49 results on '"Nick Bass"'
Search Results
2. Investigating the association between schizophrenia and distance visual acuity: Mendelian randomisation study
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Natalie Shoham, Diana Dunca, Claudia Cooper, Joseph F. Hayes, Andrew McQuillin, Nick Bass, Gemma Lewis, and Karoline Kuchenbaecker
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Psychiatric epidemiology ,visual impairment ,schizophrenia ,psychosis ,Mendelian randomisation ,Psychiatry ,RC435-571 - Abstract
Background Increased rates of visual impairment are observed in people with schizophrenia. Aims We assessed whether genetically predicted poor distance acuity is causally associated with schizophrenia, and whether genetically predicted schizophrenia is causally associated with poorer visual acuity. Method We used bidirectional, two-sample Mendelian randomisation to assess the effect of poor distance acuity on schizophrenia risk, poorer visual acuity on schizophrenia risk and schizophrenia on visual acuity, in European and East Asian ancestry samples ranging from approximately 14 000 to 500 000 participants. Genetic instrumental variables were obtained from the largest available summary statistics: for schizophrenia, from the Psychiatric Genomics Consortium; for visual acuity, from the UK Biobank; and for poor distance acuity, from a meta-analysis of case–control samples. We used the inverse variance-weighted method and sensitivity analyses to test validity of results. Results We found little evidence that poor distance acuity was causally associated with schizophrenia (odds ratio 1.00, 95% CI 0.91–1.10). Genetically predicted schizophrenia was associated with poorer visual acuity (mean difference in logMAR score: 0.024, 95% CI 0.014–0.033) in European ancestry samples, with a similar but less precise effect that in smaller East Asian ancestry samples (mean difference: 0.186, 95% CI –0.008 to 0.379). Conclusions Genetic evidence supports schizophrenia being a causal risk factor for poorer visual acuity, but not the converse. This highlights the importance of visual care for people with psychosis and refutes previous hypotheses that visual impairment is a potential target for prevention of schizophrenia.
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- 2023
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3. Genetic risk scores and dementia risk across different ethnic groups in UK Biobank.
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Naaheed Mukadam, Olga Giannakopoulou, Nick Bass, Karoline Kuchenbaecker, and Andrew McQuillin
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Medicine ,Science - Abstract
BackgroundGenetic Risk Scores (GRS) for predicting dementia risk have mostly been used in people of European ancestry with limited testing in other ancestry groups.MethodsWe conducted a logistic regression with all-cause dementia as the outcome and z-standardised GRS as the exposure across diverse ethnic groups.FindingsThere was variation in frequency of APOE alleles across ethnic groups. Per standard deviation (SD) increase in z-GRS including APOE, the odds ratio (OR) for dementia was 1.73 (95%CI 1.69-1.77). Z-GRS excluding APOE also increased dementia risk (OR 1.21 per SD increase, 95% CI 1.18-1.24) and there was no evidence that ethnicity modified this association. Prediction of secondary outcomes was less robust in those not of European ancestry when APOE was excluded from the GRS.Interpretationz-GRS derived from studies in people of European ancestry can be used to quantify genetic risk in people from more diverse ancestry groups. Urgent work is needed to include people from diverse ancestries in future genetic risk studies to make this field more inclusive.
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- 2022
- Full Text
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4. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
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Eilis Hannon, Emma L Dempster, Georgina Mansell, Joe Burrage, Nick Bass, Marc M Bohlken, Aiden Corvin, Charles J Curtis, David Dempster, Marta Di Forti, Timothy G Dinan, Gary Donohoe, Fiona Gaughran, Michael Gill, Amy Gillespie, Cerisse Gunasinghe, Hilleke E Hulshoff, Christina M Hultman, Viktoria Johansson, René S Kahn, Jaakko Kaprio, Gunter Kenis, Kaarina Kowalec, James MacCabe, Colm McDonald, Andrew McQuillin, Derek W Morris, Kieran C Murphy, Colette J Mustard, Igor Nenadic, Michael C O'Donovan, Diego Quattrone, Alexander L Richards, Bart PF Rutten, David St Clair, Sebastian Therman, Timothea Toulopoulou, Jim Van Os, John L Waddington, Wellcome Trust Case Control Consortium (WTCCC), CRESTAR consortium, Patrick Sullivan, Evangelos Vassos, Gerome Breen, David Andrew Collier, Robin M Murray, Leonard S Schalkwyk, and Jonathan Mill
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epigenetics ,DNA methylation ,psychosis ,schizophrenia ,clozapine ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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- 2021
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5. The role of thyroid function in borderline personality disorder and schizophrenia: a Mendelian Randomisation study
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Babajide, Oladapo, Kjaergaard, Alisa D., Deng, Weichen, Kuś, Aleksander, Sterenborg, Rosalie B. T. M., Åsvold, Bjørn Olav, Burgess, Stephen, Teumer, Alexander, Medici, Marco, Ellervik, Christina, Nick, Bass, Deloukas, Panos, and Marouli, Eirini
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- 2024
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6. The role of thyroid function in borderline personality disorder and schizophrenia:a Mendelian Randomisation study
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Babajide, Oladapo, Kjaergaard, Alisa D., Deng, Weichen, Kuś, Aleksander, Sterenborg, Rosalie B.T.M., Åsvold, Bjørn Olav, Burgess, Stephen, Teumer, Alexander, Medici, Marco, Ellervik, Christina, Nick, Bass, Deloukas, Panos, Marouli, Eirini, Babajide, Oladapo, Kjaergaard, Alisa D., Deng, Weichen, Kuś, Aleksander, Sterenborg, Rosalie B.T.M., Åsvold, Bjørn Olav, Burgess, Stephen, Teumer, Alexander, Medici, Marco, Ellervik, Christina, Nick, Bass, Deloukas, Panos, and Marouli, Eirini
- Abstract
Background Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ. Methods We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association. Results Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function. Conclusions We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality., Background: Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ. Methods: We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association. Results: Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function. Conclusions: We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality.
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- 2024
7. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia
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Duncan S. Palmer, Daniel P. Howrigan, Sinéad B. Chapman, Rolf Adolfsson, Nick Bass, Douglas Blackwood, Marco P. M. Boks, Chia-Yen Chen, Claire Churchhouse, Aiden P. Corvin, Nicholas Craddock, David Curtis, Arianna Di Florio, Faith Dickerson, Nelson B. Freimer, Fernando S. Goes, Xiaoming Jia, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, Mikael Landén, Adam E. Locke, Andrew M. McIntosh, Andrew McQuillin, Derek W. Morris, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Nancy L. Pedersen, Danielle Posthuma, Andreas Reif, Neil Risch, Catherine Schaefer, Laura Scott, Tarjinder Singh, Jordan W. Smoller, Matthew Solomonson, David St. Clair, Eli A. Stahl, Annabel Vreeker, James T. R. Walters, Weiqing Wang, Nicholas A. Watts, Robert Yolken, Peter P. Zandi, Benjamin M. Neale, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Child and Adolescent Psychiatry / Psychology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, and Amsterdam Reproduction & Development (AR&D)
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Bipolar Disorder ,Human Genome ,A Kinase Anchor Proteins ,Biological Sciences ,Serious Mental Illness ,Medical and Health Sciences ,Article ,Brain Disorders ,Mental Health ,SDG 3 - Good Health and Well-being ,Clinical Research ,Exome Sequencing ,Schizophrenia ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Genetic Predisposition to Disease ,Exome ,Aetiology ,Genome-Wide Association Study ,Biotechnology ,Developmental Biology - Abstract
We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10−9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.
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- 2022
8. New insights into the genetic etiology of Alzheimer's disease and related dementias
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Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. A., Piñol-Ripoll, G., Pisanu, C., Polak, T., Popp, J., Posthuma, D., Priller, J., Puerta, R., Quenez, O., Quintela, I., Thomassen, J. Q., Rábano, A., Rainero, I., Rajabli, F., Ramakers, I., Real, L. M., Reinders, M. J. T., Reitz, C., Reyes-Dumeyer, D., Ridge, P., Riedel-Heller, S., Riederer, P., Roberto, N., Rodriguez-Rodriguez, E., Rongve, A., Allende, I. R., Rosende-Roca, M., Royo, J. L., Rubino, E., Rujescu, D., Sáez, M. E., Sakka, P., Saltvedt, I., Sanabria, Á., Sánchez-Arjona, M. B., Sanchez-Garcia, F., Juan, P. S., Sánchez-Valle, R., Sando, S. B., Sarnowski, C., Satizabal, C. L., Scamosci, M., Scarmeas, N., Scarpini, E., Scheltens, P., Scherbaum, N., Scherer, M., Schmid, M., Schneider, A., Schott, J. M., Selbæk, G., Seripa, D., Serrano, M., Sha, J., Shadrin, A. A., Skrobot, O., Slifer, S., Snijders, G. J. L., Soininen, H., Solfrizzi, V., Solomon, A., Song, Y. E., Sorbi, S., Sotolongo-Grau, O., Spalletta, G., Spottke, A., Squassina, A., Stordal, E., Tartan, J. P., Tárraga, L., Tesí, N., Thalamuthu, A., Thomas, T., Tosto, G., Traykov, L., Tremolizzo, L., Tybjærg-Hansen, A., Uitterlinden, A., Ullgren, A., Ulstein, I., Valero, S., Valladares, O., Broeckhoven, C. V., Vance, J., Vardarajan, B. N., van der Lugt, A., Dongen, J. V., van Rooij, J., van Swieten, J., Vandenberghe, R., Verhey, F., Vidal, J. -S., Vogelgsang, J., Vyhnalek, M., Wagner, M., Wallon, D., Wang, L. -S., Wang, R., Weinhold, L., Wiltfang, J., Windle, G., Woods, B., Yannakoulia, M., Zare, H., Zhao, Y., Zhang, X., Zhu, C., Zulaica, M., Laczo, J., Matoska, V., Serpente, M., Assogna, F., Piras, F., Ciullo, V., Shofany, J., Ferrarese, C., Andreoni, S., Sala, G., Zoia, C. P., Zompo, M. D., Benussi, A., Bastiani, P., Takalo, M., Natunen, T., Laatikainen, T., Tuomilehto, J., Antikainen, R., Strandberg, T., Lindström, J., Peltonen, M., Abraham, R., Al-Chalabi, A., Bass, N. J., Brayne, C., Brown, K. S., Collinge, J., Craig, D., Deloukas, P., Fox, N., Gerrish, A., Gill, M., Gwilliam, R., Harold, D., Hollingworth, P., Johnston, J. A., Jones, L., Lawlor, B., Livingston, G., Lovestone, S., Lupton, M., Lynch, A., Mann, D., Mcguinness, B., Mcquillin, A., O’Donovan, M. C., Owen, M. J., Passmore, P., Powell, J. F., Proitsi, P., Rossor, M., Shaw, C. E., Smith, A. D., Gurling, H., Todd, S., Mummery, C., Ryan, N., Lacidogna, G., Adarmes-Gómez, A., Mauleón, A., Pancho, A., Gailhajenet, A., Lafuente, A., Macias-García, D., Martín, E., Pelejà, E., Carrillo, F., Merlín, I. S., Garrote-Espina, L., Vargas, L., Carrion-Claro, M., Marín, M., Labrador, M., Buendia, M., Alonso, M. D., Guitart, M., Moreno, M., Ibarria, M., Periñán, M., Aguilera, N., Gómez-Garre, P., Cañabate, P., Escuela, R., Pineda-Sánchez, R., Vigo-Ortega, R., Jesús, S., Preckler, S., Rodrigo-Herrero, S., Diego, S., Vacca, A., Roveta, F., Salvadori, N., Chipi, E., Boecker, H., Laske, C., Perneczky, R., Anastasiou, C., Janowitz, D., Malik, R., Anastasiou, A., Parveen, K., López-García, S., Antonell, A., Mihova, K. Y., Belezhanska, D., Weber, H., Kochen, S., Solis, P., Medel, N., Lisso, J., Sevillano, Z., Politis, D. G., Cores, V., Cuesta, C., Ortiz, C., Bacha, J. I., Rios, M., Saenz, A., Abalos, M. S., Kohler, E., Palacio, D. L., Etchepareborda, I., Kohler, M., Novack, G., Prestia, F. A., Galeano, P., Castaño, E. M., Germani, S., Toso, C. R., Rojo, M., Ingino, C., Mangone, C., Rubinsztein, D. C., Teipel, S., Fievet, N., Deramerourt, V., Forsell, C., Thonberg, H., Bjerke, M., Roeck, E. D., Martínez-Larrad, M. T., Olivar, N., Cano, A., Macias, J., Maroñas, O., Nuñez-Llaves, R., Olivé, C., Adarmes-Gómez, A. D., Amer-Ferrer, G., Antequera, M., Burguera, J. A., Casajeros, M. J., Martinez de Pancorbo, M., Hevilla, S., Espinosa, M. A. L., Legaz, A., Manzanares, S., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, V., Martínez-Lage Álvarez, P., Iriarte, M. M., Periñán-Tocino, M. T., Real de Asúa, D., Rodrigo, S., Sastre, I., Vicente, M. P., Vivancos, L., Epelbaum, J., Hannequin, D., Campion, D., Deramecourt, V., Tzourio, C., Brice, A., Dubois, B., Williams, A., Thomas, C., Davies, C., Nash, W., Dowzell, K., Morales, A. C., Bernardo-Harrington, M., Turton, J., Lord, J., Brown, K., Vardy, E., Fisher, E., Warren, J. D., Ryan, N. S., Guerreiro, R., Uphill, J., Bass, N., Heun, R., Kölsch, H., Schürmann, B., Lacour, A., Herold, C., Powell, J., Patel, Y., Hodges, A., Becker, T., Warden, D., Wilcock, G., Clarke, R., Ben-Shlomo, Y., Hooper, N. M., Pickering-Brown, S., Sussams, R., Warner, N., Bayer, A., Heuser, I., Drichel, D., Klopp, N., Mayhaus, M., Riemenschneider, M., Pinchler, S., Feulner, T., Gu, W., van den Bussche, H., Hüll, M., Frölich, L., Wichmann, H. -E., Jöckel, K. -H., O’Donovan, M., Owen, M., Bahrami, S., Bosnes, I., Selnes, P., Bergh, S., Palotie, A., Daly, M., Jacob, H., Matakidou, A., Runz, H., John, S., Plenge, R., Mccarthy, M., Hunkapiller, J., Ehm, M., Waterworth, D., Fox, C., Malarstig, A., Klinger, K., Call, K., Behrens, T., Loerch, P., Mäkelä, T., Kaprio, J., Virolainen, P., Pulkki, K., Kilpi, T., Perola, M., Partanen, J., Pitkäranta, A., Kaarteenaho, R., Vainio, S., Turpeinen, M., Serpi, R., Laitinen, T., Mäkelä, J., Kosma, V. -M., Kujala, U., Tuovila, O., Hendolin, M., Pakkanen, R., Waring, J., Riley-Gillis, B., Liu, J., Biswas, S., Diogo, D., Marshall, C., Hu, X., Gossel, M., Graham, R., Cummings, B., Ripatti, S., Schleutker, J., Arvas, M., Carpén, O., Hinttala, R., Kettunen, J., Mannermaa, A., Laukkanen, J., Julkunen, V., Remes, A., Kälviäinen, R., Peltola, J., Tienari, P., Rinne, J., Ziemann, A., Esmaeeli, S., Smaoui, N., Lehtonen, A., Eaton, S., Lahdenperä, S., van Adelsberg, J., Michon, J., Kerchner, G., Bowers, N., Teng, E., Eicher, J., Mehta, V., Gormley, P., Linden, K., Whelan, C., Xu, F., Pulford, D., Färkkilä, M., Pikkarainen, S., Jussila, A., Blomster, T., Kiviniemi, M., Voutilainen, M., Georgantas, B., Heap, G., Rahimov, F., Usiskin, K., Lu, T., Oh, D., Kalpala, K., Miller, M., Mccarthy, L., Eklund, K., Palomäki, A., Isomäki, P., Pirilä, L., Kaipiainen-Seppänen, O., Huhtakangas, J., Lertratanakul, A., Hochfeld, M., Bing, N., Gordillo, J. E., Mars, N., Pelkonen, M., Kauppi, P., Kankaanranta, H., Harju, T., Close, D., Greenberg, S., Chen, H., Betts, J., Ghosh, S., Salomaa, V., Niiranen, T., Juonala, M., Metsärinne, K., Kähönen, M., Junttila, J., Laakso, M., Pihlajamäki, J., Sinisalo, J., Taskinen, M. -R., Tuomi, T., Challis, B., Peterson, A., Chu, A., Parkkinen, J., Muslin, A., Joensuu, H., Meretoja, T., Aaltonen, L., Mattson, J., Auranen, A., Karihtala, P., Kauppila, S., Auvinen, P., Elenius, K., Popovic, R., Schutzman, J., Loboda, A., Chhibber, A., Lehtonen, H., Mcdonough, S., Crohns, M., Kulkarni, D., Kaarniranta, K., Turunen, J. A., Ollila, T., Seitsonen, S., Uusitalo, H., Aaltonen, V., Uusitalo-Järvinen, H., Luodonpää, M., Hautala, N., Loomis, S., Strauss, E., Podgornaia, A., Hoffman, J., Tasanen, K., Huilaja, L., Hannula-Jouppi, K., Salmi, T., Peltonen, S., Koulu, L., Harvima, I., Wu, Y., Choy, D., Pussinen, P., Salminen, A., Salo, T., Rice, D., Nieminen, P., Palotie, U., Siponen, M., Suominen, L., Mäntylä, P., Gursoy, U., Anttonen, V., Sipilä, K., Davis, J. W., Quarless, D., Petrovski, S., Wigmore, E., Chen, C. -Y., Bronson, P., Tsai, E., Huang, Y., Maranville, J., Shaikho, E., Mohammed, E., Wadhawan, S., Kvikstad, E., Caliskan, M., Chang, D., Bhangale, T., Pendergrass, S., Holzinger, E., Chen, X., Hedman, Å., King, K. 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Kathleen, A Welsh-Bohmer, Patrice, L Whitehead, Ellen, M Wijsman, Kirk, C Wilhelmsen, Benjamin, Williams, Jennifer, Williamson, Henrik, Wilms, Thomas, S Wingo, Thomas, Wisniewski, Randall, L Woltjer, Martin, Woon, Clinton, B Wright, Chuang-Kuo, Wu, Steven, G Younkin, Chang-En, Yu, Lei, Yu, Yuanchao, Zhang, Zhao, Yi, Xiongwei, Zhu, Hieab, Adams, Rufus, O Akinyemi, Muhammad, Ali, Nicola, Armstrong, Hugo, J Aparicio, Maryam, Bahadori, Monique, Breteler, Daniel, Chasman, Ganesh, Chauhan, Hata, Comic, Simon, Cox, Adrienne, L Cupples, Gail, Davies, Charles, S DeCarli, Marie-Gabrielle, Duperron, Josée, Dupuis, Tavia, Evans, Frank, Fan, Annette, Fitzpatrick, Alison, E Fohner, Mary, Ganguli, Mirjam, Geerlings, Stephen, J Glatt, Hector, M Gonzalez, Monica, Goss, Hans, Grabe, Mohamad, Habes, Susan, R Heckbert, Edith, Hofer, Elliot, Hong, Timothy, Hughes, Tiffany, F Kautz, Maria, Knol, William, Kremen, Paul, Lacaze, Jari, Lahti, Quentin Le Grand, Elizabeth, Litkowski, Shuo, Li, Dan, Liu, Xuan, Liu, Marisa, Loitfelder, Alisa, Manning, Pauline, Maillard, Riccardo, Marioni, Bernard, Mazoyer, Debora Melo van Lent, Hao, Mei, Aniket, Mishra, Paul, Nyquist, Jeffrey, O'Connell, Yash, Patel, Tomas, Paus, Zdenka, Pausova, Katri, Raikkonen-Talvitie, Moeen, Riaz, Stephen, Rich, Jerome, Rotter, Jose, Romero, Gena, Roshchupkin, Yasaman, Saba, Murali, Sargurupremraj, Helena, Schmidt, Reinhold, Schmidt, Joshua, M Shulman, Jennifer, Smith, Hema, Sekhar, Reddy, Rajula, Jean, Shin, Jeannette, Simino, Eeva, Sliz, Alexander, Teumer, Alvin, Thomas, Adrienne, Tin, Elliot, Tucker-Drob, Dina, Vojinovic, Yanbing, Wang, Galit, Weinstein, Dylan, Williams, Katharina, Wittfeld, Lisa, Yanek, Yunju, Yang, Bellenguez, C, Küçükali, F, Jansen, I, Kleineidam, L, Moreno-Grau, S, Amin, N, Naj, A, Campos-Martin, R, Grenier-Boley, B, Andrade, V, Holmans, P, Boland, A, Damotte, V, van der Lee, S, Costa, M, Kuulasmaa, T, Yang, Q, de Rojas, I, Bis, J, Yaqub, A, Prokic, I, Chapuis, J, Ahmad, S, Giedraitis, V, Aarsland, D, Garcia-Gonzalez, P, Abdelnour, C, Alarcón-Martín, E, Alcolea, D, Alegret, M, Alvarez, I, Álvarez, V, Armstrong, N, Tsolaki, A, Antúnez, C, Appollonio, I, Arcaro, M, Archetti, S, Pastor, A, Arosio, B, Athanasiu, L, Bailly, H, Banaj, N, Baquero, M, Barral, S, Beiser, A, Below, J, Benchek, P, Benussi, L, Berr, C, Besse, C, Bessi, V, Binetti, G, Bizarro, A, Blesa, R, Boada, M, Boerwinkle, E, Borroni, B, Boschi, S, Bossù, P, Bråthen, G, Bressler, J, Bresner, C, Brodaty, H, Brookes, K, Brusco, L, Buiza-Rueda, D, Bûrger, K, Burholt, V, Bush, W, Calero, M, Cantwell, L, Chene, G, Chung, J, Cuccaro, M, Carracedo, Á, Cecchetti, R, Cervera-Carles, L, Charbonnier, C, Chen, H, Chillotti, C, Ciccone, S, Claassen, J, Clark, C, Conti, E, Corma-Gómez, A, Costantini, E, Custodero, C, Daian, D, Dalmasso, M, Daniele, A, Dardiotis, E, Dartigues, J, de Deyn, P, de Paiva Lopes, K, de Witte, L, Debette, S, Deckert, J, Del Ser, T, Denning, N, Destefano, A, Dichgans, M, Diehl-Schmid, J, Diez-Fairen, M, Rossi, P, Djurovic, S, Duron, E, Düzel, E, Dufouil, C, Eiriksdottir, G, Engelborghs, S, Escott-Price, V, Espinosa, A, Ewers, M, Faber, K, Fabrizio, T, Nielsen, S, Fardo, D, Farotti, L, Fenoglio, C, Fernández-Fuertes, M, Ferrari, R, Ferreira, C, Ferri, E, Fin, B, Fischer, P, Fladby, T, Fließbach, K, Fongang, B, Fornage, M, Fortea, J, Foroud, T, Fostinelli, S, Fox, N, Franco-Macías, E, Bullido, M, Frank-García, A, Froelich, L, Fulton-Howard, B, Galimberti, D, García-Alberca, J, García-González, P, Garcia-Madrona, S, Garcia-Ribas, G, Ghidoni, R, Giegling, I, Giorgio, G, Goate, A, Goldhardt, O, Gomez-Fonseca, D, González-Pérez, A, Graff, C, Grande, G, Green, E, Grimmer, T, Grünblatt, E, Grunin, M, Gudnason, V, Guetta-Baranes, T, Haapasalo, A, Hadjigeorgiou, G, Haines, J, Hamilton-Nelson, K, Hampel, H, Hanon, O, Hardy, J, Hartmann, A, Hausner, L, Harwood, J, Heilmann-Heimbach, S, Helisalmi, S, Heneka, M, Hernández, I, Herrmann, M, Hoffmann, P, Holmes, C, Holstege, H, Vilas, R, Hulsman, M, Humphrey, J, Biessels, G, Jian, X, Johansson, C, Jun, G, Kastumata, Y, Kauwe, J, Kehoe, P, Kilander, L, Ståhlbom, A, Kivipelto, M, Koivisto, A, Kornhuber, J, Kosmidis, M, Kukull, W, Kuksa, P, Kunkle, B, Kuzma, A, Lage, C, Laukka, E, Launer, L, Lauria, A, Lee, C, Lehtisalo, J, Lerch, O, Lleó, A, Longstreth, W, Lopez, O, de Munain, A, Love, S, Löwemark, M, Luckcuck, L, Lunetta, K, Ma, Y, Macías, J, Macleod, C, Maier, W, Mangialasche, F, Spallazzi, M, Marquié, M, Marshall, R, Martin, E, Montes, A, Rodríguez, C, Masullo, C, Mayeux, R, Mead, S, Mecocci, P, Medina, M, Meggy, A, Mehrabian, S, Mendoza, S, Menéndez-González, M, Mir, P, Moebus, S, Mol, M, Molina-Porcel, L, Montrreal, L, Morelli, L, Moreno, F, Morgan, K, Mosley, T, Nöthen, M, Muchnik, C, Mukherjee, S, Nacmias, B, Ngandu, T, Nicolas, G, Nordestgaard, B, Olaso, R, Orellana, A, Orsini, M, Ortega, G, Padovani, A, Paolo, C, Papenberg, G, Parnetti, L, Pasquier, F, Pastor, P, Peloso, G, Pérez-Cordón, A, Pérez-Tur, J, Pericard, P, Peters, O, Pijnenburg, Y, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, Tárraga, L, Tesí, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Broeckhoven, C, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael 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[0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A 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Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
- Subjects
tau Proteins/genetics ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurologi ,MED/03 - GENETICA MEDICA ,45/43 ,Medizin ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,genetics [Alzheimer Disease] ,Genome-Wide Association Study ,Humans ,tau Proteins ,Alzheimer Disease ,Cognitive Dysfunction ,VARIANTS ,pathology [Alzheimer Disease] ,Tau Proteins ,Settore BIO/13 - Biologia Applicata ,Cognitive Dysfunction/psychology ,692/699/375/365/1283 ,IMPUTATION ,article ,1184 Genetics, developmental biology, physiology ,Biología y Biomedicina / Biología ,AMYLOID-BETA ,Settore MED/26 - NEUROLOGIA ,Neurology ,psychology [Cognitive Dysfunction] ,Medical Genetics ,Human ,Neuroscience(all) ,631/208/205/2138 ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,ddc:570 ,Genetics ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Medicinsk genetik ,MED/26 - NEUROLOGIA ,Alzheimer Disease/genetics ,neurology ,tau Protein ,NECROSIS-FACTOR-ALPHA ,RISK LOCI ,genetics [tau Proteins] ,PREDICTION MODELS ,Human medicine ,GENERATION ,RESPONSES - Abstract
25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
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- 2022
9. The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce: Randomised Controlled Trial
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Michaela Poppe, Larisa Duffy, Natalie Marchant, Julie Barber, Rachael Hunter, Nick Bass, Annemarie Minihane, Kate Walters, Paul Higgs, Penny Rapaport, Iain Lang, Sarah Morgan-Trimmer, Jonathan Huntley, Zuzana Walker, Henry Brodaty, Helen Kales, Karen Ritchie, Alexandra Burton, Jennifer Wenborn, Anna Betz, and Claudia Cooper
- Abstract
Background Largescale trials of multi-domain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over two years. Methods A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to Mild Cognitive Impairment (MCI) or Subjective Cognitive Decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE-Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term conditions self-management Two facilitators trained and supervised by a clinical psychologist deliver ten, one-hour group video call sessions over 6 months (approximately every fortnight), video-call “tea breaks” (less structured, facilitated social sessions) in intervening weeks, and individual goal-setting phone calls every two weeks. From 6–12 months, participants meet monthly for “tea breaks”, with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer, and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality adjusted life year (QALY), and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. Discussion If effective, the intervention design, involving remote delivery and non-clinical facilitators would facilitate intervention roll-out to older people with memory concerns. Trial registration: ISRCTN17325135. Registration date 27th November 2019. https://doi.org/10.1186/ISRCTN17325135
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- 2022
10. GENETIC LIABILITY FOR ADHD PREDICTS INCREASED RISK FOR SUBSTANCE ABUSE AND SUICIDE IN RAPID CYCLING BIPOLAR DISORDER
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Tracey van der Veen, Nick Bass, and Andrew McQuillin
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Pharmacology ,Psychiatry and Mental health ,Neurology ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Published
- 2022
11. Communication and understanding of mild cognitive impairment diagnoses
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Nick Bass, Jemima Dooley, Rose McCabe, Cate Bailey, and Penny Xanthopoulou
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understanding ,medicine.medical_specialty ,diagnosis ,BF ,03 medical and health sciences ,mild cognitive impairment ,0302 clinical medicine ,mental disorders ,medicine ,Humans ,Dementia ,Cognitive Dysfunction ,Stage (cooking) ,Medical diagnosis ,Psychiatry ,Cognitive impairment ,Association (psychology) ,vascular cognitive impairment ,030214 geriatrics ,communication ,business.industry ,Communication ,Prognosis ,medicine.disease ,Psychiatry and Mental health ,Increased risk ,Conversation analysis ,Ageing ,Disease Progression ,RC0321 ,prognosis ,Geriatrics and Gerontology ,business - Abstract
BackgroundCommunication of mild cognitive impairment (MCI) diagnoses is challenging due to its heterogeneity and unclear prognosis.AimTo identify how MCI is communicated and to explore the relationship with patient and companion understanding.MethodConversation analysis identified whether MCI was named and explained in 43 video recorded diagnosis feedback meetings. Afterward, patients and companions were asked to name the diagnosis to assess understanding.ResultsMild cognitive impairment was not named in 21% meetings. Symptoms were explained as (a) a result of vascular conditions (49%), (b) a stage between normal ageing and dementia (30%), or (c) caused by psychological factors (21%). Fifty‐four percentage of prognosis discussions included mention of dementia. There was no association between symptom explanations and whether prognosis discussions included dementia. Fifty‐seven percentage patients and 37% companions reported not having or not knowing their diagnosis after the meeting. They were more likely to report MCI when prognosis discussions included dementia.ConclusionsDoctors offer three different explanations of MCI to patients. The increased risk of dementia was not discussed in half the diagnostic feedback meetings. This is likely to reflect the heterogeneity in the definition, cause and likely prognosis of MCI presentations. Clearer and more consistent communication, particularly about the increased risk of dementia, may increase patient understanding and enable lifestyle changes to prevent some people progressing to dementia.
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- 2020
12. SCHIZOPHRENIA SNP-SET WAVE3 (2022) PREDICTS PSYCHOSIS, AGE OF ONSET AND AGE OF ONSET OF FIRST DEPRESSIVE EPISODE IN BIPOLAR I DISORDER
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Maria Grigoroiu-Serbanescu, Tim Bigdeli, Stefan Herms, Carmen C. Diaconu, Ana Iulia Neagu, Tracey van der Veen, Nick Bass, Markus M. Nöthen, Andreas J. Forstner, and Andrew McQuillin
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Pharmacology ,Psychiatry and Mental health ,Neurology ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Published
- 2022
13. Longitudinal association of apolipoprotein E and sleep with incident dementia
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Eleni Palpatzis, Naaheed Mukadam, Nick Bass, and Rebecca M. Jones
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Apolipoprotein E ,Adult ,Sleep Wake Disorders ,medicine.medical_specialty ,Epidemiology ,Cellular and Molecular Neuroscience ,Apolipoproteins E ,Developmental Neuroscience ,Risk Factors ,Internal medicine ,medicine ,Insomnia ,Dementia ,Humans ,Longitudinal Studies ,Association (psychology) ,business.industry ,Proportional hazards model ,Health Policy ,Hazard ratio ,Middle Aged ,medicine.disease ,Sleep in non-human animals ,Confidence interval ,Psychiatry and Mental health ,Neurology (clinical) ,Geriatrics and Gerontology ,medicine.symptom ,business ,Sleep - Abstract
Introduction Few longitudinal studies have explored the association between apolipoprotein E gene (APOE) status, sleep disturbances, and incident dementia among middle-aged participants. Methods Cox regression analyses explored the association of sleep duration, insomnia, and daytime napping with incident all-cause dementia and their interaction with APOE genetic risk among 397,777 middle-aged adults. Results During a median of 10.8 years follow-up, sleeping more or fewer than 7 hours was associated with a higher dementia risk (hazard ratio [HR] for 5 vs 7 hours: 1.35, 95% confidence interval [CI] 1.11-1.64; HR for 9 vs 7 hours: 1.59; 95% CI 1.37-1.85) as was daytime napping (HR for often/all of the time vs never/rarely: 1.67; 95% CI 1.37-2.03). Stratified analyses revealed that the effects of sleep disturbances were similar across all APOE genetic risk groups. Discussion Short and long sleep duration and daytime napping in middle-aged individuals are associated with the development of dementia in later life. Sleep duration and quality are important for everyone regardless of their genetic risk by APOE genotype.
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- 2021
14. Patient and companion shared decision making and satisfaction with decisions about starting cholinesterase medication at dementia diagnosis
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Jemima Dooley, Nick Bass, Penny Xanthopoulou, Rose McCabe, Hana Pavlickova, and Gill Livingston
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Adult ,Male ,Aging ,medicine.medical_specialty ,shared decision making ,Emotions ,older people ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Physicians ,medicine ,Humans ,Dementia ,Dementia diagnosis ,030212 general & internal medicine ,Cognitive skill ,Medical diagnosis ,Referral and Consultation ,Aged ,Aged, 80 and over ,Physician-Patient Relations ,030214 geriatrics ,communication ,business.industry ,Memory clinic ,satisfaction ,General Medicine ,Middle Aged ,medicine.disease ,Confidence interval ,Patient Satisfaction ,Family medicine ,Scale (social sciences) ,RC0321 ,Female ,Cholinesterase Inhibitors ,Patient Participation ,Geriatrics and Gerontology ,business ,Alzheimer’s disease ,Decision Making, Shared ,Healthcare providers ,dementia ,RC - Abstract
Background there is little research on how people with dementia are involved in treatment decisions at diagnosis. Objective to measure shared decision making when starting cholinesterase inhibitors, investigate associations with contextual factors and explore satisfaction and experience of the diagnostic meeting. Setting nine UK memory clinics in two geographical locations. Subjects 74 people receiving dementia diagnoses (with 69 companions) and 21 doctors. Methods we video-recorded 74 memory clinic consultations and rated doctor-shared decision making behaviours using the Observing Patient Involvement in Decision Making scale (OPTION-5 scale). Patients and companions rated their satisfaction and experience. Mixed-effects regressions investigated involvement and (i) number people present, meeting length, capacity, cognitive functioning, diagnosis; and (ii) patient/companion satisfaction and consultation experience. Results mean consultation time was 26.7 min. Mean OPTION-5 score was 22.5/100 (Standard Deviation = 17.3). Doctors involved patients in decisions more often when patients had mixed dementia (β = 10.13, 95% confidence interval 1.25–19.0, P = 0.025) and in shorter meetings (β = −0.51, 95% CI −0.87 to −0.15, P = 0.006). Patient and companion satisfaction were high and not associated with whether doctors invited patient involvement. Half of patients and one-third companions were uncertain about the meeting outcome, experienced communication barriers and negative emotions. Conclusions consultations scored low on shared decision making, but were comparable to other settings and were not lower with more cognitively impaired patients. Negative patient and companion experiences reflect the importance of supporting healthcare providers to address patient and companion emotions and need for information.
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- 2019
15. Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia
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Matthew Solomonson, Michael Conlon O'Donovan, Nancy L. Pedersen, Faith Dickerson, Eli A. Stahl, Neil Risch, Catherine Schaefer, Laura J. Scott, René S. Kahn, Duncan S. Palmer, Derek W. Morris, Claire Churchhouse, Xiaoming Jia, James T.R. Walters, Andrew M. McIntosh, Chia-Yen Chen, Michael John Owen, Arianna Di Florio, Lina Jonsson, Benjamin M. Neale, Roel A. Ophoff, Annabel Vreeker, Tarjinder Singh, Douglas Blackwood, Nicholas John Craddock, Jordan W. Smoller, Ian Jones, Weiqing Wang, Peter P. Zandi, Marco P. Boks, Fernando S. Goes, Lisa Jones, Robert H. Yolken, Mikael Landén, David Curtis, Danielle Posthuma, Andreas Reif, David St Clair, Sinéad B. Chapman, Nicholas A. Watts, Rolf Adolfsson, Adam E. Locke, Aiden Corvin, Nick Bass, Daniel P. Howrigan, and Andrew McQuillin
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Genetics ,business.industry ,Schizophrenia ,Medicine ,Risk gene ,Genome-wide association study ,Bipolar disorder ,business ,medicine.disease ,Exome ,Gene ,GSK3B ,Exome sequencing - Abstract
Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA,AKAP11emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06,P= 2.83 × 10−9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.
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- 2021
16. Increasing the Reproducibility and Replicability of Supervised AI/ML in the Earth Systems Science by Leveraging Social Science Methods
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Christopher D. Wirz, Carly Sutter, Julie L. Demuth, Kirsten J. Mayer, William E. Chapman, Mariana Goodall Cains, Jacob Radford, Vanessa Przybylo, Aaron Evans, Thomas Martin, Lauriana C. Gaudet, Kara Sulia, Ann Bostrom, David John Gagne II, Nick Bassill, Andrea Schumacher, and Christopher Thorncroft
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artificial intelligence ,machine learning ,methodology ,interdisciplinary ,hand labeling ,Astronomy ,QB1-991 ,Geology ,QE1-996.5 - Abstract
Abstract Artificial intelligence (AI) and machine learning (ML) pose a challenge for achieving science that is both reproducible and replicable. The challenge is compounded in supervised models that depend on manually labeled training data, as they introduce additional decision‐making and processes that require thorough documentation and reporting. We address these limitations by providing an approach to hand labeling training data for supervised ML that integrates quantitative content analysis (QCA)—a method from social science research. The QCA approach provides a rigorous and well‐documented hand labeling procedure to improve the replicability and reproducibility of supervised ML applications in Earth systems science (ESS), as well as the ability to evaluate them. Specifically, the approach requires (a) the articulation and documentation of the exact decision‐making process used for assigning hand labels in a “codebook” and (b) an empirical evaluation of the reliability” of the hand labelers. In this paper, we outline the contributions of QCA to the field, along with an overview of the general approach. We then provide a case study to further demonstrate how this framework has and can be applied when developing supervised ML models for applications in ESS. With this approach, we provide an actionable path forward for addressing ethical considerations and goals outlined by recent AGU work on ML ethics in ESS.
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- 2024
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17. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
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Joe Burrage, Gerome Breen, Gunter Kenis, Jim van Os, Sebastian Therman, Christina M. Hultman, Bart P. F. Rutten, Gary Donohoe, Igor Nenadic, Michael Gill, Kaarina Kowalec, Robin M. Murray, Jaakko Kaprio, Marc M. Bohlken, Michael Conlon O'Donovan, Hilleke E Hulshoff, Fiona Gaughran, Evangelos Vassos, Timothea Toulopoulou, Leonard S. Schalkwyk, Charles Curtis, David St Clair, Cerisse Gunasinghe, John L. Waddington, Colm McDonald, Emma Dempster, Viktoria Johansson, Nick Bass, Patrick F. Sullivan, Eilis Hannon, Kieran C. Murphy, Amy Gillespie, Marta Di Forti, Georgina Mansell, Derek W. Morris, Alexander Richards, Colette J Mustard, Andrew McQuillin, David A. Collier, Timothy G. Dinan, Diego Quattrone, David Dempster, Aiden Corvin, James H. MacCabe, René S. Kahn, Jonathan Mill, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, MUMC+: MA Niet Med Staf Psychiatrie (9), MUMC+: MA Psychiatrie (3), Institute for Molecular Medicine Finland, Department of Public Health, University of Helsinki, and Toulopoulou, Timothea
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0301 basic medicine ,Male ,BLOOD ,HIGH-POTENCY CANNABIS ,Bioinformatics ,DISEASE ,Epigenome ,0302 clinical medicine ,WIDE ASSOCIATION ,genetics ,psychosis ,Biology (General) ,Clozapine ,Psychiatry ,RISK ,DNA methylation ,clozapine ,General Neuroscience ,General Medicine ,Middle Aged ,3. Good health ,TRAIT ,England ,Schizophrenia ,Meta-analysis ,Medicine ,Female ,HUMAN BRAIN-TISSUE ,BURDEN ,Medical Genetics ,Schizophrenia, Treatment-Resistant ,medicine.drug ,Research Article ,Human ,Adult ,Psychosis ,QH301-705.5 ,medicine.drug_class ,Science ,METHYLOMIC VARIATION ,Atypical antipsychotic ,General Biochemistry, Genetics and Molecular Biology ,Psykiatri ,03 medical and health sciences ,Young Adult ,mental disorders ,medicine ,genomics ,Humans ,Epigenetics ,human ,1ST-EPISODE PSYCHOSIS ,Genetic association ,Medicinsk genetik ,Aged ,Sweden ,General Immunology and Microbiology ,epigenetics ,business.industry ,Genetics and Genomics ,medicine.disease ,schizophrenia ,030104 developmental biology ,Psychotic Disorders ,Scotland ,3111 Biomedicine ,business ,Ireland ,030217 neurology & neurosurgery - Abstract
We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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- 2021
18. Distinct gene-set burden patterns underlie common generalized and focal epilepsies
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Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L Heinzen, Ryan S Dhindsa, Kate E Stanley, Gianpiero L Cavalleri, Hakon Hakonarson, Ingo Helbig, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M Sisodiya, Patrick Cossette, Chris Cotsapas, Peter DeJonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G Marson, Randy Stewart, Chantal Depondt, Dennis J Dlugos, Ingrid E Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M Regan, Susannah T Bellows, Costin Leu, Caitlin A Bennett, Esther M C Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J O'Brien, Marian Todaro, Hannah Stamberger, Danielle M Andrade, Tara R Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S Papacostas, Ioanna Kousiappa, George A Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S Reif, Susanne Knake, Wolfram S Kunz, Gábor Zsurka, Christian E Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas vanBaalen, Sarah vonSpiczak, Ulrich Stephani, Zaid Afawi, Amos D Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R Lemke, Ilona Krey, Yvonne G Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F Maisch, Bernhard J Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I Rees, Seo-Kyung Chung, William O Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R Johnson, Pauls Auce, Graeme J Sills, Larry W Baum, Pak C Sham, Stacey S Cherny, Colin H T Lui, Nina Barišić, Norman Delanty, Colin P Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G Sadleir, Chontelle King, Emily Mountier, Hande S Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R Shiedley, Catherine Shain, Russell J Buono, Thomas N Ferraro, Michael R Sperling, Warren Lo, Michael Privitera, Jacqueline A French, Steven Schachter, Ruben I Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L Helbig, Colin A Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T Pato, Carlos N Pato, Evelyn J Bromet, Celia Barreto Carvalho, Eric D Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S Lehrer, Dolores Malaspina, Stephen R Marder, Helena Medeiros, Christopher P Morley, Diana O Perkins, Janet L Sobell, Peter F Buckley, Fabio Macciardi, Mark H Rapaport, James A Knowles, Genomic Psychiatry Cohort, Ayman H Fanous, Steven A McCarroll, Namrata Gupta, Stacey B Gabriel, Mark J Daly, Eric S Lander, Daniel H Lowenstein, David B Goldstein, Samuel F Berkovic, Benjamin M Neale, Epi25 Collaborative, Koko M., Krause R., Sander T., Bobbili D.R., Nothnagel M., May P., Lerche H., Bisulli F., Tinuper P., Pippucci T., Abbott, Liam E., Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Tashman, Katherine, Korinthenberg, Rudolf, Brockmann, Knut, Kurlemann, Gerhard, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Cerrato, Felecia, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Singh, Tarjinder, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, Heyne, Henrike, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Byrnes, Andrea, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Churchhouse, Claire, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Watts, Nick, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, Hande S., Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Solomonson, Matthew, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Lal, Dennis, Kesim, Yesim, Özkara, Çigdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, Heinzen, Erin L., French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Dhindsa, Ryan S., Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Stanley, Kate E., Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Cavalleri, Gianpiero L., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Cohort, Genomic Psychiatry, Fanous, Ayman H., Hakonarson, Hakon, McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, DeJonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O'Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Feng, Yen-Chen Anne, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Howrigan, Daniel P., Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
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Exome sequencing ,Male ,Medicine (General) ,Neurology [D14] [Human health sciences] ,Gene-set ,Genome-wide association study ,Disease ,Biology ,Epileptogenesis ,General Biochemistry, Genetics and Molecular Biology ,Whole Exome Sequencing ,Epilepsy ,R5-920 ,medicine ,Missense mutation ,Humans ,Exome ,Genetic Predisposition to Disease ,Gene ,Genetic association ,Ultra-rare variant ,Genetics ,Neurologie [D14] [Sciences de la santé humaine] ,Burden analysis ,Genetic Variation ,General Medicine ,medicine.disease ,Ultra-rare variants ,Gene-sets ,Case-Control Studies ,Medicine ,epilepsy ,Epilepsy, Generalized ,Female ,Genetics & genetic processes [F10] [Life sciences] ,Epilepsies, Partial ,Human medicine ,Burden analysi ,Génétique & processus génétiques [F10] [Sciences du vivant] ,Case-Control Studie ,Research Paper ,Genome-Wide Association Study ,Human - Abstract
EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]
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- 2021
19. Author response: DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
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Robin M. Murray, Alexander Richards, Gerome Breen, Colette J Mustard, Jim van Os, Bart P. F. Rutten, Patrick Sullivan, David St Clair, David A. Collier, Marc M. Bohlken, Fiona Gaughran, Michael Conlon O'Donovan, John L. Waddington, Timothy G. Dinan, Diego Quattrone, Aiden Corvin, Joe Burrage, Michael Gill, Hilleke E Hulshoff, Jonathan Mill, Eilis Hannon, Nick Bass, Georgina Mansell, Gunter Kenis, Christina M. Hultman, Kieran C. Murphy, Evangelos Vassos, Kaarina Kowalec, Sebastian Therman, Charles Curtis, Andrew McQuillin, Leonard S. Schalkwyk, Gary Donohoe, David Dempster, Amy Gillespie, Marta Di Forti, James H. MacCabe, René S. Kahn, Timothea Toulopoulou, Emma Dempster, Igor Nenadic, Cerisse Gunasinghe, Colm McDonald, Viktoria Johansson, Derek W. Morris, and Jaakko Kaprio
- Subjects
Psychosis ,business.industry ,Meta-analysis ,DNA methylation ,Medicine ,Treatment resistant schizophrenia ,business ,Bioinformatics ,medicine.disease - Published
- 2020
20. Patient and companion concerns when receiving a dementia diagnosis: an observational study of dementia diagnosis feedback meetings
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Ilaria Meo, Nick Bass, Penny Xanthopoulou, Jemima Dooley, and Rose McCabe
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Medical consultation ,medicine.medical_specialty ,Health (social science) ,Social Psychology ,business.industry ,Public Health, Environmental and Occupational Health ,Physical health ,medicine.disease ,RT ,03 medical and health sciences ,Arts and Humanities (miscellaneous) ,030502 gerontology ,Family medicine ,RC0321 ,medicine ,Dementia ,Dementia diagnosis ,Observational study ,Geriatrics and Gerontology ,0305 other medical science ,business ,RC - Abstract
Receiving a diagnosis of dementia is a life-changing event and can cause strong emotional reactions. The aim of this study was to examine patient and companion concerns expressed during dementia diagnosis feedback meetings. Sixty consultations between 19 health-care professionals (HCPs), 60 patients and 59 companions were video-recorded and transcribed. Concerns were identified from the transcripts and were (a) content analysed, (b) coded aselicitedby the HCP orvolunteeredby the patient or companion, and (c) coded according to whether the HCPencouragedordiscouragedelaboration of the concern. A total of 249 concerns were identified (average four concerns per consultation). There were three areas of findings: (a) patients and companions were concerned about the symptoms of dementia and receiving a diagnosis; other concerns related to patients’ mental and physical health, and prognosis, (b) HCPs elicited more patient than companion concerns and mostly elicited concerns aligned with the agenda of diagnosis feedback, and (c) HCPs were more likely to encourage elaboration when they elicited the concern. Nearly 40 per cent of concerns were discouraged by the HPC changing topic, with concerns about prognosis most commonly discouraged. The findings suggest that there were a wide variety of concerns at dementia diagnosis, many extending beyond the experience of dementia symptoms. HCP avoidance of concerns about prognosis demonstrated delicacy in discussing the deteriorating course of dementia.
- Published
- 2018
21. How do doctors deliver a diagnosis of dementia in memory clinics?
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Rose McCabe, Nick Bass, and Jemima Dooley
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Male ,medicine.medical_specialty ,Compromise ,media_common.quotation_subject ,Video Recording ,MEDLINE ,Disease ,Truth Disclosure ,Secondary Care ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Health care ,Humans ,Medicine ,Dementia ,030212 general & internal medicine ,Psychiatry ,Aged ,media_common ,Aged, 80 and over ,Physician-Patient Relations ,030214 geriatrics ,business.industry ,Middle Aged ,medicine.disease ,United Kingdom ,Cognitive test ,Psychiatry and Mental health ,Conversation analysis ,RC0321 ,Female ,business ,RC - Abstract
BackgroundDementia diagnosis rates are increasing. Guidelines recommend that people with dementia should be told their diagnosis clearly and honestly to facilitate future planning.AimsTo analyse how doctors deliver a dementia diagnosis in practice.MethodConversation analysis was conducted on 81 video-recorded diagnosis feedback meetings with 20 doctors from nine UK memory clinics.ResultsAll doctors named dementia; 59% (n = 48) approached the diagnosis indirectly but delicately (‘this is dementia’) and 41% (n = 33) approached this directly but bluntly (‘you have Alzheimer's disease’). Direct approaches were used more often with people with lower cognitive test scores. Doctors emphasised that the dementia was mild and tended to downplay its progression, with some avoiding discussing prognosis altogether.ConclusionsDoctors are naming dementia to patients. Direct approaches reflect attempts to ensure clear diagnosis. Downplaying and avoiding prognosis demonstrates concerns about preserving hope but may compromise understanding about and planning for the future.Declaration of interestNone.
- Published
- 2018
22. The Genetic Architecture of Depression in Individuals of East Asian Ancestry
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Murray B. Stein, Xiangrui Meng, Yiping Chen, Ming-Chyi Huang, Po-Hsiu Kuo, Niamh Mullins, Robin G. Walters, Arden Moscati, Andrew M. McIntosh, Mei-Hsin Su, Stephan Ripke, Olga Giannakopoulou, Nick Bass, Hsi-Chung Chen, Cathryn M. Lewis, Mong Liang Lu, Chao Tian, Jess Tyrrell, Eli A. Stahl, Robert J. Ursano, Iona Y Millwood, Roseann E. Peterson, Kenneth S. Kendler, Ruth J. F. Loos, Karoline Kuchenbaecker, Ronald C. Kessler, Laura J. Scott, Yu Fang, Kuang Lin, Erin C. Dunn, Margit Burmeister, Swapnil Awasthi, Yunxuan Jiang, Zhengming Chen, Srijan Sen, Jonathan R. I. Coleman, Chun-Hsin Chen, Oral Implantology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Biological Psychology, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, and Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics
- Subjects
Adult ,Male ,DISORDER ,SYMPTOMS ,LOCI ,Genome-wide association study ,ASSESS RISK ,VARIANTS ,BIOBANK ,Logistic regression ,White People ,CHINA ,Asian People ,DESIGN ,Asians/ethnology ,SCORE ,Online First ,Humans ,Medicine ,Depression (differential diagnoses) ,Original Investigation ,Genetic association ,Depressive Disorder ,Depressive Disorder/ethnology ,Depression ,Asia, Eastern ,business.industry ,Research ,Far East/ethnology ,Middle Aged ,RESILIENCE ,Depression/ethnology ,Genetic architecture ,Psychiatry and Mental health ,East Asian Studies ,Cohort ,Female ,business ,Body mass index ,Comments ,Genome-Wide Association Study ,Whites/genetics ,Demography - Abstract
Key Points Question Are the genetic risk factors for depression the same in individuals of East Asian and European descent? Findings In this genome-wide association meta-analysis of depression in 194 548 individuals with East Asian ancestry, 2 novel genetic associations were identified, one of which is specific to individuals of East Asian descent living in East Asian countries. There was limited evidence for transferability with only 11% of depression loci previously identified in individuals of European descent reaching nominal significance levels in the individuals of East Asian descent. Meaning Caution is advised against generalizing findings about genetic risk factors for depression beyond the studied population., This genetic association study investigates the genetics of depression across multiple data sets of individuals of East Asian and European descent living in different countries and within different nongenetic cultural contexts., Importance Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures Depression status was defined based on health records and self-report questionnaires. Results There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = −0.018, SE = 0.003, P = 4.43x10−8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10−9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = −0.003, SE = 0.005, P = .53 for rs4656484 and β = −0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = −0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.
- Published
- 2021
23. Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk
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Jerry Guintivano, Eilis Hannon, Steve Horvath, Loes M. Olde Loohuis, Nick Bass, Anil P.S. Ori, Patrick F. Sullivan, Andrew McQuillin, Emma Dempster, David St Clair, Roel A. Ophoff, Jonathan Mill, and René S. Kahn
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Oncology ,0303 health sciences ,medicine.medical_specialty ,business.industry ,Biological age ,dNaM ,Polygenic disease ,Age and sex ,medicine.disease ,Mental illness ,030227 psychiatry ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Schizophrenia ,Internal medicine ,DNA methylation ,medicine ,Epigenetics ,business ,030304 developmental biology - Abstract
BackgroundThe study of biological age acceleration may help identify at-risk individuals and contribute to reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a severe mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a multi-cohort whole blood sample consisting of 1,090 SCZ cases and 1,206 controls, we investigated differential aging using three DNAm clocks (i.e. Hannum, Horvath, Levine). These clocks are highly predictive of chronological age and are known to capture different processes of biological aging.ResultsWe found that blood-based DNAm aging is significantly altered in SCZ with age- and sex-specific effects that differ between clocks and map to distinct chronological age windows. Most notably, differential phenotypic age (Levine clock) was most pronounced in female SCZ patients in later adulthood compared to matched controls. Female patients with high SCZ polygenic risk scores (PRS) present the highest age acceleration in this age group with +4.30 years (CI: 2.40-6.20, P=1.3E-05). Phenotypic age and SCZ PRS contribute additively to the illness and together explain up to 22.4% of the variance in disease status in this study. This suggests that combining genetic and epigenetic predictors may improve predictions of disease outcomes.ConclusionsSince increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. These results provide new biological insights into the aging landscape of SCZ with age- and sex-specific effects and warrant further investigations into the potential of DNAm clocks as clinical biomarkers that may help with disease management in schizophrenia.
- Published
- 2019
24. APPLE-Tree (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline) programme: Protocol
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Penny Rapaport, Elisa Aguirre, Jonathan Huntley, Jennifer Wenborn, Claudia Cooper, Helen C. Kales, Karen Ritchie, Paul Higgs, Natalie L. Marchant, Anne Marie Minihane, Alexandra Burton, Henry Brodaty, Zuzana Walker, Rachael Hunter, Iain A. Lang, Julie Barber, Kate Walters, Sarah Morgan-Trimmer, and Nick Bass
- Subjects
Gerontology ,Technology ,Apple tree ,Cognition ,medicine.disease ,Mental health ,law.invention ,Trees ,Psychiatry and Mental health ,Randomized controlled trial ,England ,law ,Intervention (counseling) ,Malus ,medicine ,Dementia ,Humans ,Observational study ,Geriatrics and Gerontology ,Cognitive decline ,Psychology ,Life Style - Abstract
Background: Observational studies indicate that approximately a third of dementia cases are attributable to modifiable cardiometabolic, physical and mental health, and social and lifestyle risk factors. There is evidence that intensive behaviour change interventions targeting these factors can reduce cognitive decline. (Figure presented.) Our planned intervention [Colour figure can be viewed at wileyonlinelibrary.com]. Methods and analysis: We will design and test a low intensity, secondary dementia-prevention programme (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline, “APPLE-Tree”) to slow cognitive decline in people with subjective cognitive decline with or without objective cognitive impairment. We will embed our work within social science research to understand how dementia prevention is currently delivered and structured. We will carry out systematic reviews and around 50 qualitative interviews with stakeholders, using findings to coproduce the APPLE-Tree intervention. We plan a 10-session group intervention, involving personalised goal-setting, with individual sessions for those unable or unwilling to attend groups, delivered by psychology assistants who will be trained and supervised by clinical psychologists. The coproduction group (including public and patient involvement [PPI], academic and clinical/third-sector professional representatives) will use the Behaviour Change Wheel theoretical framework to develop it. We will recruit and randomly allocate 704 participants, 1:1 to the intervention: informational control group. This sample size is sufficient to detect a between-group difference at 2 years of 0.15 on the primary outcome (cognition: modified neuropsychological test battery; 90% power, 5% significance, effect size 0.25, SD 0.6). Dissemination: We will work with Public Health England and third-sector partners to produce an effective national implementation approach, so that if our intervention works, it is used in practice.
- Published
- 2019
25. Genetics of Intellectual Disability
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Andre Strydom, Kate Wolfe, and Nick Bass
- Subjects
medicine.medical_specialty ,Intellectual disability ,medicine ,Psychiatry ,Psychology ,medicine.disease - Published
- 2019
26. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
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Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barišić, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale, Wellcome Trust, Department of Health, Institute of Neurology, UCL, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC), Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Singh T., Heyne H., Byrnes A., Churchhouse C., Watts N., Solomonson M., Lal D., Heinzen E.L., Dhindsa R.S., Stanley K.E., Cavalleri G.L., Hakonarson H., Helbig I., Krause R., May P., Weckhuysen S., Petrovski S., Kamalakaran S., Sisodiya S.M., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Kwan P., Marson A.G., Stewart R., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., McKenna K., Regan B.M., Bellows S.T., Leu C., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Tumiene B., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Poduri A., Shiedley B.R., Shain C., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Reif A., McQuillin A., Bass N., McIntosh A., Blackwood D., Johnstone M., Palotie A., Pato M.T., Pato C.N., Bromet E.J., Carvalho C.B., Achtyes E.D., Azevedo M.H., Kotov R., Lehrer D.S., Malaspina D., Marder S.R., Medeiros H., Morley C.P., Perkins D.O., Sobell J.L., Buckley P.F., Macciardi F., Rapaport M.H., Knowles J.A., Fanous A.H., McCarroll S.A., Gupta N., Gabriel S.B., Daly M.J., Lander E.S., Lowenstein D.H., Goldstein D.B., Lerche H., Berkovic S.F., Neale B.M., Epi25 Collaborative, YÜCESAN, EMRAH, Institute for Molecular Medicine Finland, Children's Hospital, HUS Children and Adolescents, Department of Medical and Clinical Genetics, University Management, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders
- Subjects
s.berkovic@unimelb.edu.au [Epi25 Collaborative. Electronic address] ,0301 basic medicine ,GAMMA-2-SUBUNIT ,burden analysi ,DNA Mutational Analysis ,PROTEIN ,Neurodegenerative ,VARIANTS ,SUSCEPTIBILITY ,Medical and Health Sciences ,Epilepsy ,0302 clinical medicine ,2.1 Biological and endogenous factors ,EPIDEMIOLOGY ,Missense mutation ,Exome ,Aetiology ,Genetics (clinical) ,Exome sequencing ,11 Medical and Health Sciences ,seizures ,GABRG2 ,Genetics ,Genetics & Heredity ,0303 health sciences ,biology ,COMMON EPILEPSIES ,1184 Genetics, developmental biology, physiology ,sequencing ,Biological Sciences ,Epi25 Collaborative ,Phenotype ,GENOME ,epileptic encephalopathy ,burden analysis ,Neurological ,Biotechnology ,Genetic Markers ,seizure ,EEF1A2 ,Burden analysis ,epilepsy ,exome ,Article ,03 medical and health sciences ,Clinical Research ,Exome Sequencing ,Genetic variation ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,EPILEPTIC SEIZURES ,METAANALYSIS ,030304 developmental biology ,Human Genome ,Neurosciences ,Genetic Variation ,06 Biological Sciences ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Genetic marker ,DE-NOVO MUTATIONS ,Case-Control Studies ,biology.protein ,3111 Biomedicine ,Human medicine ,030217 neurology & neurosurgery - Abstract
Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
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- 2019
27. Involving patients with dementia in decisions to initiate treatment: effect on patient acceptance, satisfaction and medication prescription
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Jemima Dooley, Rose McCabe, Gill Livingston, and Nick Bass
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Male ,medicine.medical_specialty ,Decision Making ,Coding (therapy) ,Affect (psychology) ,Medication prescription ,Drug Prescriptions ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Dementia ,Humans ,030212 general & internal medicine ,Medical prescription ,Association (psychology) ,Psychiatry ,Aged ,Aged, 80 and over ,medication decision ,Physician-Patient Relations ,Passive resistance ,communication ,business.industry ,Communication ,shared decision-making ,Patient Preference ,Alzheimer's disease ,medicine.disease ,030227 psychiatry ,Cognitive test ,Psychiatry and Mental health ,Patient Satisfaction ,Female ,Patient Participation ,business - Abstract
BackgroundShared decision-making is advocated but may be affected by cognitive impairment. Measures of shared decision-making provide global descriptions of communication without detailed analysis of the subtle ways in which doctors invite patient input.AimsWe aimed to explore medication decisions in dementia, using a standardised Treatment Recommendation Coding Scheme.MethodWe analysed 71 video-recorded dementia diagnostic meetings from nine memory clinics. Recommendations were coded as pronouncements (‘I will start you on medication’), proposals (‘Shall we try medication?’), suggestions (‘Would you like to try medication?’), offers (‘I can prescribe medication’) or assertions (‘There is medication’). Patient responses were coded as acceptance (‘I'd like to have that’), active resistance (‘I'm not very keen’) and passive resistance (minimal or no response). Cognitive test scores, prescription rates and satisfaction were assessed and associations were explored.ResultsDoctors used suggestions in 42% of meetings, proposals in 25%, assertions in 13%, pronouncements in 11% and offers in 9%. Over 80% of patients did not indicate clear acceptance. Patients were most likely to actively resist after suggestions. There was no association between cognitive impairment and recommendation format. Patients were less satisfied with pronouncements. Patient preference did not influence whether medication was prescribed.ConclusionsDoctors initially nominate people with dementia as the decision maker, and this is unaffected by cognitive impairment. Over 80% of patients resisted starting medication, mostly through passive resistance, the most common form of disagreement in communication. Medication still tended to be prescribed, indicating that factors other than patient preference affect prescription.Declarations of interestNone.
- Published
- 2018
28. SA140GENETIC RISK FACTORS OF ALCOHOL DEPENDENCE AND ANTISOCIAL PERSONALITY DISORDER
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Johan H. Thygesen, Nick Bass, Wenqianglong Li, Joel Gelernter, and Andrew McQuillin
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Pharmacology ,Psychiatry and Mental health ,Neurology ,Antisocial personality disorder ,Alcohol dependence ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,medicine.disease ,Psychology ,Biological Psychiatry ,Clinical psychology - Published
- 2019
29. HIGH RATES OF NEURODEVELOPMENTAL RISK CNVs IN PATIENTS WITH INTELLECTUAL DISABILITIES AND CO-MORBID PSYCHIATRIC DISORDERS
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Nick Bass, Griet Van Buggenhout, Nathalie Brison, Marina Viñas-Jornet, Ramon Novell, Andre Strydom, Núria Ribas-Vidal, Johan H. Thygesen, Susanna Esteba-Castillo, Annick Vogels, Andrew McQuillin, Kate Wolfe, and Miriam Guitart Feliubadaló
- Subjects
Pharmacology ,congenital, hereditary, and neonatal diseases and abnormalities ,Candidate gene ,education.field_of_study ,medicine.medical_specialty ,business.industry ,Genetic counseling ,Population ,medicine.disease ,Psychiatry and Mental health ,Neurology ,Schizophrenia ,Angelman syndrome ,mental disorders ,Medicine ,Autism ,Pharmacology (medical) ,Neurology (clinical) ,Copy-number variation ,business ,education ,Psychiatry ,Biological Psychiatry ,Psychiatric genetics - Abstract
Background Rare Copy Number Variants (CNVs) are known to be important risk factors for Neurodevelopmental Disorders (NDDs). Pathogenic CNVs identified to date confer moderate to large effect sizes (OR 1.5 - 50 or higher) and have important clinical implications for affected individuals and at-risk family members. Several studies have investigated pathogenic CNVs in paediatric cohorts with Intellectual Disabilities (ID), or in schizophrenia/Autism Spectrum Disorders (ASD) only samples. However, adult populations – in particular those who exhibit ID and co-morbid psychiatric diagnoses – are less well characterised. Methods We undertook Chromosomal Microarray Analysis (CMA) and clinical phenotyping in 599 adults with ID and co-morbid psychiatric disorders recruited from three European research sites (Catalonia, Spain; Leuven, Belgium; and England, UK). We compared the carrier frequency of 63 established NDD CNV risk loci to reported frequencies in healthy controls, schizophrenia and ID/ASD populations. We determine the clinical diagnostic yield of CMA in our sample and describe likely pathogenic CNVs affecting NDD candidate genes. Results We identified 58 carriers of NDD risk CNVs at 23 of the 63 risk loci investigated. The five most frequent CNVs were: 22q11.2 deletion (N=7, 1.2%), 15q11.2 (Prader-Willi syndrome/Angelman syndrome region) duplication (N=6, 1%), 16p11.2 duplication (N=5, 0.8%), 15q13.3 deletion (N=5, 0.8%) and 16p12.1 deletion (N=4, 0.7%). The frequency of NDD risk CNVs was significantly higher in our cohort (10%), compared to healthy controls (1.2%, p Discussion There is a paucity of research on CNVs in adults with ID and co-morbid psychiatric diagnoses. This poses a challenge for genetic counselling of rare CNVs, as descriptions of later-life phenotypes are largely unavailable. In our sample, the largest multi-population sample of its kind to date, we find a significantly higher rate of NDD risk CNVs compared to schizophrenia and ID/ASD only cohorts. Our high diagnostic yield of 13% pathogenic CNVs demonstrates the diagnostic utility of CMA in this patient group. We also find a high yield of likely pathogenic CNVs (21.5%), which enables us to phenotypically characterise rare recurrent CNVs. Increased clinical testing and research in this population should be a priority for both clinicians and researchers in the field of psychiatric genetics.
- Published
- 2019
30. Genetic testing in intellectual disability psychiatry: Opinions and practices of UK child and intellectual disability psychiatrists
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Nick Bass, Frances Flinter, Andre Strydom, Fatima Jichi, Kerstin Stueber, Christine Patch, Andrew McQuillin, and Kate Wolfe
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Referral ,Adolescent ,Attitude of Health Personnel ,diagnosis ,030105 genetics & heredity ,behavioral disciplines and activities ,Education ,03 medical and health sciences ,0302 clinical medicine ,Intellectual Disability ,Intellectual disability ,mental disorders ,Developmental and Educational Psychology ,Clinical genetic ,medicine ,clinical management ,Humans ,copy number variant ,Genetic Testing ,Medical diagnosis ,Practice Patterns, Physicians' ,Psychiatry ,Child ,Bespoke ,Genetic testing ,learning disability ,medicine.diagnostic_test ,business.industry ,Original Articles ,medicine.disease ,United Kingdom ,Patient management ,Family medicine ,Health Care Surveys ,Learning disability ,service provision ,Original Article ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background An increasing number of genetic causes of intellectual disabilities (ID) are identifiable by clinical genetic testing, offering the prospect of bespoke patient management. However, little is known about the practices of psychiatrists and their views on genetic testing. Method We undertook an online survey of 215 psychiatrists, who were contacted via the Royal College of Psychiatrist's Child and Adolescent and Intellectual Disability Psychiatry mailing lists. Results In comparison with child and adolescent psychiatrists, intellectual disability psychiatrists ordered more genetic tests, referred more patients to genetic services, and were overall more confident in the genetic testing process. Respondents tended to agree that genetic diagnoses can help patient management; however, management changes were infrequently found in clinical practice. Conclusions Differences are apparent in the existing views and practices of child and adolescent and intellectual disability psychiatrists. Developing training and collaboration with colleagues working in genetic services could help to reduce discrepancies and improve clinical practice.
- Published
- 2017
31. Dementia diagnostic criteria in Down syndrome
- Author
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Ingrid Bohnen, Zuzana Walker, Kamalika Mukherji, Vijaya Sharma, Simon Bonell, Asim Naeem, Amanda Sinai, Pippa Blatchford, Rory Sheehan, Natalia Perez-Achiaga, Nick Bass, Angela Hassiotis, Ken Courtenay, Therese Markar, Dimitrios Paschos, Jane McCarthy, David Thomas, and Andre Strydom
- Subjects
Down syndrome ,medicine.medical_specialty ,Pediatrics ,business.industry ,Concurrent validity ,ICD-10 ,Disease ,medicine.disease ,Psychiatry and Mental health ,mental disorders ,Intellectual disability ,Medicine ,Dementia ,Geriatrics and Gerontology ,Stage (cooking) ,Medical diagnosis ,business ,Psychiatry - Abstract
Objective: Dementia is a common clinical presentation among older adults with Down syndrome. The presentation of dementia in Down syndrome differs compared with typical Alzheimer's disease. The performance of manualised dementia criteria in the International Classification of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) is uncertain in this population.We aimed to determine the concurrent validity and reliability of clinicians' diagnoses of dementia against ICD-10 and DSM-IV-TR diagnoses. Validity of clinical diagnoses were also explored by establishing the stability of diagnoses over time. / Methods: We used clinical data from memory assessments of 85 people with Down syndrome, of whom 64 (75.3%) had a diagnosis of dementia. The cases of dementia were presented to expert raters who rated the case as dementia or no dementia using ICD-10 and DSM-IV-TR criteria and their own clinical judgement. / Results: We found that clinician's judgement corresponded best with clinically diagnosed cases of dementia, identifying 84.4% cases of clinically diagnosed dementia at the time of diagnosis. ICD-10 criteria identified 70.3% cases, and DSM-IV-TR criteria identified 56.3% cases at the time of clinically diagnosed dementia. Over time, the proportion of cases meeting ICD-10 or DSM-IV-TR diagnoses increased, suggesting that experienced clinicians used their clinical knowledge of dementia presentation in Down syndrome to diagnose the disorder at an earlier stage than would have been possible had they relied on the classic description contained in the diagnostic systems. / Conclusions: Clinical diagnosis of dementia in Down syndrome is valid and reliable and can be used as the standard against which new criteria such as the DSM-5 are measured.
- Published
- 2014
32. Genetic investigation for adults with intellectual disability
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F. Raymond, Nick Bass, and Kate Baker
- Subjects
medicine.medical_specialty ,business.industry ,Gene Expression Profiling ,Diagnostic test ,Microdeletion syndrome ,Microarray Analysis ,medicine.disease ,Clinical neurology ,Neurology ,Intellectual Disability ,Intellectual disability ,medicine ,Humans ,Neurology (clinical) ,Global developmental delay ,Copy-number variation ,Psychiatry ,business ,Genome-Wide Association Study - Abstract
This review discusses diagnostic genetic assessment for adults with idiopathic intellectual disability, considering the potential yields and limitations of currently available investigations.Genome-wide microarray analysis is now a routine diagnostic test. Estimated yields for clinically significant copy number variants in adults with idiopathic intellectual disability are at least 10%. The medical and neuropsychiatric phenotypes of recurrent genomic disorders are being established. Many single gene causes of intellectual disability have been identified, most notably for X-linked intellectual disability. Ascribing causality, determination of recurrence risk, and prognostication for rare or unique variants remain challenging.Clinical evaluation and investigations (both nongenetic and genetic) can yield an aetiological diagnosis for a growing proportion of individuals with intellectual disability. Not all adults with intellectual disability will ever have received such an assessment. Genetic diagnosis can provide an explanation for lifelong disabling cognitive disorder, guide prognosis, and highlight medical comorbidities. A key outcome is clarification of recurrence risk and facilitation of reproductive choices. However, there are limited data on the desirability and acceptability of genetic diagnosis amongst adult patients with intellectual disability and their families, and concern that ethical principles and practices may be changing without scrutiny. The decision to embark on diagnostic review requires careful consideration for each individual.
- Published
- 2012
33. Genome-wide association study of suicide attempts in mood disorder patients
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Roy H, Perlis, Jie, Huang, Shaun, Purcell, Maurizio, Fava, A John, Rush, Patrick F, Sullivan, Steven P, Hamilton, Francis J, McMahon, Thomas G, Schulze, Thomas, Schulze, James B, Potash, Peter P, Zandi, Virginia L, Willour, Brenda W, Penninx, Dorret I, Boomsma, Nicole, Vogelzangs, Christel M, Middeldorp, Marcella, Rietschel, Markus, Nöthen, Sven, Cichon, Hugh, Gurling, Nick, Bass, Andrew, McQuillin, Marian, Hamshere, Nick, Craddock, Pamela, Sklar, Jordan W, Smoller, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Psychiatry, NCA - Anxiety & Depression, and EMGO - Mental health
- Subjects
Netherlands Twin Register (NTR) ,medicine.medical_specialty ,Genotype ,Suicide, Attempted ,Polymorphism, Single Nucleotide ,Article ,SDG 3 - Good Health and Well-being ,mental disorders ,medicine ,Humans ,Genetic Predisposition to Disease ,Bipolar disorder ,Psychiatry ,Depression (differential diagnoses) ,Suicide attempt ,Mood Disorders ,medicine.disease ,Twin study ,Psychiatry and Mental health ,Mood ,Cohort ,Major depressive disorder ,Anxiety ,medicine.symptom ,Psychology ,Genome-Wide Association Study ,Clinical psychology - Abstract
Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
- Published
- 2010
34. A Genomewide Association Study of Response to Lithium for Prevention of Recurrence in Bipolar Disorder
- Author
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Shaun Purcell, Gary S. Sachs, Roy H. Perlis, Manuel A. R. Ferreira, Jacob Lawrence, Vishwajit L. Nimgaonkar, Nick Bass, Edward M. Scolnick, Andrew McQuillin, Jordan W. Smoller, Hugh Gurling, and Pamela Sklar
- Subjects
Adult ,Male ,Oncology ,Olanzapine ,medicine.medical_specialty ,Bipolar Disorder ,Bipolar I disorder ,Genotype ,Lithium (medication) ,medicine.drug_class ,Polymorphism, Single Nucleotide ,Bipolar II disorder ,chemistry.chemical_compound ,Lithium Carbonate ,Internal medicine ,mental disorders ,Secondary Prevention ,medicine ,Humans ,Receptors, AMPA ,Bipolar disorder ,Psychiatry ,Alleles ,Genome ,Lithium carbonate ,Mood stabilizer ,medicine.disease ,Diagnostic and Statistical Manual of Mental Disorders ,Psychiatry and Mental health ,Mood ,chemistry ,Female ,Chromosomes, Human, Pair 4 ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder.The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London.The strongest association in the STEP-BD cohort (minimum p=5.5 x 10(-7)) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p5 x 10(-4)) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2.Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.
- Published
- 2009
35. A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia
- Author
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Gursharan Kalsi, Neil Walker, Jacob Lawrence, Andrew McQuillin, Khalid Choudhury, Susmita Datta, Hugh Gurling, Mie Rizig, Radhika Kandaswamy, Vinay Puri, D. St Clair, Gillian Fraser, David Curtis, Nick Bass, Caroline Crombie, E Blaveri, Ana C. Parente Pereira, Marketa Zvelebil, Srinivasa Thirumalai, and Jonathan Pimm
- Subjects
Threonine ,Heterozygote ,Genotype ,Mutation, Missense ,Cell Cycle Proteins ,medicine.disease_cause ,Autoantigens ,Cellular and Molecular Neuroscience ,Exon ,DISC1 ,medicine ,Humans ,Missense mutation ,Isoleucine ,Allele ,Molecular Biology ,Genotyping ,Gene ,Alleles ,Genetic Association Studies ,Genetics ,Mutation ,biology ,Haplotype ,Exons ,Psychiatry and Mental health ,England ,Haplotypes ,Scotland ,Schizophrenia ,biology.protein - Abstract
Markers at the pericentriolar material 1 gene (PCM1) have shown genetic association with schizophrenia in both a University College London (UCL) and a USA-based case-control sample. In this paper we report a statistically significant replication of the PCM1 association in a large Scottish case-control sample from Aberdeen. Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine to isoleucine missense mutation in exon 24 which was likely to change the structure and function of PCM1 (rs370429). This mutation was found only as a heterozygote in 98 schizophrenic research subjects and controls out of 2246 case and control research subjects. Among the 98 carriers of rs370429, 67 were affected with schizophrenia. The same alleles and haplotypes were associated with schizophrenia in both the London and Aberdeen samples. Another potential aetiological base pair change in PCM1 was rs445422, which altered a splice site signal. A further mutation, rs208747, was shown by electrophoretic mobility shift assays to create or destroy a promoter transcription factor site. Five further non-synonymous changes in exons were also found. Genotyping of the new variants discovered in the UCL case-control sample strengthened the evidence for allelic and haplotypic association (P = 0.02-0.0002). Given the number and identity of the haplotypes associated with schizophrenia, further aetiological base pair changes must exist within and around the PCM1 gene. PCM1 protein has been shown to interact directly with the disrupted-in-schizophrenia 1 (DISC1) protein, Bardet-Biedl syndrome 4, and Huntingtin-associated protein 1, and is important in neuronal cell growth. In a separate study we found that clozapine but not haloperidol downregulated PCM1 expression in the mouse brain. We hypothesize that mutant PCM1 may be responsible for causing a subtype of schizophrenia through abnormal cell division and abnormal regeneration in dividing cells in the central nervous system. This is supported by our previous finding of orbitofrontal volumetric deficits in PCM1-associated schizophrenia patients as opposed to temporal pole deficits in non-PCM1-associated schizophrenia patients. Caution needs to be exercised in interpreting the actual biological effects of the mutations we have found without further cell biology. However, the DNA changes we have found deserve widespread genotyping in multiple case-control populations. Molecular Psychiatry (2010) 15, 615-628; doi: 10.1038/mp.2008.128; published online 2 December 2008
- Published
- 2008
36. Whole-genome association study of bipolar disorder
- Author
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Walter J. Muir, Stacey Gabriel, Kimberly Chambert, Carrie Sougnez, Vishwajit L. Nimgaonkar, Michael E. Thase, Matthew Defelice, David Curtis, Jinbo Fan, Jennifer Franklin, Roy H. Perlis, MP D VanBeck, Andrew McQuillin, Mark J. Daly, Nick Bass, P. I. W. de Bakker, Casey Gates, Shaun Purcell, Matthew B. McQueen, Katherine Todd-Brown, Matthew Robinson, Hugh Gurling, Adebayo Anjorin, Pamela Sklar, Douglas Blackwood, Donald J. MacIntyre, Kevin A. McGhee, Gary S. Sachs, M N Ogdie, Stephen V. Faraone, Jordan W. Smoller, Manuel A. R. Ferreira, Andrew Kirby, Brendan Blumenstiel, Kristin G. Ardlie, Jacob Lawrence, Edward M. Scolnick, and Alan W. McLean
- Subjects
Genetic Markers ,Candidate gene ,Bipolar Disorder ,Genotype ,Tetraspanins ,Myosin Type V ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,Cellular and Molecular Neuroscience ,Gene Frequency ,Antigens, Neoplasm ,Reference Values ,medicine ,Humans ,SNP ,ANK3 ,Bipolar disorder ,Medical History Taking ,Molecular Biology ,Genotyping ,Genetics ,Membrane Glycoproteins ,Myosin Heavy Chains ,Genome, Human ,Patient Selection ,Haplotype ,Chromosome Mapping ,DNA ,medicine.disease ,ErbB Receptors ,Psychiatry and Mental health - Abstract
We performed a genome wide association scan in 1,461 patients with bipolar 1 disorder and 2,008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and University College London sample collections with successful genotyping for 372,193 SNPs. Our strongest single SNP results are found in myosin5B (MYO5B; p=1.66 × 10−7) and tetraspanin-8 (TSPAN8; p=6.11 × 10−7). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; p=2.04 × 10−8, TSPAN8; p=7.57 × 10−7 and EGFR; p=8.36 × 10−8). For replication, we genotyped 304 SNPs in a family-based NIMH sample (n=409 trios) and a University of Edinburgh case-control sample (n=365 cases, 351 controls) which do not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1,868 patients with bipolar disorder and 2,938 controls completed as part of the Wellcome Trust Case-Control Consortium (1) indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene, but no other single SNP associations are highly significant in both studies. Given the heritability of bipolar disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.
- Published
- 2008
37. Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders
- Author
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Jacob Lawrence, Hugh Gurling, M. Kosmin, David Curtis, Khalid Choudhury, Andrew McQuillin, Vinay Puri, and Nick Bass
- Subjects
Heterozygote ,Bipolar Disorder ,Glutamine ,Single-nucleotide polymorphism ,Biology ,Arginine ,Linkage Disequilibrium ,Cellular and Molecular Neuroscience ,Gene Frequency ,Genetic linkage ,Polymorphism (computer science) ,Genotype ,medicine ,Humans ,Genetic Predisposition to Disease ,Bipolar disorder ,Allele ,Molecular Biology ,Genes, Dominant ,Genetics ,Depressive Disorder ,Chromosomes, Human, Pair 12 ,Receptors, Purinergic P2 ,Homozygote ,Haplotype ,medicine.disease ,Psychiatry and Mental health ,Amino Acid Substitution ,Haplotypes ,Schizophrenia ,Case-Control Studies ,Receptors, Purinergic P2X7 ,Microsatellite Repeats - Abstract
Three linkage studies of bipolar disorder have implicated chromosome 12q24.3 with lod scores of over 3.0 and several other linkage studies have found lods between 2 and 3. Fine mapping within the original chromosomal linkage regions has identified several loci that show association with bipolar disorder. One of these is the P2RX7 gene encoding a central nervous system-expressed purinergic receptor. A non-synonymous single nucleotide polymorphism, rs2230912 (P2RX7-E13A, G allele) and a microsatellite marker NBG6 were both previously found to be associated with bipolar disorder (P=0.00071 and 0.008, respectively). rs2230912 has also been found to show association with unipolar depression. The effect of the polymorphism is non-conservative and results in a glutamine to arginine change (Gln460Arg), which is likely to affect P2RX7 dimerization and protein-protein interactions. We have confirmed the allelic associations between bipolar disorder and the markers rs2230912 (P2RX7-E13A, G allele, P=0.043) and NBG6 (P=0.010) in a London-based sample of 604 bipolar cases and 560 controls. When we combined these data with the published case-control studies of P2RX7 and mood disorder (3586 individuals) the association between rs2230912 (Gln460Arg) and affective disorders became more robust (P=0.002). The increase in Gln460Arg was confined to heterozygotes rather than homozygotes suggesting a dominant effect (odds ratio 1.302, CI=1.129-1.503). Although further research is needed to prove that the Gln460Arg change has an aetiological role, it is so far the most convincing mutation to have been found with a role for increasing susceptibility to bipolar and genetically related unipolar disorders.
- Published
- 2008
38. The psychiatric intensive care unit (PICU): Patient characteristics, treatment and outcome
- Author
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Steve Brown and Nick Bass
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Public health ,Psychiatric intensive care unit ,Patient characteristics ,Social environment ,General Medicine ,Mental health ,Intensive care unit ,law.invention ,Psychiatry and Mental health ,law ,Intensive care ,Emergency medicine ,medicine ,Psychiatric hospital ,business - Abstract
Background: Psychiatric Intensive Care Units (PICU) are small, highly staffed, low secure wards, designed to treat acute challenging psychotic behaviour. They have become a standard component of psychiatric hospital design despite minimal published data about their clinical activity and effectiveness. Aims: To compare the characteristics, treatment and outcome of a series of patients admitted to a PICU unit with a control group treated on the open wards of the same hospital. Method: Case controlled retrospective case note analysis. Results: PICU patients were predominantly young male Caucasians, with psychotic illness, a history of violence and substance misuse. Most had a relatively brief PICU admission. The PICU also acted as a de facto long stay low secure unit because of a shortage of more appropriate facilities. Conclusions: The PICU appears to be a useful resource for treating highly disturbed individuals who are at high risk of violence and who would be difficult to manage safely on an open ward. M...
- Published
- 2004
39. Semantic Modeling and Analysis of Natural Language System Requirements
- Author
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Konstantinos Mokos, Theodoros Nestoridis, Panagiotis Katsaros, and Nick Bassiliades
- Subjects
Embedded systems ,ontologies ,requirements validation ,semantic reasoning ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
System requirements specify how a system meets stakeholder needs. They are a partial definition of the system under design in natural language that may be restricted in syntax terms. Any natural language specification inevitably lacks a unique interpretation and includes underspecified terms and inconsistencies. If the requirements are not validated early in the system development cycle and refined, as needed, specification flaws may cause costly cycles of corrections in design, implementation and testing. However, validation should be based on a consistent interpretation with respect to a rigorously defined semantic context of the domain of the system. We propose a specification approach that, while sufficiently expressive, it restricts the requirements definition to terms from an ontology with precisely defined concepts and semantic relationships in the domain of the system under design. This enables a series of semantic analyses, which guide the engineer towards improving the requirement specification as well as eliciting tacit knowledge. The problems addressed are prerequisites to enable the derivation of verifiable specifications, which is of fundamental importance for the design of critical embedded systems. We present the results from a case study of modest size from the space system domain, as well as an evaluation of our approach from the user’s point of view. The requirement types that have been covered demonstrate the applicability of the approach in an industrial context, although the effectiveness of the analysis depends on pre-existing domain ontologies.
- Published
- 2022
- Full Text
- View/download PDF
40. Behavioral Phenotypes and Genetic Syndromes
- Author
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Dimitrios Paschos, Andre Strydom, and Nick Bass
- Subjects
Behavioral phenotypes ,education.field_of_study ,medicine.diagnostic_test ,Population ,Cognition ,medicine.disease ,Phenotype ,Angelman syndrome ,Intellectual disability ,Etiology ,medicine ,Psychology ,education ,Clinical psychology ,Genetic testing - Abstract
Over the past few decades genetic advances have resulted in increasing understanding of the etiology of intellectual disability (ID) syndromes while detailed phenotypic descriptions of behavior and mental disorders have become possible with validated and reliable assessment tools. Although the concept that certain ID syndromes are associated with a recognizable physical, behavioral, and cognitive “phenotype” is not new, it has gained considerable popularity among psychiatrists and psychologists working with this population. In this chapter, we will review the key aspects of behavioral phenotypes and genetic testing before describing some of the phenotypes associated with specific syndromes. For terms in italics, see “Glossary.”
- Published
- 2013
41. Affective illness and schizophrenia in families with multiple schizophrenic members: independent illnesses or variant gene(s)?
- Author
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Sarah Henn, Timothy J. Crow, Gail Shields, Nick Bass, and Lynn E. DeLisi
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychosis ,Schizoaffective disorder ,behavioral disciplines and activities ,mental disorders ,medicine ,Humans ,Pharmacology (medical) ,Sex Distribution ,Psychiatry ,Biological Psychiatry ,Depression (differential diagnoses) ,Psychiatric Status Rating Scales ,Pharmacology ,High rate ,Depressive Disorder ,Mood Disorders ,medicine.disease ,Psychiatry and Mental health ,Neurology ,Schizophrenia ,Female ,Schizophrenic Psychology ,Neurology (clinical) ,Psychology ,Clinical psychology - Abstract
Affective disorder occurs in some families with schizophrenia, and schizophrenic patients often describe concurrent episode(s) of depression that may lead them to be diagnosed schizoaffective. The present study examines the pattern of affective disorder in families with two or more members with schizophrenia or schizoaffective disorder. We find that affective disorders are more frequently inherited from the same parental side of the family as schizophrenia-like psychosis. When unipolar, it more often is expressed in female than male relatives (particularly mothers), and when bipolar it is more likely in males. In contrast, schizophrenia with and without depression is equally prevalent in both sexes. Unipolar illness was more common in relatives of schizophrenics whose illnesses are characterized by recurrent episodes of depression than in those whose are not. These data are consistent with the hypothesis that the same genes could contribute to susceptibility to both schizophrenia and affective disorder in some families, and that sex and phenotypic expression are in some way related. However, the phenomenon of high rates of depression in mothers of schizophrenic patients needs explanation.
- Published
- 1995
42. DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder
- Author
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Walter J. Muir, Nick Bass, William Hennah, Sarah E. Harris, Jacob Lawrence, Michelle Robinson, Erkki Isometsä, Ian J. Deary, Pippa A. Thomson, Timo Partonen, S Thirumalai, Adebayo Anjorin, David Curtis, Pia Soronen, Jaana Suvisaari, Anu Loukola, Douglas Blackwood, Aarno Palotie, David J. Porteous, D. St Clair, Jouko Lönnqvist, E Pylkkö, Hugh Gurling, Kirsi Suominen, Andrew McQuillin, Leena Peltonen, and Tiina Paunio
- Subjects
Oncology ,Male ,medicine.medical_specialty ,Bipolar Disorder ,Genotype ,International Cooperation ,Single-nucleotide polymorphism ,Genome-wide association study ,Schizoaffective disorder ,Nerve Tissue Proteins ,Neuropsychological Tests ,Polymorphism, Single Nucleotide ,Cohort Studies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,DISC1 ,0302 clinical medicine ,Sex Factors ,Gene Frequency ,Internal medicine ,medicine ,Odds Ratio ,Humans ,Genetic Predisposition to Disease ,Bipolar disorder ,Molecular Biology ,030304 developmental biology ,Genetics ,Psychiatric Status Rating Scales ,0303 health sciences ,biology ,Case-control study ,Odds ratio ,medicine.disease ,3. Good health ,Europe ,Psychiatry and Mental health ,Schizophrenia ,Case-Control Studies ,biology.protein ,Female ,Psychology ,030217 neurology & neurosurgery - Abstract
Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.
- Published
- 2008
43. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3
- Author
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Andrew McQuillin, Nick Bass, David Curtis, Hugh Gurling, Gursharan Kalsi, Vinay Puri, Sevilla D. Detera-Wadleigh, Khalid Choudhury, and Jacob Lawrence
- Subjects
Linkage disequilibrium ,Bipolar Disorder ,Chromosomes, Human, Pair 21 ,TRPM Cation Channels ,Locus (genetics) ,Biology ,Linkage Disequilibrium ,Cellular and Molecular Neuroscience ,Exon ,Genetic linkage ,Humans ,Genetic Predisposition to Disease ,Allele ,Molecular Biology ,Genetics ,Polymorphism, Genetic ,Mood Disorders ,Haplotype ,Chromosome Mapping ,Pedigree ,Psychiatry and Mental health ,Amino Acid Substitution ,Haplotypes ,Genetic marker ,Case-Control Studies ,sense organs ,Chromosome 21 ,Microsatellite Repeats - Abstract
Linkage analyses of bipolar families have confirmed that there is a susceptibility locus near the telomere on chromosome 21q. To fine map this locus we carried out tests of allelic association using 30 genetic markers near the telomere at 21q22.3 in 600 bipolar research subjects and 450 ancestrally matched supernormal control subjects. We found significant allelic association with the microsatellite markers D21S171 (P=0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P=0.008) and rs1785467 (P=0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P=0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P=0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P=0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. These changes need further investigation to establish any aetiological role in bipolar disorder.
- Published
- 2005
44. Search for linkage to schizophrenia on the X and Y chromosomes
- Author
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Antonio Vita, Raymond Lofthouse, Timothy J. Crow, Gail Shields, Angela B. Smith, Jurg Ott, Lynn E. DeLisi, Mark Poulter, Nick Bass, Carla Morganti, Marcella Devoto, and Gang Chen
- Subjects
Genetics ,Genetic Markers ,Non-Mendelian inheritance ,X Chromosome ,Genetic Linkage ,Chromosome Mapping ,Locus (genetics) ,Biology ,Gene mapping ,Genetic linkage ,Y Chromosome ,Homologous chromosome ,Schizophrenia ,Humans ,Allele ,Restriction fragment length polymorphism ,Lod Score ,Genetics (clinical) ,X chromosome - Abstract
Markers for X chromosome loci were used in linkage studies of a large group of small families (n = 126) with at least two schizophrenic members in one sibship. Based on the hypothesis that a gene for schizophrenia could be X-Y linked, with homologous loci on both X and Y, our analyses included all families regardless of the pattern of familial inheritance. Lod scores were computed with both standard X-linked and a novel X-Y model, and sib-pair analyses were performed for all markers examining the sharing of maternal alleles. Small positive lod scores were obtained for loci pericentromeric, from Xp11.4 to Xq12. Lod scores were also computed separately in families selected for evidence of maternal inheritance and absence of male to male transmission of psychosis. The lod scores for linkage to the locus DXS7 reached a maximum of 1.83 at 0.08% recombination, assuming dominant inheritance on the X chromosome in these families (n = 34). Further investigation of the X-Y homologous gene hypothesis focussing on this region is warranted. 39 refs. 1 fig., 6 tabs.
- Published
- 1994
45. Age of onset in familial schizophrenia
- Author
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Lynn E. DeLisi, Carla Morganti, Angela Boccio, Antonio Vita, Gail Shields, and Nick Bass
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Adult ,Male ,medicine.medical_specialty ,Affected sibling ,First admission ,Mental illness ,medicine.disease ,Mean difference ,Psychiatry and Mental health ,Age Distribution ,Sex Factors ,Arts and Humanities (miscellaneous) ,Schizophrenia ,Early adulthood ,medicine ,Humans ,Family ,Female ,Family history ,Age of onset ,Age of Onset ,Psychiatry ,Psychology ,Demography - Abstract
The age of onset of schizophrenia chatacteristically peaks in early adulthood, although spanning at least four decades of life among unrelated individuals, and on average, it peaks a few years earlier in males than females. 1,2 It also has been previously shown that the age of onset, rather than the time of onset, is highly correlated among affected sibling pairs, thus suggesting a genetic determination of the age of on set. There recently have been reports of a curious lack of gender differences in the age of onset when only schizophrenic individuals with a positive family history of schizophrenia (ie, multiplex families) are examined. 4-6 However, L. S. Penrose, in a large cohort of familial mental illness, previously observed that the age of onset for males was lower than for females (mean difference, 3.7 years), with a wider scatter in male ages at first admission than in female and a
- Published
- 1994
46. Work of the Mental Health Act Commission
- Author
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Jan Falkowski, Andrew Cobb, Eleni Palazidou, T Read, David Curtis, Jogin Thakore, and Nick Bass
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Psychiatry and Mental health ,Mental health law ,medicine.medical_specialty ,Nursing ,Work (electrical) ,Mental Health Act ,medicine ,Commission ,Psychiatry ,Psychology - Published
- 1998
47. Mechanism Design for Efficient Offline and Online Allocation of Electric Vehicles to Charging Stations
- Author
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Emmanouil S. Rigas, Enrico H. Gerding, Sebastian Stein, Sarvapali D. Ramchurn, and Nick Bassiliades
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electric vehicles ,charging ,scheduling ,mechanism design ,fixed price ,VCG ,Technology - Abstract
The industry related to electric vehicles (EVs) has seen a substantial increase in recent years, as such vehicles have the ability to significantly reduce total CO2 emissions and the related global warming effect. In this paper, we focus on the problem of allocating EVs to charging stations, scheduling and pricing their charging. Specifically, we developed a Mixed Integer Program (MIP) which executes offline and optimally allocates EVs to charging stations. On top, we propose two alternative mechanisms to price the electricity the EVs charge. The first mechanism is a typical fixed-price one, while the second is a variation of the Vickrey–Clark–Groves (VCG) mechanism. We also developed online solutions that incrementally call the MIP-based algorithm and solve it for branches of EVs. In all cases, the EVs’ aim is to minimize the price to pay and the impact on their driving schedule, acting as self-interested agents. We conducted a thorough empirical evaluation of our mechanisms and we observed that they had satisfactory scalability. Additionally, the VCG mechanism achieved an up to 2.2% improvement in terms of the number of vehicles that were charged compared to the fixed-price one and, in cases where the stations were congested, it calculated higher prices for the EVs and provided a higher profit for the stations, but lower utility to the EVs. However, in a theoretical evaluation, we proved that the variant of the VCG mechanism being proposed in this paper still guaranteed truthful reporting of the EVs’ preferences. In contrast, the fixed-price one was found to be vulnerable to agents’ strategic behavior as non-truthful EVs can charge instead of truthful ones. Finally, we observed the online algorithms to be, on average, at 95.6% of the offline ones in terms of the average number of serviced EVs.
- Published
- 2022
- Full Text
- View/download PDF
48. Male siblings with schizophrenia share alleles at the androgen receptor above chance expectation
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A. Boccio-Smith, Raymond Lofthouse, Nick Bass, L. E. Delisis, Mark Poulter, Antonio Vita, G. Shields, G. Chen, Carla Morganti, Cassandra L. Smith, Timothy J. Crow, and T. Shah
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Male ,Linkage (software) ,Genetics ,Psychosis ,X Chromosome ,Genetic inheritance ,Genetic Linkage ,fungi ,Biology ,medicine.disease ,Mental illness ,Androgen receptor ,Receptors, Androgen ,Schizophrenia ,medicine ,Humans ,Allele ,Gene ,Alleles ,Genetics (clinical) ,Probability - Abstract
In families that included two or more siblings with schizophrenia or schizo-affective disorder male-male pairs were found to share alleles at the androgen receptor (AR) gene (in Xq11.2-q12) above chance expectation (p < 0.003); female-female and mixed sex pairs showed no such tendency. The findings are compatible with X-Y linkage or with an X-linked contribution to liability in males. © 1993 Wiley-Liss, Inc.
- Published
- 1993
49. SENSE: A Flow-Down Semantics-Based Requirements Engineering Framework
- Author
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Kalliopi Kravari, Christina Antoniou, and Nick Bassiliades
- Subjects
boilerplates engineering ,designing software ,ontologies ,requirements engineering ,semantics ,software management ,Industrial engineering. Management engineering ,T55.4-60.8 ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
The processes involved in requirements engineering are some of the most, if not the most, important steps in systems development. The need for well-defined requirements remains a critical issue for the development of any system. Describing the structure and behavior of a system could be proven vague, leading to uncertainties, restrictions, or improper functioning of the system that would be hard to fix later. In this context, this article proposes SENSE, a framework based on standardized expressions of natural language with well-defined semantics, called boilerplates, that support a flow-down procedure for requirement management. This framework integrates sets of boilerplates and proposes the most appropriate of them, depending, among other considerations, on the type of requirement and the developing system, while providing validity and completeness verification checks using the minimum consistent set of formalities and languages. SENSE is a consistent and easily understood framework that allows engineers to use formal languages and semantics rather than the traditional natural languages and machine learning techniques, optimizing the requirement development. The main aim of SENSE is to provide a complete process of the production and standardization of the requirements by using semantics, ontologies, and appropriate NLP techniques. Furthermore, SENSE performs the necessary verifications by using SPARQL (SPIN) queries to support requirement management.
- Published
- 2021
- Full Text
- View/download PDF
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