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1. Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders

Author

Kämpe, Anders, Suvisaari, Jaana, Lähteenvuo, Markku, Singh, Tarjinder, Ahola-Olli, Ari, Urpa, Lea, Haaki, Willehard, Hietala, Jarmo, Isometsä, Erkki, Jukuri, Tuomas, Kampman, Olli, Kieseppä, Tuula, Lahdensuo, Kaisla, Lönnqvist, Jouko, Männynsalo, Teemu, Paunio, Tiina, Niemi-Pynttäri, Jussi, Suokas, Kimmo, Tuulio-Henriksson, Annamari, Veijola, Juha, Wegelius, Asko, Daly, Mark, Taylor, Jacob, Kendler, Kenneth S., Palotie, Aarno, and Pietiläinen, Olli

Published
2024
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2. Genetic variants for head size share genes and pathways with cancer

Author

Knol, Maria J, Poot, Raymond A, Evans, Tavia E, Satizabal, Claudia L, Mishra, Aniket, Sargurupremraj, Muralidharan, van der Auwera, Sandra, Duperron, Marie-Gabrielle, Jian, Xueqiu, Hostettler, Isabel C, van Dam-Nolen, Dianne HK, Lamballais, Sander, Pawlak, Mikolaj A, Lewis, Cora E, Carrion-Castillo, Amaia, van Erp, Theo GM, Reinbold, Céline S, Shin, Jean, Scholz, Markus, Håberg, Asta K, Kämpe, Anders, Li, Gloria HY, Avinun, Reut, Atkins, Joshua R, Hsu, Fang-Chi, Amod, Alyssa R, Lam, Max, Tsuchida, Ami, Teunissen, Mariël WA, Aygün, Nil, Patel, Yash, Liang, Dan, Beiser, Alexa S, Beyer, Frauke, Bis, Joshua C, Bos, Daniel, Bryan, R Nick, Bülow, Robin, Caspers, Svenja, Catheline, Gwenaëlle, Cecil, Charlotte AM, Dalvie, Shareefa, Dartigues, Jean-François, DeCarli, Charles, Enlund-Cerullo, Maria, Ford, Judith M, Franke, Barbara, Freedman, Barry I, Friedrich, Nele, Green, Melissa J, Haworth, Simon, Helmer, Catherine, Hoffmann, Per, Homuth, Georg, Ikram, M Kamran, Jack, Clifford R, Jahanshad, Neda, Jockwitz, Christiane, Kamatani, Yoichiro, Knodt, Annchen R, Li, Shuo, Lim, Keane, Longstreth, WT, Macciardi, Fabio, Consortium, The Cohorts for Heart and Aging Research in Genomic Epidemiology, Amouyel, Philippe, Arfanakis, Konstantinos, Aribisala, Benjamin S, Bastin, Mark E, Chauhan, Ganesh, Chen, Christopher, Cheng, Ching-Yu, de Jager, Philip L, Deary, Ian J, Fleischman, Debra A, Gottesman, Rebecca F, Gudnason, Vilmundur, Hilal, Saima, Hofer, Edith, Janowitz, Deborah, Jukema, J Wouter, Liewald, David CM, Lopez, Lorna M, Lopez, Oscar, Luciano, Michelle, Martinez, Oliver, Niessen, Wiro J, Nyquist, Paul, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Schmidt, Helena, Tiemeier, Henning, Trompet, Stella, van der Grond, Jeroen, Völzke, Henry, Wardlaw, Joanna M, Yanek, Lisa, Yang, Jingyun, and Consortium, The Enhancing NeuroImaging Genetics through Meta-Analysis

Subjects
Biomedical and Clinical Sciences, Neurosciences, Biotechnology, Genetics, Cancer, Stem Cell Research, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Humans, Genome-Wide Association Study, Head, Neoplasms, Female, Male, Polymorphism, Single Nucleotide, Genetic Variation, Organ Size, Signal Transduction, Adult, Genetic Predisposition to Disease, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium, cancer, genetics, genome-wide association study, head circumference, head size, intracranial volume, meta-analysis, Biomedical and clinical sciences
Abstract

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Published
2024

3. Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study

Author

Koch, Elise, Kämpe, Anders, Alver, Maris, Sigurðarson, Sindri, Einarsson, Guðmundur, Partanen, Juulia, Smith, Robert L., Jaholkowski, Piotr, Taipale, Heidi, Lähteenvuo, Markku, Steen, Nils Eiel, Smeland, Olav B., Djurovic, Srdjan, Molden, Espen, Sigurdsson, Engilbert, Stefánsson, Hreinn, Stefánsson, Kári, Palotie, Aarno, Milani, Lili, O’Connell, Kevin S., and Andreassen, Ole A.

Published
2024
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4. An atlas of genetic determinants of forearm fracture

Author

Nethander, Maria, Movérare-Skrtic, Sofia, Kämpe, Anders, Coward, Eivind, Reimann, Ene, Grahnemo, Louise, Borbély, Éva, Helyes, Zsuzsanna, Funck-Brentano, Thomas, Cohen-Solal, Martine, Tuukkanen, Juha, Koskela, Antti, Wu, Jianyao, Li, Lei, Lu, Tianyuan, Gabrielsen, Maiken E., Mägi, Reedik, Hoff, Mari, Lerner, Ulf H., Henning, Petra, Ullum, Henrik, Erikstrup, Christian, Brunak, Søren, Langhammer, Arnulf, Tuomi, Tiinamaija, Oddsson, Asmundur, Stefansson, Kari, Pettersson-Kymmer, Ulrika, Ostrowski, Sisse Rye, Pedersen, Ole Birger Vesterager, Styrkarsdottir, Unnur, Mäkitie, Outi, Hveem, Kristian, Richards, J. Brent, and Ohlsson, Claes

Published
2023
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5. Antipsychotic medications and sleep problems in patients with schizophrenia

Author

Kyttälä, Aija, Kämpe, Anders, Tuulio-Henriksson, Annamari, Ahola-Olli, Ari, Wegelius, Asko, Toivola, Auli, Neale, Benjamin, Shen, Huei-yi, Västrik, Imre, Lönnqvist, Jouko, Veijola, Juha, Niemi-Pynttäri, Jussi, Häkkinen, Katja, Suokas, Kimmo, Daly, Mark, Ristiluoma, Noora, Pietiläinen, Olli, Kajanne, Risto, Hyman, Steven E., Singh, Tarjinder, Männynsalo, Teemu, Jukuri, Tuomas, Haaki, Willehard, Cederlöf, Erik, Holm, Minna, Taipale, Heidi, Tiihonen, Jari, Tanskanen, Antti, Lähteenvuo, Markku, Lahdensuo, Kaisla, Kampman, Olli, Isometsä, Erkki, Kieseppä, Tuula, Palotie, Aarno, Suvisaari, Jaana, and Paunio, Tiina

Published
2024
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6. High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study.

Author

Partanen, Juulia J., Häppölä, Paavo, Kämpe, Anders, Ahola-Olli, Ari, Hellsten, Anni, Rask, Susanna M., Haaki, Willehard, Hietala, Jarmo, Kampman, Olli, Tiihonen, Jari, Tanskanen, Antti J., Daly, Mark J., Ripatti, Samuli, Palotie, Aarno, Taipale, Heidi, Lähteenvuo, Markku, and Koskela, Jukka T.

Subjects
TYPE 2 diabetes, RESPIRATORY infections, ELECTRONIC health records, CYTOCHROME P-450, PSYCHOSES
Abstract

Objective: The authors used longitudinal biobank data with up to 25 years of follow-up on over 2,600 clozapine users to derive reliable estimates of the real-world burden of clozapine adverse drug events (ADEs). Methods: A total of 2,659 participants in the FinnGen biobank project had a schizophrenia diagnosis and clozapine purchases with longitudinal electronic health record follow-up for up to 25 years after clozapine initiation. Diseases and health-related events enriched during clozapine use were identified, adjusting for disease severity. The incidence and recurrence of ADEs over years of clozapine use, their effect on clozapine discontinuation and deaths, and their pharmacogenetics were studied. Results: Median follow-up time after clozapine initiation was 12.7 years. Across 2,157 diseases and health-related events, 27 were enriched during clozapine use, falling into five disease categories: gastrointestinal hypomotility, seizures, pneumonia, other acute respiratory tract infections, and tachycardia, along with a heterogeneous group including neutropenia and type 2 diabetes, among others. Cumulative incidence estimates for ileus (severe gastrointestinal hypomotility) and pneumonia were 5.3% and 29.5%, respectively, 20 years after clozapine initiation. Both events were significantly associated with increased mortality among clozapine users (ileus: odds ratio=4.5; pneumonia: odds ratio=2.8). Decreased genotype-predicted CYP2C19 and CYP1A2 activities were associated with higher pneumonia risk. Conclusions: Clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality. Two CYP genes influenced pneumonia risk. Pneumonia and ileus call for improved utilization of available preventive measures. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Genetic variants for head size share genes and pathways with cancer

Author

Knol, Maria J., Poot, Raymond A., Evans, Tavia E., Satizabal, Claudia L., Mishra, Aniket, Sargurupremraj, Muralidharan, van der Auwera, Sandra, Duperron, Marie Gabrielle, Jian, Xueqiu, Hostettler, Isabel C., van Dam-Nolen, Dianne H.K., Lamballais, Sander, Pawlak, Mikolaj A., Lewis, Cora E., Carrion-Castillo, Amaia, van Erp, Theo G.M., Reinbold, Céline S., Shin, Jean, Scholz, Markus, Håberg, Asta K., Kämpe, Anders, Li, Gloria H.Y., Avinun, Reut, Atkins, Joshua R., Hsu, Fang Chi, Amod, Alyssa R., Lam, Max, Bos, Daniel, Cecil, Charlotte A.M., Longstreth, W. T., Hilal, Saima, Niessen, Wiro J., Schmidt, Helena, Tiemeier, Henning, Bernard, Manon, Blanken, Laura M.E., Hottenga, Jouke Jan, Ophoff, Roel A., Pappa, Irene, Shen, Li, Van Haren, Neeltje E.M., Muetzel, Ryan, Roshchupkin, Gennady V., Teumer, Alexander, van der Lugt, Aad, Vernooij, Meike W., White, Tonya, Koudstaal, Peter J., Ikram, M. Arfan, Adams, Hieab H.H., Knol, Maria J., Poot, Raymond A., Evans, Tavia E., Satizabal, Claudia L., Mishra, Aniket, Sargurupremraj, Muralidharan, van der Auwera, Sandra, Duperron, Marie Gabrielle, Jian, Xueqiu, Hostettler, Isabel C., van Dam-Nolen, Dianne H.K., Lamballais, Sander, Pawlak, Mikolaj A., Lewis, Cora E., Carrion-Castillo, Amaia, van Erp, Theo G.M., Reinbold, Céline S., Shin, Jean, Scholz, Markus, Håberg, Asta K., Kämpe, Anders, Li, Gloria H.Y., Avinun, Reut, Atkins, Joshua R., Hsu, Fang Chi, Amod, Alyssa R., Lam, Max, Bos, Daniel, Cecil, Charlotte A.M., Longstreth, W. T., Hilal, Saima, Niessen, Wiro J., Schmidt, Helena, Tiemeier, Henning, Bernard, Manon, Blanken, Laura M.E., Hottenga, Jouke Jan, Ophoff, Roel A., Pappa, Irene, Shen, Li, Van Haren, Neeltje E.M., Muetzel, Ryan, Roshchupkin, Gennady V., Teumer, Alexander, van der Lugt, Aad, Vernooij, Meike W., White, Tonya, Koudstaal, Peter J., Ikram, M. Arfan, and Adams, Hieab H.H.

Abstract

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Published
2024

8. Antipsychotic medications and sleep problems in patients with schizophrenia

Author

Cederlöf, Erik, Holm, Minna, Taipale, Heidi, Tiihonen, Jari, Tanskanen, Antti, Lähteenvuo, Markku, Lahdensuo, Kaisla, Kampman, Olli, Wegelius, Asko, Isometsä, Erkki, Kieseppä, Tuula, Palotie, Aarno, Suvisaari, Jaana, Paunio, Tiina, Kyttälä, Aija, Kämpe, Anders, Tuulio-Henriksson, Annamari, Ahola-Olli, Ari, Toivola, Auli, Neale, Benjamin, Shen, Huei-yi, Västrik, Imre, Lönnqvist, Jouko, Veijola, Juha, Niemi-Pynttäri, Jussi, Häkkinen, Katja, Suokas, Kimmo, Daly, Mark, Ristiluoma, Noora, Pietiläinen, Olli, Kajanne, Risto, Hyman, Steven E., Singh, Tarjinder, Männynsalo, Teemu, Jukuri, Tuomas, Haaki, Willehard, Cederlöf, Erik, Holm, Minna, Taipale, Heidi, Tiihonen, Jari, Tanskanen, Antti, Lähteenvuo, Markku, Lahdensuo, Kaisla, Kampman, Olli, Wegelius, Asko, Isometsä, Erkki, Kieseppä, Tuula, Palotie, Aarno, Suvisaari, Jaana, Paunio, Tiina, Kyttälä, Aija, Kämpe, Anders, Tuulio-Henriksson, Annamari, Ahola-Olli, Ari, Toivola, Auli, Neale, Benjamin, Shen, Huei-yi, Västrik, Imre, Lönnqvist, Jouko, Veijola, Juha, Niemi-Pynttäri, Jussi, Häkkinen, Katja, Suokas, Kimmo, Daly, Mark, Ristiluoma, Noora, Pietiläinen, Olli, Kajanne, Risto, Hyman, Steven E., Singh, Tarjinder, Männynsalo, Teemu, Jukuri, Tuomas, and Haaki, Willehard

Abstract

Background: Sleep problems are common and related to a worse quality of life in patients with schizophrenia. Almost all patients with schizophrenia use antipsychotic medications, which usually increase sleep. Still, the differences in subjective sleep outcomes between different antipsychotic medications are not entirely clear. Methods: This study assessed 5466 patients with schizophrenia and is part of the nationwide Finnish SUPER study. We examined how the five most common antipsychotic medications (clozapine, olanzapine, quetiapine, aripiprazole, and risperidone) associate with questionnaire-based sleep problems in logistic regression analyses, including head-to-head analyses between different antipsychotic medications. The sleep problems were difficulties initiating sleep, early morning awakenings, fatigue, poor sleep quality, short (≤6 h) and long sleep duration (≥10 h). Results: The average number of antipsychotic medications was 1.59 per patient. Clozapine was associated with long sleep duration (49.0 % of clozapine users vs 30.2 % of other patients, OR = 2.05, 95 % CI 1.83–2.30, p < .001). Olanzapine and risperidone were in head-to-head analyses associated with less sleep problems than patients using aripiprazole, quetiapine, or no antipsychotic medication. Aripiprazole and quetiapine were associated with more insomnia symptoms and poorer sleep quality. Patients without antipsychotic medications (N = 159) had poorer sleep quality than patients with antipsychotic use, and short sleep duration was common (21.5 % of patients using antipsychotics vs 7.8 % of patients using antipsychotics, OR = 2.97, 95 % CI 1.98–4.44, p < .001). Conclusions: Prevalence of sleep problems is markedly related to the antipsychotic medication the patient uses. These findings underline the importance of considering and assessing sleep problems when treating schizophrenia patients with antipsychotics.

Published
2024
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9. Integrating a Polygenic Risk Score into a clinical setting would impact risk predictions in familial breast cancer

Author

Baliakas, Panagiotis, Munters, Arielle R, Kämpe, Anders, Tesi, Bianca, Bondeson, Marie-Louise, Ladenvall, Claes, Eriksson, Daniel, Baliakas, Panagiotis, Munters, Arielle R, Kämpe, Anders, Tesi, Bianca, Bondeson, Marie-Louise, Ladenvall, Claes, and Eriksson, Daniel

Abstract

Background Low-impact genetic variants identified in population-based genetic studies are not routinely measured as part of clinical genetic testing in familial breast cancer (BC). We studied the consequences of integrating an established Polygenic Risk Score (PRS) (BCAC 313, PRS313) into clinical sequencing of women with familial BC in Sweden. Methods We developed an add-on sequencing panel to capture 313 risk variants in addition to the clinical screening of hereditary BC genes. Index patients with no pathogenic variant from 87 families, and 1000 population controls, were included in comparative PRS calculations. Including detailed family history, sequencing results and tumour pathology information, we used BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.6 to estimate contralateral and lifetime risks without and with PRS313. Results Women with BC but no pathogenic variants in hereditary BC genes have a higher PRS313 compared with population controls (mean+0.78 SD, p<3e-9). Implementing PRS313 in the clinical risk estimation before their BC diagnosis would have changed the recommended follow-up in 24%–45% of women. Conclusions Our results show the potential impact of incorporating PRS313 directly in the clinical genomic investigation of women with familial BC.

Published
2024
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10. W88. PHENOTYPIC AND GENETIC CHARACTERIZATION OF INDIVIDUALS WITH SCHIZOPHRENIA AND HIGH PSYCHIATRIC HOSPITALIZATION BURDEN

Author

Kämpe, Anders, primary, Suvisaari, Jaana, additional, Lähteenvuo, Markku, additional, Vartiainen, Emilia, additional, Singh, Tarjinder, additional, Ahola-Olli, Ari, additional, Urpa, Lea, additional, Researchers, SUPER-Finland, additional, Daly, Mark, additional, Taylor, Jacob, additional, Kendler, Kenneth, additional, Palotie, Aarno, additional, and Pietiläinen, Olli, additional

Published
2023
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11. Genetic variants for head size share genes and pathways with cancer

Author

Amouyel, Philippe, Arfanakis, Konstantinos, Aribisala, Benjamin S., Bastin, Mark E., Chauhan, Ganesh, Chen, Christopher, Cheng, Ching-Yu, de Jager, Philip L., Deary, Ian J., Fleischman, Debra A., Gottesman, Rebecca F., Gudnason, Vilmundur, Hilal, Saima, Hofer, Edith, Janowitz, Deborah, Jukema, J. Wouter, Liewald, David C.M., Lopez, Lorna M., Lopez, Oscar, Luciano, Michelle, Martinez, Oliver, Niessen, Wiro J., Nyquist, Paul, Rotter, Jerome I., Rundek, Tatjana, Sacco, Ralph L., Schmidt, Helena, Tiemeier, Henning, Trompet, Stella, van der Grond, Jeroen, Völzke, Henry, Wardlaw, Joanna M., Yanek, Lisa, Yang, Jingyun, Agartz, Ingrid, Alhusaini, Saud, Almasy, Laura, Ames, David, Amunts, Katrin, Andreassen, Ole A., Armstrong, Nicola, Bernard, Manon, Blangero, John, Blanken, Laura M.E., Boks, Marco P., Boomsma, Dorret I., Brickman, Adam M., Brodaty, Henry, Buckner, Randy L., Buitelaar, Jan K., Cannon, Dara M., Carr, Vaughan J., Catts, Stanley V., Chakravarty, M. Mallar, Chen, Qiang, Ching, Christopher R.K., Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Davies, Gareth E., de Geus, Eco J.C., de Zubicaray, Greig I., den Braber, Anouk, Desrivières, Sylvane, Dillman, Allissa, Djurovic, Srdjan, Drevets, Wayne C., Duggirala, Ravi, Ehrlich, Stefan, Erk, Susanne, Espeseth, Thomas, Fedko, Iryna O., Fernández, Guillén, Fisher, Simon E., Foroud, Tatiana M., Ge, Tian, Giddaluru, Sudheer, Glahn, David C., Goldman, Aaron L., Green, Robert C., Greven, Corina U., Grimm, Oliver, Hansell, Narelle K., Hartman, Catharina A., Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans, Hibar, Derrek P., Ho, Beng-Choon, Hoekstra, Pieter J., Holmes, Avram J., Hoogman, Martine, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E., Jablensky, Assen, Jenkinson, Mark, Jia, Tianye, Jöckel, Karl-Heinz, Jönsson, Erik G., Kim, Sungeun, Klein, Marieke, Kochunov, Peter, Kwok, John B., Lawrie, Stephen M., Le Hellard, Stephanie, Lemaître, Hervé, Loughland, Carmel, Marquand, Andre F., Martin, Nicholas G., Martinot, Jean-Luc, Matarin, Mar, Mathalon, Daniel H., Mather, Karen A., Mattay, Venkata S., McDonald, Colm, McMahon, Francis J., McMahon, Katie L., E, Rebekah, McWhirter, Mecocci, Patrizia, Melle, Ingrid, Meyer-Lindenberg, Andreas, Michie, Patricia T., Milaneschi, Yuri, Morris, Derek W., Mowry, Bryan, Nho, Kwangsik, Nichols, Thomas E., Nöthen, Markus N., Olvera, Rene L., Oosterlaan, Jaap, Ophoff, Roel A., Pandolfo, Massimo, Pantelis, Christos, Pappa, Irene, Penninx, Brenda, Pike, G. Bruce, Rasser, Paul E., Rentería, Miguel E., Reppermund, Simone, Rietschel, Marcella, Risacher, Shannon L., Romanczuk-Seiferth, Nina, Rose, Emma Jane, Sachdev, Perminder S., Sämann, Philipp G., Saykin, Andrew J., Schall, Ulrich, Schofield, Peter R., Schramm, Sara, Schumann, Gunter, Scott, Rodney, Shen, Li, Sisodiya, Sanjay M., Soininen, Hilkka, Sprooten, Emma, Srikanth, Velandai, Steen, Vidar M., Strike, Lachlan T., Thalamuthu, Anbupalam, Toga, Arthur W., Tooney, Paul, Tordesillas-Gutiérrez, Diana, Turner, Jessica A., Valdés Hernández, Maria del C., van der Meer, Dennis, Van der Wee, Nic J.A., Van Haren, Neeltje E.M., van 't Ent, Dennis, Veltman, Dick J., Walter, Henrik, Weinberger, Daniel R., Weiner, Michael W., Wen, Wei, Westlye, Lars T., Westman, Eric, Winkler, Anderson M., Woldehawariat, Girma, Wright, Margaret J., Wu, Jingqin, Knol, Maria J., Poot, Raymond A., Evans, Tavia E., Satizabal, Claudia L., Mishra, Aniket, Sargurupremraj, Muralidharan, van der Auwera, Sandra, Duperron, Marie-Gabrielle, Jian, Xueqiu, Hostettler, Isabel C., van Dam-Nolen, Dianne H.K., Lamballais, Sander, Pawlak, Mikolaj A., Lewis, Cora E., Carrion-Castillo, Amaia, van Erp, Theo G.M., Reinbold, Céline S., Shin, Jean, Scholz, Markus, Håberg, Asta K., Kämpe, Anders, Li, Gloria H.Y., Avinun, Reut, Atkins, Joshua R., Hsu, Fang-Chi, Amod, Alyssa R., Lam, Max, Tsuchida, Ami, Teunissen, Mariël W.A., Aygün, Nil, Patel, Yash, Liang, Dan, Beiser, Alexa S., Beyer, Frauke, Bis, Joshua C., Bos, Daniel, Bryan, R. Nick, Bülow, Robin, Caspers, Svenja, Catheline, Gwenaëlle, Cecil, Charlotte A.M., Dalvie, Shareefa, Dartigues, Jean-François, DeCarli, Charles, Enlund-Cerullo, Maria, Ford, Judith M., Franke, Barbara, Freedman, Barry I., Friedrich, Nele, Green, Melissa J., Haworth, Simon, Helmer, Catherine, Hoffmann, Per, Homuth, Georg, Ikram, M. Kamran, Jack, Clifford R., Jr., Jahanshad, Neda, Jockwitz, Christiane, Kamatani, Yoichiro, Knodt, Annchen R., Li, Shuo, Lim, Keane, Longstreth, W.T., Macciardi, Fabio, Mäkitie, Outi, Mazoyer, Bernard, Medland, Sarah E., Miyamoto, Susumu, Moebus, Susanne, Mosley, Thomas H., Muetzel, Ryan, Mühleisen, Thomas W., Nagata, Manabu, Nakahara, Soichiro, Palmer, Nicholette D., Pausova, Zdenka, Preda, Adrian, Quidé, Yann, Reay, William R., Roshchupkin, Gennady V., Schmidt, Reinhold, Schreiner, Pamela J., Setoh, Kazuya, Shapland, Chin Yang, Sidney, Stephen, St Pourcain, Beate, Stein, Jason L., Tabara, Yasuharu, Teumer, Alexander, Uhlmann, Anne, van der Lugt, Aad, Vernooij, Meike W., Werring, David J., Windham, B. Gwen, Witte, A. Veronica, Wittfeld, Katharina, Yang, Qiong, Yoshida, Kazumichi, Brunner, Han G., Le Grand, Quentin, Sim, Kang, Stein, Dan J., Bowden, Donald W., Cairns, Murray J., Hariri, Ahmad R., Cheung, Ching-Lung, Andersson, Sture, Villringer, Arno, Paus, Tomas, Cichon, Sven, Calhoun, Vince D., Crivello, Fabrice, Launer, Lenore J., White, Tonya, Koudstaal, Peter J., Houlden, Henry, Fornage, Myriam, Matsuda, Fumihiko, Grabe, Hans J., Ikram, M. Arfan, Debette, Stéphanie, Thompson, Paul M., Seshadri, Sudha, and Adams, Hieab H.H.

Published
2024
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18. A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

Author

Formosa, Melissa M., primary, Bergen, Dylan J. M., additional, Gregson, Celia L., additional, Maurizi, Antonio, additional, Kämpe, Anders, additional, Garcia-Giralt, Natalia, additional, Zhou, Wei, additional, Grinberg, Daniel, additional, Ovejero Crespo, Diana, additional, Zillikens, M. Carola, additional, Williams, Graham R., additional, Bassett, J. H. Duncan, additional, Brandi, Maria Luisa, additional, Sangiorgi, Luca, additional, Balcells, Susanna, additional, Högler, Wolfgang, additional, Van Hul, Wim, additional, and Mäkitie, Outi, additional

Published
2021
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19. AnARHGAP25variant links aberrantRac1function to early‐onset skeletal fragility

Author

Mäkitie, Riikka E., primary, Henning, Petra, additional, Jiu, Yaming, additional, Kämpe, Anders, additional, Kogan, Konstantin, additional, Costantini, Alice, additional, Välimäki, Ville‐Valtteri, additional, Medina‐Gomez, Carolina, additional, Pekkinen, Minna, additional, Salusky, Isidro B., additional, Schalin‐Jäntti, Camilla, additional, Haanpää, Maria K., additional, Rivadeneira, Fernando, additional, Bassett, John H. Duncan, additional, Williams, Graham R., additional, Lerner, Ulf H., additional, Pereira, Renata C., additional, Lappalainen, Pekka, additional, and Mäkitie, Outi, additional

Published
2021
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20. Genetic causes and underlying disease mechanisms in early-onset osteoporosis

Author

Kämpe, Anders and Kämpe, Anders

Abstract

Adult-onset osteoporosis is a disorder that affects a significant proportion of the elderly population worldwide and entails a substantial disease burden for the affected individuals. Childhood-onset osteoporosis is a rare condition often associating with a severe bone disease and recurrent fractures already in early childhood. Both childhood-onset and adult-onset osteoporosis have a large genetic component, but in children the disorder is usually genetically less complex and often caused by a single gene variant. This makes genetic studies a well-suited approach to explore primary osteoporosis in children, which is the focus of this thesis. Genetic studies can also be used to study bone metabolism in healthy children because of the dynamic stage of the skeleton during growth. Studies in children also have the advantage of involving less confounding environmental factors and other co-morbidities than studies in adults. Our genetic studies had two main goals. First of all, for individuals affected with a severe bone phenotype, a molecular diagnosis is important for several reasons, but particularly for prognostic purposes and for decisions related to treatment strategy. Secondly, the hope is that uncovering genetic regulators of bone metabolism in severely affected children will reveal universal mechanisms that are important also for the adult osteoporosis population. Paper I and Paper II had a monogenic focus and investigated individuals with childhood-onset osteoporosis or fracture propensity. In Paper I we identified two novel disease causing variants in the PLS3 (Plastin 3) gene. The findings allowed us to conclude that PLS3 screening should be recommended in children with primary osteoporosis, especially if vertebral compression fractures are a dominant feature. In Paper II we showed for the first time that PLS3 gene deletions can cause osteoporosis in children. We also found evidence suggesting that PLS3 has an important role in bone matrix mineralization. Pape

Published
2020

28. New Insights Into Monogenic Causes of Osteoporosis

Author

Mäkitie, Riikka E., Costantini, Alice, Kämpe, Anders, Alm, Jessica J., Mäkitie, Outi, Research Programs Unit, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, HUS Children and Adolescents, University Management, Lastentautien yksikkö, and Children's Hospital

Subjects
PLS3 MUTATIONS, X-LINKED OSTEOPOROSIS, early-onset osteoporosis, osteogenesis imperfecta, TURNOVER MARKERS, Wnt signaling, PLS3, POSTMENOPAUSAL WOMEN, RECESSIVE OSTEOGENESIS IMPERFECTA, 3121 General medicine, internal medicine and other clinical medicine, FRACTURE PREDICTION, PSEUDOGLIOMA SYNDROME, bone metabolism, 3111 Biomedicine, BONE-MINERAL DENSITY, BRUCK-SYNDROME
Abstract

Osteoporosis, characterized by deteriorated bone microarchitecture and low bone mineral density, is a chronic skeletal disease with high worldwide prevalence. Osteoporosis related to aging is the most common form and causes significant morbidity and mortality. Rare, monogenic forms of osteoporosis have their onset usually in childhood or young adulthood and have specific phenotypic features and clinical course depending on the underlying cause. The most common form is osteogenesis imperfecta linked to mutations in COL1A1 and COL1A2, the two genes encoding type I¬ collagen. However, in the past years, remarkable advancements in bone research have expanded our understanding of the intricacies behind bone metabolism and identified novel molecular mechanisms contributing to skeletal health and disease. Especially high-throughput sequencing techniques have made family-based studies an efficient way to identify single genes causative of rare monogenic forms of osteoporosis and these have yielded several novel genes that encode proteins partaking in type I collagen modification or regulating bone cell function directly. New forms of monogenic osteoporosis, such as autosomal dominant osteoporosis caused by WNT1 mutations or X-linked osteoporosis due to PLS3 mutations, have revealed previously unidentified bone-regulating proteins and clarified specific roles of bone cells, expanded our understanding of possible inheritance mechanisms and paces of disease progression, and highlighted the potential of monogenic bone diseases to extend beyond the skeletal tissue. The novel gene discoveries have introduced new challenges to the classification and diagnosis of monogenic osteoporosis, but also provided promising new molecular targets for development of pharmacotherapies. In this article we give an overview of the recent discoveries in the area of monogenic forms of osteoporosis, describing the key cellular mechanisms leading to skeletal fragility, the major recent research findings and the essential challenges and avenues in future diagnostics and treatments.

Published
2019

29. An ARHGAP25 variant links aberrant Rac1 function to early‐onset skeletal fragility.

Author

Mäkitie, Riikka E., Henning, Petra, Jiu, Yaming, Kämpe, Anders, Kogan, Konstantin, Costantini, Alice, Välimäki, Ville‐Valtteri, Medina‐Gomez, Carolina, Pekkinen, Minna, Salusky, Isidro B., Schalin‐Jäntti, Camilla, Haanpää, Maria K., Rivadeneira, Fernando, Bassett, John H. Duncan, Williams, Graham R., Lerner, Ulf H., Pereira, Renata C., Lappalainen, Pekka, and Mäkitie, Outi

Subjects
MONONUCLEAR leukocytes, GTPASE-activating protein, BONE remodeling, BONE resorption, BONE metabolism, MACROPHAGE colony-stimulating factor, MONOCYTES, LUMBAR vertebrae
Abstract

Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase‐activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early‐onset, autosomal‐dominant skeletal fragility in a three‐generation Finnish family. Affected individuals (n = 13) presented with multiple low‐energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho‐family GTPase Rac1. Variants in the ARHGAP25 5′ untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta‐analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony‐stimulating factor (M‐CSF)–stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject‐derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R‐mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP‐activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Published
2021
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31. Unique, Gender‐Dependent Serum microRNA Profile in PLS3 Gene‐Related Osteoporosis.

Author

Mäkitie, Riikka E, Hackl, Matthias, Weigl, Moritz, Frischer, Amelie, Kämpe, Anders, Costantini, Alice, Grillari, Johannes, and Mäkitie, Outi

Abstract

Plastin 3 (PLS3), encoded by PLS3, is a newly recognized regulator of bone metabolism, and mutations in the encoding gene result in severe childhood‐onset osteoporosis. Because it is an X chromosomal gene, PLS3 mutation‐positive males are typically more severely affected whereas females portray normal to increased skeletal fragility. Despite the severe skeletal pathology, conventional metabolic bone markers tend to be normal and are thus insufficient for diagnosing or monitoring patients. Our study aimed to explore serum microRNA (miRNA) concentrations in subjects with defective PLS3 function to identify novel markers that could differentiate subjects according to mutation status and give insight into the molecular mechanisms by which PLS3 regulates skeletal health. We analyzed fasting serum samples for a custom‐designed panel comprising 192 miRNAs in 15 mutation‐positive (five males, age range 8–76 years, median 41 years) and 14 mutation‐negative (six males, age range 8–69 years, median 40 years) subjects from four Finnish families with different PLS3 mutations. We identified a unique miRNA expression profile in the mutation‐positive subjects with seven significantly upregulated or downregulated miRNAs (miR‐93‐3p, miR‐532‐3p, miR‐133a‐3p, miR‐301b‐3p, miR‐181c‐5p, miR‐203a‐3p, and miR‐590‐3p; p values, range.004–.044). Surprisingly, gender subgroup analysis revealed the difference to be even more distinct in female mutation‐positive subjects (congruent p values, range.007–.086) than in males (p values, range.127–.843) in comparison to corresponding mutation‐negative subjects. Although the seven identified miRNAs have all been linked to bone metabolism and two of them (miR‐181c‐5p and miR‐203a‐3p) have bioinformatically predicted targets in the PLS3 3′ untranslated region (3′‐UTR), none have previously been reported to associate with PLS3. Our results indicate that PLS3 mutations are reflected in altered serum miRNA levels and suggest there is crosstalk between PLS3 and these miRNAs in bone metabolism. These provide new understanding of the pathomechanisms by which mutations in PLS3 lead to skeletal disease and may provide novel avenues for exploring miRNAs as biomarkers in PLS3 osteoporosis or as target molecules in future therapeutic applications. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Published
2020
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33. PLS3Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization

Author

Kämpe, Anders J, primary, Costantini, Alice, additional, Levy-shraga, Yael, additional, Zeitlin, Leonid, additional, Roschger, Paul, additional, Taylan, Fulya, additional, Lindstrand, Anna, additional, Paschalis, Eleftherios P, additional, Gamsjaeger, Sonja, additional, Raas-Rothschild, Annick, additional, Hövel, Matthias, additional, Jiao, Hong, additional, Klaushofer, Klaus, additional, Grasemann, Corinna, additional, and Mäkitie, Outi, additional

Published
2017
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34. CRTAP variants in early-onset osteoporosis and recurrent fractures

Author

Costantini, Alice, primary, Vuorimies, Ilkka, additional, Mäkitie, Riikka, additional, Mäyränpää, Mervi K., additional, Becker, Jutta, additional, Pekkinen, Minna, additional, Valta, Helena, additional, Netzer, Christian, additional, Kämpe, Anders, additional, Taylan, Fulya, additional, Jiao, Hong, additional, and Mäkitie, Outi, additional

Published
2016
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35. Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum

Author

Taylan, Fulya, primary, Costantini, Alice, additional, Coles, Nicole, additional, Pekkinen, Minna, additional, Héon, Elise, additional, Şıklar, Zeynep, additional, Berberoğlu, Merih, additional, Kämpe, Anders, additional, Kıykım, Ertuğrul, additional, Grigelioniene, Giedre, additional, Tüysüz, Beyhan, additional, and Mäkitie, Outi, additional

Published
2016
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36. PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.

Author

Kämpe, Anders J, Costantini, Alice, Levy-shraga, Yael, Zeitlin, Leonid, Roschger, Paul, Taylan, Fulya, Lindstrand, Anna, Paschalis, Eleftherios P, Gamsjaeger, Sonja, Raas-Rothschild, Annick, Hövel, Matthias, Jiao, Hong, Klaushofer, Klaus, Grasemann, Corinna, and Mäkitie, Outi

Abstract

ABSTRACT Mutations in the PLS3 gene, encoding Plastin 3, were described in 2013 as a cause for X-linked primary bone fragility in children. The specific role of PLS3 in bone metabolism remains inadequately understood. Here we describe for the first time PLS3 deletions as the underlying cause for childhood-onset primary osteoporosis in 3 boys from 2 families. We carried out thorough clinical, radiological, and bone tissue analyses to explore the consequences of these deletions and to further elucidate the role of PLS3 in bone homeostasis. In family 1, the 2 affected brothers had a deletion of exons 4-16 (NM_005032) in PLS3, inherited from their healthy mother. In family 2, the index patient had a deletion involving the entire PLS3 gene (exons 1-16), inherited from his mother who had osteoporosis. The 3 patients presented in early childhood with severe spinal compression fractures involving all vertebral bodies. The 2 brothers in family 1 also displayed subtle dysmorphic facial features and both had developed a myopathic gait. Extensive analyses of a transiliac bone biopsy from 1 patient showed a prominent increase in osteoid volume, osteoid thickness, and in mineralizing lag time. Results from quantitative backscattered electron imaging and Raman microspectroscopy showed a significant hypomineralization of the bone. Together our results indicate that PLS3 deletions lead to severe childhood-onset osteoporosis resulting from defective bone matrix mineralization, suggesting a specific role for PLS3 in the mineralization process. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Published
2017
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38. A novel frameshift deletion in PLS3causing severe primary osteoporosis

Author

Costantini, Alice, Krallis, Panagiotis Ν., Kämpe, Anders, Karavitakis, Emmanouil M., Taylan, Fulya, Mäkitie, Outi, and Doulgeraki, Artemis

Abstract

Mutations in the gene encoding plastin-3, PLS3, have recently been associated to severe primary osteoporosis. The molecular function of plastin-3 is not fully understood. Since PLS3is located on the X chromosome, males are usually more severely affected than females. PLS3mutations have thus far been reported in approximately 20 young patients with low bone mineral density (BMD). We describe an 8-year-old Greek boy with severe primary osteoporosis with multiple vertebral compression fractures and one low-energy long bone fracture. His clinical manifestations were consistent with osteogenesis imperfecta, including blue sclerae, joint hypermobility, low bone mineral density, kyphosis, bilateral conductive hearing loss, and mild dysmorphic features. The family history was negative for primary osteoporosis. COL1A1and COL1A2mutations were excluded by Sanger sequencing. However, Sanger sequencing of PLS3led to the identification of a de novo frameshift deletion, NM_005032: c.1096_1100delAACTT, p.(Asn366Serfs*5), in exon 10 confirming the diagnosis of PLS3 osteoporosis. In conclusion, we describe a novel frameshift deletion in PLS3causing severe primary osteoporosis in a boy. Our finding highlights the clinical overlap between type I collagen and PLS3-related skeletal fragility and underscores the importance of PLS3screening in patients with multiple fractures to enable proper genetic counseling.

Published
2018
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39. Integrating a Polygenic Risk Score into a clinical setting would impact risk predictions in familial breast cancer.

Author

Baliakas P, Munters AR, Kämpe A, Tesi B, Bondeson ML, Ladenvall C, and Eriksson D

Subjects
Humans, Female, Genetic Predisposition to Disease, Genetic Risk Score, Genetic Testing, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Breast Neoplasms diagnosis
Abstract

Background: Low-impact genetic variants identified in population-based genetic studies are not routinely measured as part of clinical genetic testing in familial breast cancer (BC). We studied the consequences of integrating an established Polygenic Risk Score (PRS) (BCAC 313, PRS 313 ) into clinical sequencing of women with familial BC in Sweden., Methods: We developed an add-on sequencing panel to capture 313 risk variants in addition to the clinical screening of hereditary BC genes. Index patients with no pathogenic variant from 87 families, and 1000 population controls, were included in comparative PRS calculations. Including detailed family history, sequencing results and tumour pathology information, we used BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.6 to estimate contralateral and lifetime risks without and with PRS 313 ., Results: Women with BC but no pathogenic variants in hereditary BC genes have a higher PRS 313 compared with population controls (mean+0.78 SD, p<3e-9). Implementing PRS 313 in the clinical risk estimation before their BC diagnosis would have changed the recommended follow-up in 24%-45% of women., Conclusions: Our results show the potential impact of incorporating PRS 313 directly in the clinical genomic investigation of women with familial BC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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