary, Knowles, Jonathan, primary, Aittokallio, Tero, primary, Heckman, Caroline A., primary, Porkka, Kimmo, primary, Kallioniemi, Olli, primary, and Wennerberg, Krister, primary

Published
2023
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16. Supplementary Table S1 from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Krister Wennerberg, Olli Kallioniemi, Kimmo Porkka, Caroline A. Heckman, Tero Aittokallio, Jonathan Knowles, Maija Wolf, Imre Västrik, Laura Turunen, Minna Suvela, Maria E. Rämet, Tero Pirttinen, Alun Parsons, Aino Palva, Satu Mustjoki, Astrid Murumägi, Pirkko Mattila, Jesus M. Lopez Marti, Muntasir Mamun Majumder, Tuija Lundán, Maija Lepistö, Anna Lehto, Sonja Lagström, Evgeny Kulesskiy, Riikka Karjalainen, Bjørn T. Gjertsen, Erkki Elonen, Pekka Ellonen, Maxim M. Bespalov, Henrikki Almusa, Agnieszka Szwajda, Samuli Eldfors, Henrik Edgren, Bhagwan Yadav, Mika Kontro, and Tea Pemovska

Abstract

XLSX file 452K, DSRT Oncology drug collection

Published
2023
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17. Supplementary Figures, Tables and Methods from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Krister Wennerberg, Olli Kallioniemi, Kimmo Porkka, Caroline A. Heckman, Tero Aittokallio, Jonathan Knowles, Maija Wolf, Imre Västrik, Laura Turunen, Minna Suvela, Maria E. Rämet, Tero Pirttinen, Alun Parsons, Aino Palva, Satu Mustjoki, Astrid Murumägi, Pirkko Mattila, Jesus M. Lopez Marti, Muntasir Mamun Majumder, Tuija Lundán, Maija Lepistö, Anna Lehto, Sonja Lagström, Evgeny Kulesskiy, Riikka Karjalainen, Bjørn T. Gjertsen, Erkki Elonen, Pekka Ellonen, Maxim M. Bespalov, Henrikki Almusa, Agnieszka Szwajda, Samuli Eldfors, Henrik Edgren, Bhagwan Yadav, Mika Kontro, and Tea Pemovska

Abstract

PDF file 400K, Supplementary Figures 1-9; Supplementary Tables 4-9 and Supplementary Methods

Published
2023
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18. Supplementary Figure 3 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

PDF file - 123K, Figure S3. Effect of cell cycle on CIP2A expression.

Published
2023
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19. Supplementary Table 1 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

PDF file - 66K, Supplementary Table S1. Co-relation between Chk1 and c-MYC nuclear staining in gastric cancer.

Published
2023
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20. Supplementary Figure 2 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

PDF file - 85K, Figure S2. Chk1 and Claspin (CLSPN) positively regulate CIP2A protein expression in human cancer cells.

Published
2023
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21. Data from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

Checkpoint kinase Chk1 is constitutively active in many cancer cell types and new generation Chk1 inhibitors show marked antitumor activity as single agents. Here we present a hitherto unrecognized mechanism that contributes to the response of cancer cells to Chk1-targeted therapy. Inhibiting chronic Chk1 activity in cancer cells induced the tumor suppressor activity of protein phosphatase protein phosphatase 2A (PP2A), which by dephosphorylating MYC serine 62, inhibited MYC activity and impaired cancer cell survival. Mechanistic investigations revealed that Chk1 inhibition activated PP2A by decreasing the transcription of cancerous inhibitor of PP2A (CIP2A), a chief inhibitor of PP2A activity. Inhibition of cancer cell clonogenicity by Chk1 inhibition could be rescued in vitro either by exogenous expression of CIP2A or by blocking the CIP2A-regulated PP2A complex. Chk1-mediated CIP2A regulation was extended in tumor models dependent on either Chk1 or CIP2A. The clinical relevance of CIP2A as a Chk1 effector protein was validated in several human cancer types, including neuroblastoma, where CIP2A was identified as an NMYC-independent prognostic factor. Because the Chk1–CIP2A–PP2A pathway is driven by DNA-PK activity, functioning regardless of p53 or ATM/ATR status, our results offer explanative power for understanding how Chk1 inhibitors mediate single-agent anticancer efficacy. Furthermore, they define CIP2A-PP2A status in cancer cells as a pharmacodynamic marker for their response to Chk1-targeted therapy. Cancer Res; 73(22); 6757–69. ©2013 AACR.

Published
2023
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22. Supplementary Figure 1 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

PDF file - 82K, Figure S1. Expression analysis of Chk1 and CIP2A in human malignancies.

Published
2023
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23. Supplementary Table 2 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

PDF file - 90K, Supplementary Table S2. List of genes which expression significantly correlates with Chk1 and CIP2A.

Published
2023
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24. Supplementary Methods, Figure Legend from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

PDF file - 205K

Published
2023
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25. Supplementary Figure 4 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Jukka Westermarck, Tapio Visakorpi, Ari Ristimäki, Carsten Weiss, Tero Aittokallio, Juha Klefström, Kristina A. Cole, Caj Haglund, Mike R. Russel, John Pimanda, Yuba R. Pokharel, Merja Helenius, Turker Bilgen, Stefanie Bormann, Agnieszka Szwajda, Johanna I. Partanen, Ilona Schreck, Anni Laine, Camilla Böckelman, Otto Kauko, and Anchit Khanna

Abstract

PDF file - 101K, Figure S4. In vitro and in vivo regulation of CIP2A mRNA expression by Chk1 and effect on cancer cell viability and anchorage independent growth by Chk1, Claspin and CIP2A.

Published
2023
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26. Data from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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27. Supplementary Figure 5 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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28. Supplementary Methods, Figure Legend from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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29. Supplementary Figure 1 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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30. Supplementary Table 2 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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31. Supplementary Figure 4 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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32. Supplementary Figure 2 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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33. Supplementary Figure 3 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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34. Supplementary Table 1 from Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Author

Khanna, Anchit, primary, Kauko, Otto, primary, Böckelman, Camilla, primary, Laine, Anni, primary, Schreck, Ilona, primary, Partanen, Johanna I., primary, Szwajda, Agnieszka, primary, Bormann, Stefanie, primary, Bilgen, Turker, primary, Helenius, Merja, primary, Pokharel, Yuba R., primary, Pimanda, John, primary, Russel, Mike R., primary, Haglund, Caj, primary, Cole, Kristina A., primary, Klefström, Juha, primary, Aittokallio, Tero, primary, Weiss, Carsten, primary, Ristimäki, Ari, primary, Visakorpi, Tapio, primary, and Westermarck, Jukka, primary

Published
2023
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35. From drug response profiling to target addiction scoring in cancer cell models

Author

Bhagwan Yadav, Peddinti Gopalacharyulu, Tea Pemovska, Suleiman A. Khan, Agnieszka Szwajda, Jing Tang, Krister Wennerberg, and Tero Aittokallio

Subjects
Cell-based drug sensitivity profiling, Drug-target addiction scoring, Experimental-computational target deconvolution, Pan-cancer modeling, Personalized cancer medicine, Medicine, Pathology, RB1-214
Abstract

Deconvoluting the molecular target signals behind observed drug response phenotypes is an important part of phenotype-based drug discovery and repurposing efforts. We demonstrate here how our network-based deconvolution approach, named target addiction score (TAS), provides insights into the functional importance of druggable protein targets in cell-based drug sensitivity testing experiments. Using cancer cell line profiling data sets, we constructed a functional classification across 107 cancer cell models, based on their common and unique target addiction signatures. The pan-cancer addiction correlations could not be explained by the tissue of origin, and only correlated in part with molecular and genomic signatures of the heterogeneous cancer cells. The TAS-based cancer cell classification was also shown to be robust to drug response data resampling, as well as predictive of the transcriptomic patterns in an independent set of cancer cells that shared similar addiction signatures with the 107 cancers. The critical protein targets identified by the integrated approach were also shown to have clinically relevant mutation frequencies in patients with various cancer subtypes, including not only well-established pan-cancer genes, such as PTEN tumor suppressor, but also a number of targets that are less frequently mutated in specific cancer types, including ABL1 oncoprotein in acute myeloid leukemia. An application to leukemia patient primary cell models demonstrated how the target deconvolution approach offers functional insights into patient-specific addiction patterns, such as those indicative of their receptor-type tyrosine-protein kinase FLT3 internal tandem duplication (FLT3-ITD) status and co-addiction partners, which may lead to clinically actionable, personalized drug treatment developments. To promote its application to the future drug testing studies, we have made available an open-source implementation of the TAS calculation in the form of a stand-alone R package.

Published
2015
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36. Quantitative analysis of PPT1 interactome in human neuroblastoma cells

Author

Enzo Scifo, Agnieszka Szwajda, Rabah Soliymani, Francesco Pezzini, Marzia Bianchi, Arvydas Dapkunas, Janusz Dębski, Kristiina Uusi-Rauva, Michał Dadlez, Anne-Claude Gingras, Jaana Tyynelä, Alessandro Simonati, Anu Jalanko, Marc H. Baumann, and Maciej Lalowski

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Science (General), Q1-390
Abstract

Mutations in the CLN1 gene that encodes Palmitoyl protein thioesterase 1 (PPT1) or CLN1, cause Infantile NCL (INCL, MIM#256730). PPT1 removes long fatty acid chains such as palmitate from modified cysteine residues of proteins. The data shown here result from isolated protein complexes from PPT1-expressing SH-SY5Y stable cells that were subjected to single step affinity purification coupled to mass spectrometry (AP-MS). Prior to the MS analysis, we utilised a modified filter-aided sample preparation (FASP) protocol. Based on label free quantitative analysis of the data by SAINT, 23 PPT1 interacting partners (IP) were identified. A dense connectivity in PPT1 network was further revealed by functional coupling and extended network analyses, linking it to mitochondrial ATP synthesis coupled protein transport and thioester biosynthetic process. Moreover, the terms: inhibition of organismal death, movement disorders and concentration of lipid were predicted to be altered in the PPT1 network. Data presented here are related to Scifo et al. (J. Proteomics, 123 (2015) 42–53).

Published
2015
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39. Taking the LEAP: study protocol for a randomized, multicentre, naturalistic, efficacy trial of the compuLsive Exercise Activity theraPy (LEAP) - a cognitive behavioral program specifically targeting compulsive exercise in patients with eating disorders

Author

Agnieszka Szwajda, Elin Monell, Emma Forsén Mantilla, and Caroline Meyer

Subjects
Adult, Male, 050103 clinical psychology, medicine.medical_specialty, Anorexia Nervosa, Population, Efficacy trial, RC435-571, Anorexia nervosa, Feeding and Eating Disorders, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Cognition, Compulsive exercise, Medicine, Humans, Multicenter Studies as Topic, 0501 psychology and cognitive sciences, In patient, education, Bulimia Nervosa, Exercise activity, Randomized Controlled Trials as Topic, Protocol (science), Psychiatry, education.field_of_study, Cognitive Behavioral Therapy, business.industry, Bulimia nervosa, 05 social sciences, medicine.disease, 030227 psychiatry, Treatment, Psychiatry and Mental health, Eating disorders, Physical therapy, Female, business
Abstract

BackgroundAbout half of Swedish eating disorder patients report exercising compulsively and compulsive exercise (CE) is prevalent in all diagnoses and both genders. Yet there are no systematic treatments targeting CE in specialist care. This study aims to evaluate the effects of The CompuLsive Exercise Activity TheraPy (LEAP) - a promising group treatment targeting compulsive exercise, in Swedish eating disorder patients.MethodOne hundred twenty-eight adult females and males suffering from anorexia nervosa, bulimia nervosa or other specified feeding and eating disorders (type 1, 2, or 4) with CE will be recruited via four specialist eating disorder treatment units. Participants will be randomized to receive treatment as usual (control group) or treatment as usual plus LEAP (intervention group). The groups will be assessed on key variables (e.g., BMI, eating disorder symptoms, exercise cognitions and behaviors) at three occasions: initially, after 3 months and after 6 months.DiscussionThe project takes place in a clinical setting, including both male and female patients with different eating disorder diagnoses with CE, enabling a good indication of the efficacy of LEAP. If our results are positive, LEAP has the potential of benefiting about half of the eating disorder population, with remission and recovery hopefully improving as a result.Trial registrationThe trial is registered with the ISRCTN registry (registration date 2020-03-25), trial ID:ISRCTN80711391.

Published
2021

43. Frailty trajectories in three longitudinal studies of aging : Is the level or the rate of change more predictive of mortality?

Author

Ida K. Karlsson, Yunzhang Wang, Anna K. Dahl Aslan, Nancy L. Pedersen, Hannah Bower, Xia Li, Agnieszka Szwajda, Sara Hägg, Boo Johansson, Ge Bai, and Juulia Jylhävä

Subjects
Aging, Frail Elderly, Population, Frailty Index, frailty, age at death, older people, AcademicSubjects/MED00280, Risk of mortality, Medicine, Humans, trajectories, Longitudinal Studies, education, Geriatric Assessment, Survival analysis, Aged, education.field_of_study, Frailty, business.industry, Hazard ratio, Age at death, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, mortality, Confidence interval, ageing/19, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Increased risk, Geriatrics and Gerontology, business, Demography, Research Paper
Abstract

BACKGROUND: frailty shows an upward trajectory with age, and higher levels increase the risk of mortality. However, it is less known whether the shape of frailty trajectories differs by age at death or whether the rate of change in frailty is associated with mortality. OBJECTIVES: to assess population frailty trajectories by age at death and to analyse whether the current level of the frailty index (FI) i.e. the most recent measurement or the person-specific rate of change is more predictive of mortality. METHODS: 3,689 individuals from three population-based cohorts with up to 15 repeated measurements of the Rockwood frailty index were analysed. The FI trajectories were assessed by stratifying the sample into four age-at-death groups: 90 years. Generalised survival models were used in the survival analysis. RESULTS: the FI trajectories by age at death showed that those who died at CC BY-NC-ND 4.0© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics SocietyAddress correspondence to: Juulia Jylhävä. Tel: 358-505351712. Email: juulia.jylhava@ki.seDeclaration of Sources of Funding: National Institutesof Health (grant numbers R01 AG04563, AG10175,AG028555, AG08861-09); the MacArthur Foundation Research Network on Successful Aging; the Swedish Council for Working Life and Social Research (FAS/FORTE) (grant numbers 97:0147:1B to N.L.P., 2009-0795 toN.L.P.); the Swedish Research Council (grant numbers 825-2007-7460, 825-2009-6141, 521-2013-8689, 2015-03255, 2018-02077 to J.J., 2016-03081, 2019-01272 to S.H.); JPND/Swedish Research Council (2015-06796 to N.L.P.); FORTE (2013-2292 to N.L.P.); the Loo & Hans Osterman Foundation to S.H. and J.J.; the Foundation for Geriatric Diseases to S.H.; the Magnus Bergwall Foundation to S.H.; the Strategic Research Program in Epidemiology at Karolinska Institutet to S.H. and J.J. and the King Gustaf V’s and Queen Victoria’s Freemason Foundation to S.H. and China Scholarship Council to G.B. and X.L. The financial sponsors had no role in the design, execution, analysis andinterpretation of data, or writing of the study.

Published
2021

45. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Sodium-Hydrogen Exchangers, Genotype, Eczema, Gene Expression, Genetic predisposition to disease, Dual Specificity Phosphatase 1, Rare variants, Matrix Attachment Region Binding Proteins, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, Cytokine Receptor Common beta Subunit, Skin diseases, Rare Diseases, Cardiovascular and Metabolic Diseases, Humans, Receptor, Notch4, Genome-Wide Association Study, Atopic dermatitis
Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema., Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Published
2020

46. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S, Marenholz, I, Esparza-Gordillo, J, Arnau-Soler, A, Pairo-Castineira, E, Rueschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, Baurecht, H, Bisgaard, H, Bonnelykke, K, Brown, SJ, Bustamante, M, Curtin, JA, Custovic, A, Dharmage, SC, Esplugues, A, Falchi, M, Fernandez-Orth, D, Ferreira, MAR, Franke, A, Gerdes, S, Gieger, C, Hakonarson, H, Holt, PG, Homuth, G, Hubner, N, Hysi, PG, Jarvelin, M-R, Karlsson, R, Koppelman, GH, Lau, S, Lutz, M, Magnusson, PKE, Marks, GB, Mueller-Nurasyid, M, Noethen, MM, Paternoster, L, Pennell, CE, Peters, A, Rawlik, K, Robertson, CF, Rodriguez, E, Sebert, S, Simpson, A, Sleiman, PMA, Standl, M, Stoelzl, D, Strauch, K, Szwajda, A, Tenesa, A, Thompson, PJ, Ullemar, V, Visconti, A, Vonk, JM, Wang, CA, Weidinger, S, Wielscher, M, Worth, CL, Xu, C-J, Lee, Y-A, Grosche, S, Marenholz, I, Esparza-Gordillo, J, Arnau-Soler, A, Pairo-Castineira, E, Rueschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, Baurecht, H, Bisgaard, H, Bonnelykke, K, Brown, SJ, Bustamante, M, Curtin, JA, Custovic, A, Dharmage, SC, Esplugues, A, Falchi, M, Fernandez-Orth, D, Ferreira, MAR, Franke, A, Gerdes, S, Gieger, C, Hakonarson, H, Holt, PG, Homuth, G, Hubner, N, Hysi, PG, Jarvelin, M-R, Karlsson, R, Koppelman, GH, Lau, S, Lutz, M, Magnusson, PKE, Marks, GB, Mueller-Nurasyid, M, Noethen, MM, Paternoster, L, Pennell, CE, Peters, A, Rawlik, K, Robertson, CF, Rodriguez, E, Sebert, S, Simpson, A, Sleiman, PMA, Standl, M, Stoelzl, D, Strauch, K, Szwajda, A, Tenesa, A, Thompson, PJ, Ullemar, V, Visconti, A, Vonk, JM, Wang, CA, Weidinger, S, Wielscher, M, Worth, CL, Xu, C-J, and Lee, Y-A

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Published
2021

47. Frailty trajectories in three longitudinal studies of aging : Is the level or the rate of change more predictive of mortality?

Author

Bai, Ge, Szwajda, Agnieszka, Wang, Yunzhang, Li, Xia, Bower, Hannah, Karlsson, Ida K., Johansson, Boo, Dahl Aslan, Anna K., Pedersen, Nancy L., Hägg, Sara, Jylhävä, Juulia, Bai, Ge, Szwajda, Agnieszka, Wang, Yunzhang, Li, Xia, Bower, Hannah, Karlsson, Ida K., Johansson, Boo, Dahl Aslan, Anna K., Pedersen, Nancy L., Hägg, Sara, and Jylhävä, Juulia

Abstract

BACKGROUND: frailty shows an upward trajectory with age, and higher levels increase the risk of mortality. However, it is less known whether the shape of frailty trajectories differs by age at death or whether the rate of change in frailty is associated with mortality. OBJECTIVES: to assess population frailty trajectories by age at death and to analyse whether the current level of the frailty index (FI) i.e. the most recent measurement or the person-specific rate of change is more predictive of mortality. METHODS: 3,689 individuals from three population-based cohorts with up to 15 repeated measurements of the Rockwood frailty index were analysed. The FI trajectories were assessed by stratifying the sample into four age-at-death groups: <70, 70-80, 80-90 and >90 years. Generalised survival models were used in the survival analysis. RESULTS: the FI trajectories by age at death showed that those who died at <70 years had a steadily increasing trajectory throughout the 40 years before death, whereas those who died at the oldest ages only accrued deficits from age ~75 onwards. Higher level of FI was independently associated with increased risk of mortality (hazard ratio 1.68, 95% confidence interval 1.47-1.91), whereas the rate of change was no longer significant after accounting for the current FI level. The effect of the FI level did not weaken with time elapsed since the last measurement. CONCLUSIONS: Frailty trajectories differ as a function of age-at-death category. The current level of FI is a stronger marker for risk stratification than the rate of change., CC BY-NC-ND 4.0© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics SocietyAddress correspondence to: Juulia Jylhävä. Tel: 358-505351712. Email: juulia.jylhava@ki.seDeclaration of Sources of Funding: National Institutesof Health (grant numbers R01 AG04563, AG10175,AG028555, AG08861-09); the MacArthur Foundation Research Network on Successful Aging; the Swedish Council for Working Life and Social Research (FAS/FORTE) (grant numbers 97:0147:1B to N.L.P., 2009-0795 toN.L.P.); the Swedish Research Council (grant numbers 825-2007-7460, 825-2009-6141, 521-2013-8689, 2015-03255, 2018-02077 to J.J., 2016-03081, 2019-01272 to S.H.); JPND/Swedish Research Council (2015-06796 to N.L.P.); FORTE (2013-2292 to N.L.P.); the Loo & Hans Osterman Foundation to S.H. and J.J.; the Foundation for Geriatric Diseases to S.H.; the Magnus Bergwall Foundation to S.H.; the Strategic Research Program in Epidemiology at Karolinska Institutet to S.H. and J.J. and the King Gustaf V’s and Queen Victoria’s Freemason Foundation to S.H. and China Scholarship Council to G.B. and X.L. The financial sponsors had no role in the design, execution, analysis andinterpretation of data, or writing of the study.

Published
2021
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48. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), and Lee, Y.-A. (Young-Ae)

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Published
2021

49. Taking the LEAP : study protocol for a randomized, multicentre, naturalistic, efficacy trial of the compuLsive Exercise Activity theraPy (LEAP) - a cognitive behavioral program specifically targeting compulsive exercise in patients with eating disorders

Author

Monell, Elin, Meyer, Caroline, Szwajda, Agnieszka, Forsén Mantilla, Emma, Monell, Elin, Meyer, Caroline, Szwajda, Agnieszka, and Forsén Mantilla, Emma

Abstract

Background About half of Swedish eating disorder patients report exercising compulsively and compulsive exercise (CE) is prevalent in all diagnoses and both genders. Yet there are no systematic treatments targeting CE in specialist care. This study aims to evaluate the effects of The CompuLsive Exercise Activity TheraPy (LEAP) - a promising group treatment targeting compulsive exercise, in Swedish eating disorder patients. Method One hundred twenty-eight adult females and males suffering from anorexia nervosa, bulimia nervosa or other specified feeding and eating disorders (type 1, 2, or 4) with CE will be recruited via four specialist eating disorder treatment units. Participants will be randomized to receive treatment as usual (control group) or treatment as usual plus LEAP (intervention group). The groups will be assessed on key variables (e.g., BMI, eating disorder symptoms, exercise cognitions and behaviors) at three occasions: initially, after 3 months and after 6 months. Discussion The project takes place in a clinical setting, including both male and female patients with different eating disorder diagnoses with CE, enabling a good indication of the efficacy of LEAP. If our results are positive, LEAP has the potential of benefiting about half of the eating disorder population, with remission and recovery hopefully improving as a result.

Published
2021
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