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1. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author: Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, F. Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O'Donovan, Shengying Qin, Akira Sawa, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Stephen J. Glatt, Xiancang Ma, Jinsong Tang, Yunfeng Ruan, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, Makoto Kinoshita, Human genetics, Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Internal medicine
Subjects: Multidisciplinary
Abstract: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.
Published: 2023
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2. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

Author: Martin Alda, Daniel R. Weinberger, Elena de la Serna, Andreas Meyer-Lindenberg, Salvador Sarró, Yoonho Chung, Sonja M C de Zwarte, Ian S. Ramsay, Benson Mwangi, Alessandro Bertolino, Marinka M.G. Koenis, Sophia I. Thomopoulos, Caroline Demro, Joaquim Radua, Ceren Hıdıroglu Ongun, Neeltje E.M. van Haren, Eduard Vieta, Sophia Frangou, Annabella Di Giorgio, Gisela Sugranyes, Scott R. Sponheim, Tomas Hajek, Bernd Kramer, Rhoshel K. Lenroot, Esma M. Simsek, Qiang Chen, Fergus Kane, Miloslav Kopecek, Anja Richter, Jim van Os, Erick J. Canales-Rodríguez, Martin Ingvar, Carrie E. Bearden, Paul M. Thompson, David C. Glahn, Scott C. Fears, Stijn Michielse, Christina M. Hultman, Nefize Yalin, Machteld Marcelis, Giulio Pergola, Aurora Bonvino, Neda Jahanshad, Wiepke Cahn, Josefina Castro-Fornieles, Vina M. Goghari, Manon H.J. Hillegers, Matthew J. Kempton, Ayşegül Özerdem, Fatma Simsek, Ingrid Agartz, Emma L. Hawkins, Sonya Foley, Elvira Bramon, Jair C. Soares, Cheryl A. Olman, Erik G. Jönsson, Oliver Gruber, René S. Kahn, Janice M. Fullerton, Leila Nabulsi, Ole A. Andreassen, Jose Manuel Goikolea, Gaelle E. Doucet, M.C. Eker, Mon Ju Wu, Aaron L. Goldman, Hilleke E. Hulshoff Pol, Stephen M. Lawrie, Venkata S. Mattay, Dara M. Cannon, Caterina del Mar Bonnín, Robin M. Murray, Marco Picchioni, Christopher R.K. Ching, Ali Saffet Gonul, Edith Pomarol-Clotet, Andreas Heinz, Silvia Alonso-Lana, Susanne Erk, Giulia Tronchin, Josselin Houenou, H. C. Whalley, Theo G.M. van Erp, Viktoria Johansson, Dolores Moreno, Henrik Walter, Timothea Toulopoulou, Bronwyn Overs, Aybala Saricicek Aydogan, Rachel M. Brouwer, Philip B. Mitchell, Colm McDonald, Peter R. Schofield, Camille Piguet, Raymond Salvador, Jason Newport, Xavier Caseras, Mar Fatjó-Vilas, Tyrone D. Cannon, Elizabeth E.L. Buimer, Gloria Roberts, Child and Adolescent Psychiatry / Psychology, Toulopoulou, Timothea, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Neurochirurgie, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Psychiatrie (3), and Ege Üniversitesi
Subjects: relatives, Library science, 050105 experimental psychology, Psykiatri, 03 medical and health sciences, 0302 clinical medicine, YOUNG-ADULTS, THICKNESS, Humans, Cognitive Dysfunction, Family, Genetic Predisposition to Disease, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, PREMORBID IQ, GENOME-WIDE ASSOCIATION, 10. No inequality, Research Articles, METAANALYSIS, National health, bipolar disorder, Psychiatry, education, neuroimaging, Radiological and Ultrasound Technology, HERITABILITY, 4. Education, 05 social sciences, intelligence, Magnetic Resonance Imaging, Educational attainment, 3. Good health, schizophrenia, INDIVIDUALS, DISCORDANT, Neurology, Research council, SCHOOL PERFORMANCE, Educational Status, Christian ministry, Neurology (clinical), Anatomy, 030217 neurology & neurosurgery, Research Article
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d= -0.42,p= 3 x 10(-5)), with weak evidence of IQ reductions among BD-FDRs (d= -0.23,p= .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. in contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment., Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1037196, 1063960, 1066177, 510135, 1176716]; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [103703, 106469, 142255]; Departament de Salut de la Generalitat de CatalunyaGeneralitat de Catalunya [SLT002/16/00331]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [1617]; Development Service Merit Review Award [I01CX000227]; Dokuz Eylul University Department of Scientific Research [2012.KB.SAG.062]; e:Med program [O1ZX1314B, O1ZX1314G]; Ege University School of Medicine Research Foundation [2009-D-00017]; Fundacio Marato TV3 [091630]; Netherlands Organisation for Health Research and DevelopmentNetherlands Organization for Health Research and Development [10-000-1002]; Generalitat de CatalunyaGeneralitat de Catalunya [2017SGR01271]; German Federal Ministry for Education and ResearchFederal Ministry of Education & Research (BMBF); Medical Research CouncilMedical Research Council UK (MRC) [G0901310]; Ministerstvo Zdravotnictvi Ceske Republiky [NR8786, NT13891]; National Alliance for Research on Schizophrenia and DepressionNARSAD [17319, 20244, 26731]; Swiss National Centre of Competence in Research Robotics [51NF40-185897]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [1S10OD017974-01, P30 NS076408, R01 MH052857, R01 MH080912, R01 MH113619, U01 MH108150, R01 MH085667]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [T32AG058507]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41 EB015922, R01 MH111671, R01 MH116147, R01 MH117601, R01MH121246, R03 MH105808, U54EB020403]; Research Council of NorwayResearch Council of Norway [223273]; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III [CPII19/00009, PI070066, PI1100683, PI1500467, PI18/00976]; Stanley Medical Research Institute; Swedish Research CouncilSwedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]; Swiss National Science FoundationSwiss National Science Foundation (SNSF) [32003B_156914]; VIDINetherlands Organization for Scientific Research (NWO) [452-11-014, 917-46-370]; Wellcome TrustWellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 064971]; ZonMwNetherlands Organization for Health Research and Development [908-02-123], Australian National Health and Medical Research Council Grants, Grant/Award Numbers: 1037196, 1063960, 1066177, 510135, 1176716; Canadian Institutes of Health Research, Grant/Award Numbers: 103703, 106469, 142255; Departament de Salut de la Generalitat de Catalunya, Grant/Award Number: SLT002/16/00331; Deutsche Forschungsgemeinschaft, Grant/Award Number: 1617; Development Service Merit Review Award, Grant/Award Number: I01CX000227; Dokuz Eylul University Department of Scientific Research Projects Funding, Grant/Award Number: 2012.KB.SAG.062; e:Med program, Grant/Award Numbers: O1ZX1314B, O1ZX1314G; Ege University School of Medicine Research Foundation, Grant/Award Number: 2009-D-00017; Fundacio Marato TV3, Grant/Award Number: 091630; Geestkracht program of the Netherlands Organisation for Health Research and Development, Grant/Award Number: 10-000-1002; Generalitat de Catalunya, Grant/Award Number: 2017SGR01271; German Federal Ministry for Education and Research; Medical Research Council, Grant/Award Number: G0901310; Ministerstvo Zdravotnictvi Ceske Republiky, Grant/Award Numbers: NR8786, NT13891; National Alliance for Research on Schizophrenia and Depression, Grant/Award Numbers: 17319, 20244, 26731; Swiss National Centre of Competence in Research Robotics, Grant/Award Number: 51NF40-185897; National Institute of Mental Health, Grant/Award Numbers: 1S10OD017974-01, P30 NS076408, R01 MH052857, R01 MH080912, R01 MH113619, U01 MH108150, R01 MH085667; National Institute on Aging, Grant/Award Number: T32AG058507; National Institutes of Health, Grant/Award Numbers: P41 EB015922, R01 MH111671, R01 MH116147, R01 MH117601, R01MH121246, R03 MH105808, U54EB020403; Research Council of Norway, Grant/Award Number: 223273; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III, Grant/Award Numbers: CPII19/00009, PI070066, PI1100683, PI1500467, PI18/00976; Stanley Medical Research Institute; Swedish Research Council, Grant/Award Numbers: K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3; Swiss National Science Foundation, Grant/Award Number: 32003B_156914; VIDI, Grant/Award Numbers: 452-11-014, 917-46-370; Wellcome Trust, Grant/Award Numbers: 085475/B/08/Z, 085475/Z/08/Z; Wellcome Trust Research Training Fellowship, Grant/Award Number: 064971; ZonMw, Grant/Award Number: 908-02-123
Published: 2022
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3. Genetic copy number variants, cognition and psychosis

Author: Ruud van Winkel, Eugenia Kravariti, Matthias Weisbrod, Jim van Os, Bart P. F. Rutten, Lieuwe de Haan, Vaughan Bell, Behrooz Z. Alizadeh, Katja Schulze, Benedicto Crespo-Facorro, Claudia J. P. Simons, Jurjen J. Luykx, Assen Jablensky, Wiepke Cahn, Conrad Iyegbe, Frederike Schirmbeck, Elvira Bramon, John Powell, Jasmine Harju-Seppänen, Jeremy Hall, Rebecca M. Jones, René S. Kahn, Robin M. Murray, Luba Kalaydjieva, Dan Rujescu, Sonja M C de Zwarte, Marco Picchioni, Johan H. Thygesen, Roel A. Ophoff, Anjali Bhat, Therese van Amelsvoort, Timothea Toulopoulou, Siri Ranlund, Rebecca Muir, Kuang Lin, Diana Prata, Mei-Hua Hall, Ignacio Mata, Muriel Walshe, Stephen M. Lawrie, Karoline Kuchenbaecker, Madiha Shaikh, Eirini Zartaloudi, Isabelle Austin-Zimmerman, Evangelos Vassos, Richard Bruggeman, Agna A. Bartels-Velthuis, Andrew M. McIntosh, Haritz Irizar, Neeltje E.M. van Haren, Marta Di Forti, Andrew McQuillin, Alvaro Diez-Revuelta, Cathryn M. Lewis, Amelia Presman, Stella Calafato, Colm McDonald, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Psychiatry, Child and Adolescent Psychiatry / Psychology, University of Groningen, Perceptual and Cognitive Neuroscience (PCN), Toulopoulou, Timothea, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, RS: MHeNs - R2 - Mental Health, MUMC+: MA Med Staf Spec Psychiatrie (9), MUMC+: Hersen en Zenuw Centrum (3), Medical Research Council (UK), Wellcome Trust, NIHR Biomedical Research Centre (UK), NHS Foundation Trust, University College London, National Institute for Health Research (UK), European Research Council, European Commission, Instituto de Salud Carlos III, Fundació Seny, Fundación Ramón Areces, and Fundación Marques de Valdecilla
Subjects: 16P11.2, Schizophrenia/genetics, endocrine system diseases, Ciências Sociais::Psicologia [Domínio/Área Científica], PHENOTYPE, Cognition, 0302 clinical medicine, DEFICITS, DUPLICATIONS, SCHIZOPHRENIA, Medicine, Copy-number variation, Psychotic Disorders/genetics, Psychiatry, RISK, 0303 health sciences, Ciências Médicas::Medicina Clínica [Domínio/Área Científica], Genetic Predisposition to Disease/genetics, ASSOCIATION, ABILITY, 3. Good health, Psychiatry and Mental health, Schizophrenia, Meta-analysis, Life Sciences & Biomedicine, Clinical psychology, Biochemistry & Molecular Biology, Psychosis, congenital, hereditary, and neonatal diseases and abnormalities, DNA Copy Number Variations, VERBAL MEMORY, DNA Copy Number Variations/genetics, Predictive markers, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, mental disorders, Genetics, Humans, Genetic Predisposition to Disease, Ciências Naturais::Ciências Biológicas [Domínio/Área Científica], Molecular Biology, 030304 developmental biology, Science & Technology, Recall, business.industry, Neurosciences, medicine.disease, DELETIONS, Psychotic Disorders, Endophenotype, Neurosciences & Neurology, Verbal memory, business, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract: The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.
Published: 2021
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4. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022
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5. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Andreas J. Forstner, Martin Alda, Manolis Kogevinas, Pak C. Sham, Patrick F. Sullivan, Michele T. Pato, John R. Kelsoe, Paul A. Tooney, Steven P. Hamilton, Dorret I. Boomsma, Gerome Breen, Tracy Air, Hannelore Ehrenreich, Nakao Iwata, Jill M. Goldstein, Olav B. Smeland, Daniel R. Weinberger, Andrew McQuillin, Stuart A. Tobet, Elvira Bramon, Gabriëlla A.M. Blokland, Jing Qin Wu, Erik G. Jönsson, Peter R. Schofield, Fabian Streit, Nicholas Bass, Aarno Palotie, Brian Kelly, Cathryn M. Lewis, Srdjan Djurovic, Thomas Damm Als, Chia-Yen Chen, Bettina Konte, Joanna Hauser, Claire O'Donovan, Laura J. Scott, Hans J. Grabe, Murray J. Cairns, Rudolf Uher, Pablo Cervantes, Nicholas G. Martin, James A. Knowles, Aiden Corvin, Espen Molden, Lili Milani, Andreas Reif, Maria Grigoroiu-Serbanescu, George Kirov, Yuri Milaneschi, David St Clair, Eco J. C. de Geus, Robert Handa, Tõnu Esko, Alexander Teumer, Anders D. Børglum, Divya Mehta, Roel A. Ophoff, Susanne Lucae, Henning Tiemeier, Marion Leboyer, Ina Giegling, Alan R. Sanders, Jouke-Jan Hottenga, Pablo V. Gejman, Bernhard T. Baune, Brenda W.J.H. Penninx, Chris Cotsapas, Martin Preisig, Thomas Werge, Jakob Grove, Ingrid Melle, Jordan W. Smoller, Marcella Rietschel, Myrna M. Weissman, Preben Bo Mortensen, Philip B. Mitchell, Jolanta Lissowska, Andrew M. McIntosh, Annette M. Hartmann, Ole A. Andreassen, Lea Sirignano, John B. Vincent, Niamh Mullins, Jimmy Lee, Gonneke Willemsen, Marian L. Hamshere, Rolf Adolfsson, Mark A. Frye, Markus M. Nöthen, Jianxin Shi, Ashley L. Comes, Robin M. Murray, Patrik K. E. Magnusson, Frank Bellivier, Stéphane Jamain, Ole Mors, Sven Cichon, Uwe Völker, Fermín Mayoral, Bryan J. Mowry, Bruno Etain, James B. Potash, Beata Świątkowska, Bertram Müller-Myhsok, Mikael Landén, Tracey L. Petryshen, Franziska Degenhardt, Mark Adams, Dan Rujescu, Jose Guzman-Parra, Thomas G. Schulze, Merete Nordentoft, Joseph D. Buxbaum, Janice M. Fullerton, Brien P. Riley, Roy H. Perlis, Arne E. Vaaler, David M. Hougaard, Eli A. Stahl, Susan L. McElroy, Sabrina K. Schaupp, Martin Begemann, Sandra Van der Auwera, Todd Lencz, Joanna M. Biernacka, Agnes A. Steixner-Kumar, Douglas F. Levinson, Sathish Periyasamy, Alexander Viktorin, and Anil K. Malhotra
Subjects: Genetics, 0303 health sciences, Medizin, Locus (genetics), Genomics, Biology, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Mood, medicine, Major depressive disorder, Bipolar disorder, Gene, NKAIN2 Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.METHODSWe conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassingNKAIN2(rs117780815;p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p−6) for cross-disorder GxS interaction (rs7302529,p=1.6×10−7; rs73033497,p=8.8×10−7; rs7914279,p=6.4×10−7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitorSLTM. Most significant in SCZ was aMOCOSgene locus (rs11665282;p=1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509;p=1.1×10−7) in a locus containingIDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDRCONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Published: 2022

6. Lack of support for the genes by early environment interaction hypothesis in the pathogenesis of schizophrenia

Author: Cathryn M. Lewis, Robin M. Murray, Christina M. Hultman, Mirella Ruggeri, Sarah E. Bergen, Michael Conlon O'Donovan, Sarah Tosato, Jiaqi Kou, Charlotte Dennison, Patrick F. Sullivan, Evangelos Vassos, Muriel Walshe, Gerome Breen, James T.R. Walters, Sophie E. Legge, Jessye Maxwell, Elvira Bramon, and Michael John Owen
Subjects: Psychosis, AcademicSubjects/MED00810, Birth weight, Bioinformatics, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Medicine, psychosis, Gene–environment interaction, placenta biology, Gene, 030304 developmental biology, 0303 health sciences, Pregnancy, business.industry, gene environment interaction, obstetric complications, medicine.disease, early life events, Psychiatry and Mental health, Schizophrenia, Cohort, polygenic risk score, business, 030217 neurology & neurosurgery, Regular Articles
Abstract: Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy.
Published: 2022

7. The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics

Author: Marta Wronska, Jasmine Harju-Seppänen, Johan H. Thygesen, Elvira Bramon, Karoline Kuchenbaecker, Anjali Bhat, Andrew McQuillin, Baihan Wang, Chris Finan, Spiros Denaxas, Eirini Zartaloudi, Isabelle Austin-Zimmerman, Olga Giannakopoulou, Ghazaleh Fatemifar, and Haritz Irizar
Subjects: Adult, Male, medicine.medical_specialty, CYP2D6, UK Biobank, HbA1c, Pharmacogenomic Variants, medicine.medical_treatment, Venlafaxine, CYP2C19, QH426-470, Risk Assessment, digestive system, Article, Diabetes mellitus, Internal medicine, medicine, Diabetes Mellitus, Genetics, Humans, Precision Medicine, Antipsychotic, skin and connective tissue diseases, Genetics (clinical), Aged, Biological Specimen Banks, pharmacogenetics, Glycated Hemoglobin, Fluoxetine, diabetes, business.industry, personalized medicine, Middle Aged, medicine.disease, Paroxetine, Antidepressive Agents, United Kingdom, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP2D6, Female, business, Pharmacogenetics, medicine.drug, Antipsychotic Agents
Abstract: CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol, p &lt, 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol, 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference −7.74 mmol/mol, p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics.
Published: 2021

8. A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

Author: Guiyan Ni, Jian Zeng, Joana A. Revez, Ying Wang, Zhili Zheng, Tian Ge, Restuadi Restuadi, Jacqueline Kiewa, Dale R. Nyholt, Jonathan R.I. Coleman, Jordan W. Smoller, Jian Yang, Peter M. Visscher, Naomi R. Wray, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Psychosis Endophenotypes International Consortium, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Kari Stefansson, Wellcome Trust Case-Control Consortium, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Héléna A. Gaspar, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Paul F. O’Reilly, Hogni Oskarsson, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, John P. Rice, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Fabian Streit, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Yunpeng Wang, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Futao Zhang, Volker Arolt, Bernhard T. Baune, Klaus Berger, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond DePaulo, Katharina Domschke, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Preben Bo Mortensen, Merete Nordentoft, Sara A. Paciga, Nancy L. Pedersen, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Ni, Guiyan, Zeng, Jian, Revez, Joana A., Wang, Ying, Zhili, Zheng, Ge, Tian, Restuadi, Restuadi, Kiewa, Jacqueline, Nyholt, Dale R, Coleman, Jonathan RI, Smoller, Jordan W, Lee, S Hong, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Econometrics, Psychiatry, Department of Technology and Operations Management, Child and Adolescent Psychiatry / Psychology, Epidemiology, Erasmus MC other, Urology, Internal Medicine, Medical Informatics, Immunology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Multifactorial Inheritance, medicine.medical_specialty, LDpred2, BF, Genomics, Disease, Major depressive disorder, risk prediction, 03 medical and health sciences, 0302 clinical medicine, MegaPRS, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetic risk, Psychiatry, Biological Psychiatry, Genetic association, Depressive Disorder, Major, business.industry, Mental Disorders, medicine.disease, Genetic architecture, Polygenic scores, Risk prediction, polygenic scores, PRS-CS, psychiatric disorders, 030104 developmental biology, SBayesR, Schizophrenia, Cohort, Lassosum, RC0321, business, Psychiatric disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.
Published: 2021
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9. Towards safer risperidone prescribing in Alzheimer’s disease

Author: Mikail Ozer, Kathy Y. Liu, Hiroyuki Uchida, Yohei Otani, Robert R. Bies, Bruce G. Pollock, Elvira Bramon, Suzanne Reeves, Julie Bertrand, Robert Howard, and Kazunari Yoshida
Subjects: medicine.medical_specialty, Psychosis, Risperidone, business.industry, medicine.medical_treatment, Disease, Logistic regression, medicine.disease, Pharmacokinetics, Internal medicine, Medicine, Dosing, business, Antipsychotic, Active metabolite, medicine.drug
Abstract: BackgroundIn the treatment of psychosis, agitation and aggression in Alzheimer’s disease (AD), guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing.AimsThis analysis investigated the pharmacokinetic profiles of risperidone and active metabolite, 9-hydroxy (OH)-risperidone, and how this related to emergent extrapyramidal side effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness-AD study.MethodA statistical model, which described the concentration-time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (108 CATIE-AD participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model based predictions were used to simulate the dose adjustments needed to avoid EPS.ResultsThe model showed an age-related reduction in risperidone clearance (pppConclusionsOur findings argue for age- and MMSE -related dose adjustments and suggest that a single plasma sample could be used to identify those with slower drug clearance.
Published: 2020
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10. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author: Eleni Giannoulatou, Nancy Buccola, Tune Pers, Sarah TOSATO, Christos Pantelis, James Walters, Hon-Cheong So, Igor Nenadić, Joseph Buxbaum, Lili Milani, Miloš Milovančević, Naomi Wray, Joanne Knight, Nicholas Wood, Srihari Gopal, Silviu-Alin Bacanu, Colin Palmer, Inez Myin-Germeys, Francis Anthony O'Neill, Matthew A Brown, Sang Hong Lee, Robert Plomin, Peter Visscher, Tracey Petryshen, Preben Bo Mortensen, Thomas Folkmann Hansen, Esben Agerbo, Digby Quested, Jianjun Liu, Engilbert Sigurdsson, Sara Marsal, Céline Bellenguez, Robert Freedman, Panos Deloukas, Ditte Demontis, Donald Black, David Collier, Fritz Zimprich, Clement C Zai, Nakao IWATA, Elvira Bramon, Masashi Ikeda, Andrew McIntosh, Bryan Mowry, Patrik Magnusson, Janis Klovins, Srdjan Djurovic, Jim Van Os, Ulrich Schall, Jan Lubinski, Milica Pejovic Milovancevic, Kang Sim, Rodney Scott, Anders Børglum, Jennifer Moran, Denise Harold, Sergi Papiol, Bradley Webb, Elisabeth Stögmann, Davidson, Michael, Germeys, Inez, Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Donohoe, Gary, Gill, Michael, Corvin, Aiden, Morris, Derek W, Lee, SH, Schizophrenia Working Group of the Psychiatric Genomics Consortuim, Wellcome Trust Case Control Consortium, National Institutes of Health, Science Foundation Ireland, Wellcome Trust, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, and Adult Psychiatry
Subjects: Male, Genome-wide association study, WHOLE-GENOME ASSOCIATION, Identity by descent, 0302 clinical medicine, Risk Factors, Databases, Genetic, 2.1 Biological and endogenous factors, GWAS, Exome, Copy-number variation, Aetiology, Genetics (clinical), Exome sequencing, Genetics & Heredity, Psychiatry, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Chromosome Mapping, Middle Aged, Serious Mental Illness, 3. Good health, Psychiatry and Mental health, Mental Health, DISEASES, Female, BURDEN, Sequence Analysis, Life Sciences & Biomedicine, Adult, GENES, DNA Copy Number Variations, Genotype, DISORDERS, Clinical Sciences, Single-nucleotide polymorphism, Computational biology, Biology, IBD mapping, Article, Databases, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetic, Clinical Research, Exome Sequencing, rare variants, Genetics, Humans, Genetic Predisposition to Disease, AUTISM, Genome‐wide association studies (GWASs), 030304 developmental biology, Genetic association, Science & Technology, risk variants, Prevention, Wellcome Trust Case Control Consortium 2, Human Genome, Haplotype, Neurosciences, DNA, Sequence Analysis, DNA, Brain Disorders, Haplotypes, DE-NOVO MUTATIONS, Case-Control Studies, API, Schizophrenia, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes. National Institutes of Health, Grant/Award Numbers: R01‐MH041953, R01‐MH083094; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359, 12/IP/1670; Wellcome Trust, Grant/Award Number: 085475/B/08/Z peer-reviewed
Published: 2019
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11. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author: Elodie Drapeau, Robert W. McCarley, Jim van Os, Svetlana A. Limborska, Elvira Bramon, Milan Macek, Divya Mehta, Lieuwe de Haan, Christos Pantelis, Inge Joa, Daniel R. Weinberger, Andrew McQuillin, Lynn E. DeLisi, Ulrich Schall, Tõnu Esko, Digby Quested, Jacob Gratten, Gary Donohoe, Kenneth S. Kendler, Derek W. Morris, Ole A. Andreassen, Peter M. Visscher, Valentina Escott-Price, Lyudmila Georgieva, John L. Waddington, Sara Marsal, Naomi R. Wray, Danielle Posthuma, Benedicto Crespo-Facorro, Rita M. Cantor, Ariel Darvasi, Béla Melegh, Jing Qin Wu, Zhihong Zhu, Kieran C. Murphy, Felix C. Tropf, Inez Myin-Germeys, Antonio Julià, Paul A. Tooney, Frans Henskens, C. Robert Cloninger, Bryan J. Mowry, Larry J. Seidman, Bernard Lerer, Andres Metspalu, Carmel M. Loughland, Mark Weiser, Gibran Hemani, Ann Olincy, Joseph D. Buxbaum, Silviu-Alin Bacanu, Srdjan Djurovic, Andrew M. McIntosh, Jian Yang, Patricia T. Michie, Harold Snieder, Richard Bruggeman, John J. McGrath, Nicola Barban, Rodney J. Scott, Nelson B. Freimer, Timothy G. Dinan, Melinda Mills, S. Hong Lee, David Cohen, Andrey Khrunin, Andrew Bakshi, Murray J. Cairns, Patrik K. E. Magnusson, Draga Toncheva, Universidad de Cantabria, Mehta, Divya, Tropf, Felix C, Gratten, Jacob, Bakshi, Andrew, Zhu, Zhihong, Bacanu, Silviu-Alin, Hemani, Gibran, Magnusson, Patrik KE, Barban, Nicola, Esko, Tonu, Metspalu, Andres, Snieder, Harold, Mowry, Bryan J, Kendler, Kenneth S, Yang, Jian, Visscher, Peter M, McGrath, John J, Mills, Melinda C, Wray, Naomi R, Lee, S Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, TwinsUK, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), Psychiatrie & Neuropsychologie, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Adult Psychiatry, Sociology/ICS, Life Course Epidemiology (LCE), Mehta Divya, Tropf Felix C., Gratten Jacob, Bakshi Andrew, Zhu Zhihong, Bacanu Silviu-Alin, Hemani Gibran, Magnusson Patrik K. E., BARBAN N, Esko Tonu, Metspalu Andre, Snieder Harold, Mowry Bryan J., Kendler Kenneth S., Yang Jian, Visscher Peter M., McGrath John J., Mills Melinda C., Wray Naomi R., and Lee S. Hong
Subjects: 0301 basic medicine, Denmark, Genome-wide association study, genetic risk, Cohort Studies, 0302 clinical medicine, Pregnancy, GWAS, genetics, Psychiatry, RISK, PSYCHIATRIC-DISORDERS, BIPOLAR DISORDER, 3. Good health, Psychiatry and Mental health, Birth order, Phenotype, PATERNAL AGE, Schizophrenia, Female, Maternal Age, Cohort study, Adult, medicine.medical_specialty, Offspring, Article, 03 medical and health sciences, PSYCHOSIS, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Alleles, Genetic association, genome-wide association study, business.industry, medicine.disease, de novo mutation, schizophrenia, 030104 developmental biology, maternal age, DE-NOVO MUTATIONS, Birth Order, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography, first birth
Abstract: IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18?957 SCZ cases and 22?673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12?247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2?=?1.1E-03, P?=?4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers. This research is supported by grants 613602, 1047956, 1078901, 1080157, 1087889, and 1067795 from the Australian National Health and Medical Research Council and by grants DE130100614 and DP160102126 from the Australian Research Council. Primary analyses of the SchizophreniaWorking Group of the Psychiatric Genomics Consortium data were conducted on the Genetic Cluster Computer (http://www .geneticcluster.org) hosted by SURFsara and supported by grant NOW480-05-003 from the Netherlands Scientific Organization, along with a supplement from the Dutch Brain Foundation and the Vrije Universitiet Amsterdam. TwinsUK was funded by theWellcome Trust, by grant FP7/2007-2013 from the European Community’s Seventh Framework Programme, and by support from the National Institute for Health Research–funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London, and single-nucleotide polymorphism genotyping was performed by theWellcome Trust Sanger Institute and National Eye Institute via the National Institute for Health/Center for Inherited Disease Research. Estonian Genome Center Biobank, University of Tartu, received targeted financing by grant IUT20-60 from the Estonian Research Council, Center of Excellence in Genomics, and University of Tartu, and data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. The Swedish Twin Registry is supported by Karolinska Institutet. Mr Tropf received funding from sciencestarter.de for a research visit to The University of Queensland. The research leading to these results received funding from the European Research Council via an ERC Consolidator Grant SOCIOGENOME (grant 615603 awarded to Dr Mills [http://www.sociogenome.com]).
Published: 2016
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12. The interplay between genetics, cognition and schizophrenia

Author: Elvira Bramon and Maria Stella Calafato
Subjects: Adult, Male, Multifactorial Inheritance, Schizophrenia (object-oriented programming), Cognition, Middle Aged, Scientific Commentaries, humanities, Young Adult, Risk Factors, Schizophrenia, Humans, Female, Genetic Predisposition to Disease, Neurology (clinical), Psychology, Clinical psychology, Signal Transduction
Abstract: Cognitive deficit is thought to represent, at least in part, genetic mechanisms of risk for schizophrenia, with recent evidence from statistical modelling of twin data suggesting direct causality from the former to the latter. However, earlier evidence was based on inferences from twin not molecular genetic data and it is unclear how much genetic influence 'passes through' cognition on the way to diagnosis. Thus, we included direct measurements of genetic risk (e.g. schizophrenia polygenic risk scores) in causation models to assess the extent to which cognitive deficit mediates some of the effect of polygenic risk scores on the disorder. Causal models of family data tested relationships among key variables and allowed parsing of genetic variance components. Polygenic risk scores were calculated from summary statistics from the current largest genome-wide association study of schizophrenia and were represented as a latent trait. Cognition was also modelled as a latent trait. Participants were 1313 members of 1078 families: 416 patients with schizophrenia, 290 unaffected siblings, and 607 controls. Modelling supported earlier findings that cognitive deficit has a putatively causal role in schizophrenia. In total, polygenic risk score explained 8.07% [confidence interval (CI) 5.45-10.74%] of schizophrenia risk in our sample. Of this, more than a third (2.71%, CI 2.41-3.85%) of the polygenic risk score influence was mediated through cognition paths, exceeding the direct influence of polygenic risk score on schizophrenia risk (1.43%, CI 0.46-3.08%). The remainder of the polygenic risk score influence (3.93%, CI 2.37-4.48%) reflected reciprocal causation between schizophrenia liability and cognition (e.g. mutual influences in a cyclical manner). Analysis of genetic variance components of schizophrenia liability indicated that 26.87% (CI 21.45-32.57%) was associated with cognition-related pathways not captured by polygenic risk score. The remaining variance in schizophrenia was through pathways other than cognition-related and polygenic risk score. Although our results are based on inference through statistical modelling and do not provide an absolute proof of causality, we find that cognition pathways mediate a significant part of the influence of cumulative genetic risk on schizophrenia. We estimate from our model that 33.51% (CI 27.34-43.82%) of overall genetic risk is mediated through influences on cognition, but this requires further studies and analyses as the genetics of schizophrenia becomes better characterized.
Published: 2019

13. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author: Laura M. Thornton, Paul Lichtenstein, Verneri Anttila, Diego Albani, Josep Antoni Ramos-Quiroga, Roger A.H. Adan, Monika Schlögelhofer, Stephen Sanders, Enrique Castelao, Klaus Berger, Nina Dalkner, Urs Heilbronner, Engilbert Sigurdsson, Pablo Mir, Fuquan Zhang, James T.R. Walters, Patrick F. Sullivan, Fragiskos Gonidakis, F. Kyle Satterstrom, Sara Marsal, Per Hoffmann, Amy Perry, Valentina Ciullo, Beate Herpertz-Dahlmann, Catharina Lavebratt, Kieran C. Murphy, Tammy Hedderly, Hyun Ju Hong, Evald Saemundsen, Sascha B. Fischer, Hailiang Huang, Andrew D. Grotzinger, Nienke Vulink, Murray B. Stein, Mark A. Frye, Laura J. Scott, David Curtis, Todd Lencz, Janiece E. DeSocio, Richard A. Belliveau, Eduard Vieta, Andrea Dietrich, Wade H. Berrettini, Kenneth S. Kendler, Marquis P. Vawter, Paul S. Nestadt, Michael E. Talkowski, Manuel Mattheisen, Ingrid Agartz, Elisa Docampo, Bernhard T. Baune, Stefan Ehrlich, Jolanta Lissowska, Felecia Cerrato, Terje Nærland, Robin M. Murray, Jennifer Reichert, Annette M. Hartmann, Hannelore Ehrenreich, Howard J. Edenberg, Katherine A. Halmi, Qingqin S. Li, Peristera Paschou, Marie Bækvad-Hansen, Esther Walton, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Frank Bellivier, Jungeun Song, D. Blake Woodside, Young Shin Kim, Jochen Seitz, Jacques Pantel, Palmiero Monteleone, Erika L. Nurmi, Rodney J. Scott, Kang Sim, Ekaterina A. Khramtsova, Udo Dannlowski, Rolf Adolfsson, Danielle Posthuma, Melissa J. Green, Laura Ibanez-Gomez, Jakob Grove, Elvira Bramon, Gregory L. Hanna, Cynthia M. Bulik, Yiran Guo, Stephan Ripke, Mary M. Robertson, Harald N. Aschauer, Adebayo Anjorin, Joanna Martin, Bertram Müller-Myhsok, Deborah Kaminská, Jose Guzman-Parra, Benedetta Nacmias, Erik G. Jönsson, Jonathan R. I. Coleman, Douglas F. Levinson, Hamdi Mbarek, Gun Peggy Knudsen, Karin Egberts, Mette Nyegaard, Patrik K. E. Magnusson, Mark Adams, Douglas Blackwood, Elisabeth B. Binder, Marcus Ising, Anna R. Docherty, Jim van Os, Nese Direk, Lina Martinsson, Maria Arranz, Christel M. Middeldorp, Stefan Kloiber, Sintia Iole Belangero, Eske M. Derks, Ingrid Melle, Erlend Bøen, Jan Haavik, Federica Piras, Unna N. Danner, Anil K. Malhotra, Gerome Breen, Stephen V. Faraone, Amanda B Zheutlin, Timothy Poterba, Stephan Ruhrmann, Inge Joa, Ulrik Fredrik Malt, Sarah E. Bergen, Federica Tozzi, Lauren A. Weiss, Hana Papezova, Dominic Holland, Elliot S. Gershon, Jaakko Kaprio, Merete Nordentoft, Scott D. Gordon, Christopher Pittenger, Keun-Ah Cheon, Jennifer Jordan, Philip Gorwood, Myrna M. Weissman, Preben Bo Mortensen, Melissa A. Munn-Chernoff, Isobel Heyman, Eun-Young Shin, Christie L. Burton, Katherine Gordon-Smith, Sietske G. Helder, Peter Nagy, Till F. M. Andlauer, Yunpeng Wang, Young Key Kim, Kate Langley, Søren Dalsgaard, Richard Delorme, Torbjørn Elvsåshagen, Bennett L. Leventhal, Giovanni Gambaro, Christos Androutsos, Jennifer Tübing, Marion Roberts, Annelie Nordin Adolfsson, Hakon Hakonarson, Dorothy E. Grice, Vaughan J. Carr, Konstantinos Tziouvas, Stephanie Zerwas, Cathy L. Barr, Michael Conlon O'Donovan, Per Qvist, Beate St Pourcain, Samuel Kuperman, Leila Karhunen, Jack Samuels, Markus M. Nöthen, Martien J H Kas, Alfonso Tortorella, Mikael Landén, Jennifer Crosbie, Marco A. Grados, Joanna M. Biernacka, Paul D. Arnold, Irene A. Malaty, Jurjen J. Luykx, Nicholas Bass, Naomi R. Wray, Catharina A. Hartman, Christina M. Hultman, Michael S. Okun, Brandon Wormley, Michael Bauer, Daniel J. Smith, Ian Jones, Kathryn Roeder, Brien P. Riley, Caroline M. Nievergelt, Katrin Gade, Sarah Kittel-Schneider, Roy H. Perlis, James R. Mitchell, Ziarih Hawi, James Lee, Liz Forty, William E. Bunney, Thomas Damm Als, Catherine Schaefer, Digby Quested, Matteo Cassina, Anna C. Koller, Patrick Turley, Agnes A. Steixner, Anu Raevuori, Assen Jablensky, Peter Holmans, Dong-Ho Song, S. Evelyn Stewart, Jan K. Buitelaar, Fernando S. Goes, Alexander Münchau, Ayman H. Fanous, Nicolas Ramoz, James B. Potash, Monica Gratacos Mayora, Tobias Banaschewski, Céline S. Reinbold, Renata Rizzo, Arianna Di Florio, Lenka Foretova, Gianfranco Spalletta, Aarno Palotie, Eleftheria Zeggini, Lawrence W. Brown, Julie K. O'Toole, Lynn E. DeLisi, Ulrich Schall, Mary Roberson, Barbara J. Coffey, Bryan J. Mowry, Murray J. Cairns, Dan J. Stein, Glyn Lewis, Marta Ribasés, C. Robert Cloninger, Bettina Konte, John B. Vincent, Duncan S. Palmer, Radhika Kandaswamy, Christine Ladd-Acosta, Lars Alfredsson, Frank Visscher, Ulrike Schmidt, Aiden Corvin, Susan L. Santangelo, Brenda W.J.H. Penninx, David J. Porteous, Tetsuya Ando, Arne E. Vaaler, Bru Cormand, Laura Carlberg, Claire Churchhouse, Manfred Stuhrmann, Niamh Mullins, Christine Søholm Hansen, Cathy L. Budman, Hartmut Imgart, Dan E. Arking, James J. McGough, Michael Gill, Christel Depienne, Roland Burghardt, Antonio Julià, Anders M. Dale, Sven Sandin, Katharina Domschke, Maria Grigoroiu-Serbanescu, Susana Jiménez-Murcia, Marianne Giørtz Pedersen, Zsanett Tarnok, Gisli Baldursson, Michele T. Pato, David M. Hougaard, Thorgeir E. Thorgeirsson, Katharina Bey, Kerstin J. Plessen, Margaret A. Richter, Ole A. Andreassen, Claudine Laurent-Levinson, Leonid Padyukov, Jacques Mallet, Daniela Degortes, John R. Kelsoe, Robert D. Levitan, Andreas Reif, Chaim Huyser, Derek W. Morris, Sina Wanderer, William Byerley, Edna Grünblatt, E.J.C. de Geus, Hyejung Won, Josephine Elia, Rudolf Uher, Jay A. Tischfield, Andreas Karwautz, Gustavo Turecki, Pieter J. Hoekstra, Dorret I. Boomsma, Jacob Rosenthal, Daniele Cusi, Michael C. Neale, Sara Mostafavi, Gwyneth Zai, F. Anthony O'Neill, Gary Donohoe, Karola Rehnström, Harry Brandt, Helena Gaspar, Francis J. McMahon, H-Erich Wichmann, Andrew W. Bergen, Giovanni Coppola, Lea K. Davis, Lenka Slachtova, Olav B. Smeland, Erin C. Dunn, Nicholas G. Martin, Allan L. Naarden, Jo Knight, Cristina Sánchez-Mora, Masashi Ikeda, Lorraine Southam, Sandro Sorbi, Barbara Franke, Martin Schalling, Russell Schachar, Yen-Chen Anne Feng, Kirsten R. Müller-Vahl, André Scherag, Zhaozhong Zhu, Eric A. Storch, Páll Magnússon, David Cohen, Olafur O Gudmundsson, Harvey S. Singer, Brian Kelly, Jonas Bybjerg-Grauholm, Blanca Garcia-Delgar, Thomas Hansen, Carmel M. Loughland, Christine Lochner, Stacy Steinberg, Martin Woods, Jorge A. Quiroz, Raquel Rabionet, Alden Y. Huang, Janice M. Fullerton, María Soler Artigas, Hans J. Grabe, Philip Asherson, Margit Burmeister, Alicia R. Martin, Martin A. Kennedy, Janet Treasure, Anders D. Børglum, Eva C. Schulte, Andreas Hartmann, Frans Henskens, Youl-Ri Kim, Jens Treutlein, Joanna Hauser, Manfred M. Fichter, Damiaan Denys, Ann E. Pulver, Kelly L. Klump, Paul Sandor, Michael Wagner, Philippe Courtet, Sandra Van der Auwera, Susanne Lucae, Eystein Stordal, Michel G. Nivard, Maurizio Clementi, Astrid Morer, Philip B. Mitchell, Huda Akil, Edwin H. Cook, Jennifer L. Moran, Donald W. Black, Jeremiah M. Scharf, Jana Strohmaier, Colm McDonald, Meg M.-J. Wang, Richard M. Myers, Stephanie Godard, Pablo V. Gejman, Athanasios Maras, Marcella Rietschel, Nancy G. Buccola, Konstantinos Hatzikotoulas, Dalila Pinto, Jouke-Jan Hottenga, Kari Stefansson, James S. Sutcliffe, Andres Metspalu, Amaia Hervás, Joel Gelernter, Wolfgang Herzog, Paula Rovira, Gunnar Morken, Tara Murphy, Mark Weiser, Vincent Millischer, Frank Dudbridge, Dan Rujescu, Vladimir Bencko, Valdo Ricca, Kimberly Chambert, Guy A. Rouleau, James J. Crowley, Thomas G. Schulze, Toni-Kim Clarke, Triinu Peters, Gudrun Wagner, Daniel A. Geller, Henry R. Kranzler, G. Bragi Walters, Vera Golimbet, Clement C. Zai, Nigel Williams, Andreas Birgegård, Joseph D. Buxbaum, Elliot M. Tucker-Drob, Jerome C. Foo, Tracey L. Petryshen, Daniel P. Howrigan, Hunna J. Watson, Franziska Degenhardt, Peter R. Schofield, Jesper Buchhave Poulsen, Stefan Herms, Johannes Hebebrand, Mario Maj, George Kirov, Fabrizio Piras, Sara McDevitt, James T. McCracken, Carol A. Mathews, Michael John Owen, Peter Falkai, Donald L. Gilbert, Enda M. Byrne, Fernando Fernández-Aranda, Csaba Barta, Stéphane Jamain, Jubao Duan, Dongmei Yu, Danielle C. Cath, Ole Mors, Sigrun Hope, Laramie E. Duncan, Alan R. Sanders, Sang-Yun Oh, Carsten Bøcker Pedersen, Henning Tiemeier, Roseann E. Peterson, Raymond K. Walters, Margarita C T Slof-Op 't Landt, Madeline Alexander, Stephanie Le Hellard, Ina Giegling, Annemarie A. van Elburg, Steven P. Hamilton, Vesna Boraska Perica, Thomas V. Fernandez, Danielle M. Dick, Francesco Bettella, Roel A. Ophoff, Grant W. Montgomery, Gerald Nestadt, Nakao Iwata, Jessica H. Baker, Walter H. Kaye, Jeremy M. Silverman, Mark J. Daly, Robert A. King, Sarah E. Medland, Anastasios Konstantinidis, Robert D. Oades, Samuel H. Zinner, Steven Crawford, Daniel H. Geschwind, Patrick W. L. Leung, Martin Alda, Marie Navratilova, Pak C. Sham, Paul A. Tooney, Tian Ge, Veit Roessner, Martin Preisig, Thomas Werge, Eli A. Stahl, David A. Collier, Stephanie H. Witt, Dermot Walsh, Miquel Casas, Anna Keski-Rahkonen, Jane H. Christensen, Silvia De Rubeis, Giorgio Pistis, Sven Cichon, Bruno Etain, Dominique Campion, O. Joseph Bienvenu, Christian Dina, Manolis Kogevinas, Thomas Espeseth, Benjamin M. Neale, Ditte Demontis, Klaus-Peter Lesch, Marina Mitjans, Tiffany A. Greenwood, Marcos Madruga-Garrido, Sibylle G. Schwab, Oedegaard Ketil Joachim, Hreinn Stefansson, Sara A. Paciga, Monica Forzan, Dieter B. Wildenauer, Lena Backlund, A. Jeremy Willsey, Carlos N. Pato, Nicholas John Craddock, Inge A. Meijer, Sandra K. Loo, Filip Rybakowski, Tracey D. Wade, Scott J. Crow, Bernard Lerer, Valsamma Eapen, Esben Agerbo, Andrew M. McIntosh, Luis Augusto Rohde, Susan L. 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Subjects: Netherlands Twin Register (NTR), cross-disorder genetics, Medizin, Genome-wide association study, Tourette syndrome, functional genomics, gene expression, genetic architecture, genetic correlation, GWAS, neurodevelopment, pleiotropy, psychiatric disorders, Psychiatric genetics, 0302 clinical medicine, Pleiotropy, functional genomic, WIDE ASSOCIATION, cross-disorder genetic, 0303 health sciences, Mental Disorders, Genetic Pleiotropy, HUMAN BRAIN, INSIGHTS, Autism spectrum disorder, Schizophrenia, DISEASES, GENETIC CORRELATIONS, medicine.medical_specialty, Neurogenesis, Quantitative Trait Loci, BF, Biology, GENOTYPE IMPUTATION, Psychiatric geneticscross-disorder geneticspsychiatric disorderspleiotropyneurodevelopmentGWASgenetic correlationgene expressiongenetic architecturefunctional genomics, Article, General Biochemistry, Genetics and Molecular Biology, psychiatric disorder, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, TRANSCRIPTOME, Psychiatry, 030304 developmental biology, Gwas, Psychiatric Genetics, Cross-disorder Genetics, Functional Genomics, Gene Expression, Genetic Architecture, Genetic Correlation, Neurodevelopment, Psychiatric Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, medicine.disease, Genetic architecture, DEMETHYLASE, RC0321, 1182 Biochemistry, cell and molecular biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
Published: 2019
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14. A correction for sample overlap in genome-wide association studies in a polygenic pleiotropy-informed framework

Author: Nicholas Schork, Peter Schofield, Nancy Buccola, Paola Giusti-Rodríguez, Verena Zuber, Sarah TOSATO, Detelina Grozeva, Christos Pantelis, James Walters, Joseph Buxbaum, Miloš Milovančević, Niklas Långström, Gunnar Morken, Julia Newton-Bishop, Pamela Mahon, Inez Myin-Germeys, Sang Hong Lee, Peter Visscher, Lisa Jones, Michael O'Donovan, Bettina Kulle Andreassen, Francis McMahon, Tracey Petryshen, Thomas Folkmann Hansen, Esben Agerbo, Benedicto Crespo-Facorro, Jianjun Liu, Engilbert Sigurdsson, William Coryell, Arnoldo Frigessi, Robert Freedman, Soumya Raychaudhuri, Donald Black, Allan Young, Fritz Zimprich, Clement C Zai, Stéphane Jamain, Nakao IWATA, Pierandrea Muglia, Elvira Bramon, Masashi Ikeda, Andrew McIntosh, Bryan Mowry, Janis Klovins, Paul Tooney, Ulrich Schall, Jan Lubinski, Milica Pejovic Milovancevic, Kang Sim, Rodney Scott, Jennifer Moran, Bradley Webb, Elisabeth Stögmann, Germeys, Inez, LeBlanc, Marissa [0000-0003-2148-2814], Apollo - University of Cambridge Repository, Le Blanc, Marissa, Zuber, Verena, Thompson, Wesley K, Andreassen, Ole A, Frigessi, Arnoldo, Andreassen, Bettina Kulle, Lee, Sang Hong, Schizophrenia and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Adult Psychiatry, and Universidad de Cantabria
Subjects: 0301 basic medicine, False discovery rate, Spurious correlation, Genome-wide association study, VARIANTS, Covariate-modulated false discovery rate, Medical and Health Sciences, Correlation, Pleiotropy, Joint probability distribution, Statistics, Genetics & Heredity, Methodology Article, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, Schizophrenia and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, 3. Good health, Phenotype, Mental Health, Cross-phenotype association, Data integration, Life Sciences & Biomedicine, TRAITS, Biotechnology, STRATEGIES, lcsh:QH426-470, Genotype, Bioinformatics, lcsh:Biotechnology, Sample (statistics), Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, lcsh:TP248.13-248.65, Information and Computing Sciences, Genetics, Humans, Computer Simulation, Polymorphism, METAANALYSIS, Statistical hypothesis testing, Meta-analysis with shared subjects, 08 Information And Computing Sciences, Science & Technology, Human Genome, nutritional and metabolic diseases, 06 Biological Sciences, Brain Disorders, lcsh:Genetics, 030104 developmental biology, Biotechnology & Applied Microbiology, Case-Control Studies, Genome-Wide Association Study
Abstract: BACKGROUND: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). RESULTS: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. CONCLUSIONS: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS. Verena Zuber is supported by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z) and the UK Medical Research Council (Grant Number MC_UU_00002/7).
Published: 2018
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15. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: a collaborative cognitive and neuroimaging genetics project

Author: Paul G. Nestor, James Lee, Vince D. Calhoun, Lynn E. DeLisi, Antje A. T. S. Reinders, Kang Sim, Neeltje E.M. van Haren, Robert W. McCarley, Anthony S. David, Wiepke Cahn, Timothea Toulopoulou, Martha E. Shenton, Paola Dazzan, Rick P.F. Wolthusen, Annette M. Hartmann, Bettina Konte, Randy L. Gollub, Jianjun Liu, Todd Lencz, Matcheri S. Keshavan, Erin W. Dickie, Jordan W. Smoller, Derek W. Morris, Lisa Osiecki, Esther Walton, Aristotle N. Voineskos, Sonja de Zwarte, Larry J. Seidman, Jill M. Goldstein, Stefan Ehrlich, New Fei Ho, Tiago Reis Marques, Marta Di Forti, Marek Kubicki, Daphne J. Holt, M. Aurora Falcone, Manuela Russo, Joey W. Trampush, Simone Ciufolini, Anil K. Malhotra, Joshua L. Roffman, Jessica A. Turner, S. Charles Schulz, Dara S. Manoach, Max Lam, René S. Kahn, Aiden Corvin, James T.R. Walters, Shaun Purcell, Elisabetta C. del Re, Jorge Jovicich, Valeria Mondelli, Ina Giegling, Elvira Bramon, Raquelle I. Mesholam-Gately, Donald C. Goff, Nasim Maleki, Michael Gill, Gary Donohoe, Dan Rujescu, Richard S.E. Keefe, Stephen L. Buka, Evangelos Vassos, Nicolas Crossley, Donna Cosgrove, Scott R. Sponheim, Sara Cherkerzian, Tracey L. Petryshen, Robin M. Murray, Marco Picchioni, Zora Kikinis, Gabriëlla A.M. Blokland, Heidi W. Thermenos, Sinead Kelly, and Toulopoulou, Timothea
Subjects: cognition, Male, neuropsychology, rare variant association, population, Genome-wide association study, heritability, Neuropsychological Tests, 0302 clinical medicine, Cognition, Image Processing, Computer-Assisted, genetics, phenotypes b-snip, Child, bipolar disorder, Aged, 80 and over, Genetics, education.field_of_study, neuroimaging, Neuropsychology, Middle Aged, Magnetic Resonance Imaging, Psychiatry and Mental health, Female, Sample collection, Psychology, metaanalysis, MRI, Adult, medicine.medical_specialty, Psychosis, polygenic risk, Adolescent, Genotype, Endophenotypes, Schizophrenia (object-oriented programming), Population, Neuroimaging, Polymorphism, Single Nucleotide, Article, Statistics, Nonparametric, Young Adult, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, education, Psychiatry, mri, Biological Psychiatry, Aged, brain structure, syndrome scale panss, medicine.disease, 030227 psychiatry, Endophenotype, genome-wide association, Schizophrenia, Cognition Disorders, 030217 neurology & neurosurgery
Abstract: Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p < 1 × 10− 10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of > 10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia. We are grateful for the support of all study staff and participants. Acknowledgements for each sample are provided in the Supplementary Materials. Data processing and analyses (of the legacy data) at the central site was supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) grant number R01MH092380 to T.L.P. supporting the Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium, and NIMH grant R21MH109819 to E.D.R. Appendix A
Published: 2018
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16. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author: Bjarni J. Vilhjálmsson, Jian Yang, Hilary K. Finucane, Alexander Gusev, Sara Lindström, Stephan Ripke, Giulio Genovese, Po-Ru Loh, Gaurav Bhatia, Ron Do, Tristan Hayeck, Hong-Hee Won, Sekar Kathiresan, Michele Pato, Carlos Pato, Rulla Tamimi, Eli Stahl, Noah Zaitlen, Bogdan Pasaniuc, Gillian Belbin, Eimear E. Kenny, Mikkel H. Schierup, Philip De Jager, Nikolaos A. Patsopoulos, Steve McCarroll, Mark Daly, Shaun Purcell, Daniel Chasman, Benjamin Neale, Michael Goddard, Peter M. Visscher, Peter Kraft, Nick Patterson, Alkes L. Price, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E. DeLisi, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Lyudmila Georgieva, Elliot S. Gershon, Ina Giegling, Paola Giusti-Rodrguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Jakob Grove, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julia, Rene S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, Brian J. Kelly, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kahler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lnnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Preben B. Mortensen, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Mller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietilinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Sderman, Srinivas Thirumalai, Draga Toncheva, Paul A. Tooney, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Jing Qin Wu, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tonu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jonsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Bryan J. Mowry, Markus M. Nthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St. Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, David J. Hunter, Muriel Adank, Habibul Ahsan, Kristiina Aittomäki, Laura Baglietto, Sonja Berndt, Carl Blomquist, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Laura Crisponi, Kamila Czene, Norbert Dahmen, Isabel dos Santos Silva, Douglas Easton, A. Heather Eliassen, Jonine Figueroa, Olivia Fletcher, Montserrat Garcia-Closas, Mia M. Gaudet, Lorna Gibson, Christopher A. Haiman, Per Hall, Aditi Hazra, Rebecca Hein, Brian E. Henderson, Albert Hofman, John L. Hopper, Astrid Irwanto, Mattias Johansson, Rudolf Kaaks, Muhammad G. Kibriya, Peter Lichtner, Eiliv Lund, Enes Makalic, Alfons Meindl, Hanne Meijers-Heijboer, Bertram Müller-Myhsok, Taru A. Muranen, Heli Nevanlinna, Petra H. Peeters, Julian Peto, Ross L. Prentice, Nazneen Rahman, María José Sánchez, Daniel F. Schmidt, Rita K. Schmutzler, Melissa C. Southey, Ruth Travis, Clare Turnbull, Andre G. Uitterlinden, Rob B. van der Luijt, Quinten Waisfisz, Zhaoming Wang, Alice S. Whittemore, Rose Yang, Wei Zheng, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Grove, Jakob, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Vilhjalmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lee, SH, Price, Alkes L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Study, Psychosis Endophenotype International Consortium, Wellcome Trust Case Control Consortium, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Human genetics, NCA - Brain mechanisms in health and disease, CCA - Oncogenesis, CCA - Quality of life, CCA - Cancer biology and immunology, Psychiatry, Department of Technology and Operations Management, Department of Organisation and Personnel Management, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Cell biology, and Internal Medicine
Subjects: Multifactorial Inheritance, Linkage disequilibrium, Complex disease, heritability, Bioinformatics, Medical and Health Sciences, Linkage Disequilibrium, 0302 clinical medicine, Theoretical, External reference, Models, Statistics, GWAS, Genetics(clinical), Genetics (clinical), Mathematics, Genetics & Heredity, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Single Nucleotide, Biological Sciences, Serious Mental Illness, Prognosis, Thresholding, Regression, Mental Health, Phenotype, polygenic risk scores, Mixed model, Multiple Sclerosis, Genotype, Quantitative Trait Loci, polygenic risk score, schizophrenia, GWAS, Discovery, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetics, Humans, p-value, Pruning (decision trees), Polymorphism, Genome-Wide Association Study, Schizophrenia, Models, Theoretical, 030304 developmental biology, genome-wide association study, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Brain Disorders, Data set, schizophrenia, Sample size determination, polygenic risk score, Polygenic risk score, 030217 neurology & neurosurgery, linkage disequilibrium
Abstract: Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed
Published: 2015
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17. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability

Author: Aarno Palotie, Daniel H. Geschwind, Christina M. Hultman, Michael J. Gandal, Michael John Owen, Mandy Johnstone, Elliott Rees, James T.R. Walters, Michael Conlon O'Donovan, Douglas Blackwood, David Curtis, George Kirov, Elvira Bramon, Marta Di Forti, Jaana Suvisaari, Pamela Sklar, Minna Torniainen, Patrick F. Sullivan, Conrad Iyegbe, Jeffrey C. Barrett, Andrew M. McIntosh, Robin M. Murray, and Tarjinder Singh
Subjects: 0301 basic medicine, Genotyping Techniques, Schizophrenia (object-oriented programming), Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Intellectual Disability, Genetic variation, Intellectual disability, mental disorders, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, Copy-number variation, Case-control study, Genetic Variation, Sequence Analysis, DNA, medicine.disease, R1, 030104 developmental biology, Neurodevelopmental Disorders, Autism spectrum disorder, Case-Control Studies, Meta-analysis, Mutation, Schizophrenia
Abstract: By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.
Published: 2017
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18. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author: Cristina Cereda, Jurjen J. Luykx, Sandra Meier, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, John Landers, Silvana Penco, Marian L. Hamshere, Frank Dudbridge, Mari Nelis, Dick Schijven, Jimmy Lee, Sarah E. Bergen, Alessandro Padovani, Nicholas W. Wood, Meraida Polak, Hannelore Ehrenreich, Nancy G. Buccola, Noa Carrera, Stefan Herms, Panos Roussos, Marion Friedl, Teimuraz Silagadze, Jim van Os, Annette M. Hartmann, Ole A. Andreassen, R. Jeroen Pasterkamp, Sibylle G. Schwab, Aleksey Shatunov, Eli A. Stahl, David A. Collier, Farooq Amin, Michael Conlon O'Donovan, Guiqing Cai, Kung-Yee Liang, Denis C. Bauer, Charles Curtis, Brion S. Maher, Ashley R. Jones, Sara L. Pulit, Sarah Tosato, Milan Macek, Vivianna M. Van Deerlin, Vincenzo Silani, Pietro Fratta, Bettina Konte, Rosanna Tortelli, Dan Rujescu, T. Scott Stroup, Elizabeth Bevilacqua, Christian Lunetta, Bradley T. Webb, Christophe Tzourio, Patrick Vourc'h, Joel N. Hirschhorn, Gilbert Bensimon, Timothy G. Dinan, Thomas G. Schulze, Richard A. Belliveau, Daniel R. Weinberger, Andrew McQuillin, Qingqin S. Li, Orla Hardiman, Claudine Laurent, Masashi Ikeda, Tim Kahlke, Rodney J. Scott, Frans Henskens, Tune H. Pers, Wolfgang Lieb, Christian Hammer, Elvira Bramon, Hana Kuzelova-Ptackova, Raquelle I. Mesholam-Gately, Ingrid Melle, Nadine Cohen, David Cohen, Nazli Basak, Elisabeth Stögmann, Nelson B. Freimer, Peter Eichhammer, J. Mallet, Preben Bo Mortensen, Robert H. Brown, Wouter van Rheenen, Roberto Del Bo, Dai Wang, Laurent Essioux, Larry J. Seidman, Hreinn Stefansson, Erik G. Jönsson, Mads V. Hollegaard, Raymond C.K. Chan, Susana Pinto, Alexander Richards, Jubao Duan, Peter Holmans, George Kirov, Pablo V. Gejman, Philippe Amouyel, Stephanie Godard, Dieter B. Wildenauer, Martina Wiedau-Pazos, Stacy Steinberg, Ole Mors, Andres Metspalu, Rolf Adolfsson, Shaun Purcell, Hugh Gurling, Joseph I. Friedman, Erik Söderman, Mark Weiser, Giacomo P. Comi, James A. Knowles, Peter M. Andersen, Brien P. Riley, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Digby Quested, Srinivas Thirumalai, Ulrich Schall, Jan Lubinski, Dragan M. Svrakic, Aaron R. Wolen, S. Hong Lee, Andrew Pocklington, Bernard Lerer, Vahram Haroutunian, Matthew C. Kiernan, Kenneth L. Davis, Assen Jablensky, William Byerley, Karol Estrada, Aarno Palotie, Cinzia Tiloca, Eadbhard O'Callaghan, Perry T.C. van Doormaal, Colm McDonald, Federico Casale, Thomas Meitinger, Robert Freedman, Gerome Breen, Milena Blagojevic-Radivojkov, Ian P. Blair, Ann E. Pulver, Jan H. Veldink, Giancarlo Logroscino, Miaoxin Li, Abraham Reichenberg, Esben Agerbo, Siddharthan Chandran, Patrik K. E. Magnusson, Andrew M. McIntosh, Gianni Sorarù, Maura Brunetti, Xuebin Zheng, Madeline Alexander, James L. Kennedy, Douglas Blackwood, Menachem Fromer, Martilias S. Farrell, Alan R. Sanders, Dominic B. Rowe, Alexis Brice, Jonathan Pimm, Emily H. M. Wong, Jana Strohmaier, André G. Uitterlinden, Andrea Calvo, Carsten Drepper, John Q. Trojanowski, Marcella Rietschel, Siow Ann Chong, Karen E. Morrison, Sang-Yun Oh, Laura Nisenbaum, Margaret O'Brien, Alkes L. Price, Carin J. Meijer, Michael Davidson, John Powell, Petr Slominsky, Wiepke Cahn, Cinzia Gellera, Vihra Milanova, Peter M. Visscher, Patricia T. Michie, Dimitris Dikeos, Jianxin Shi, Veikko Salomaa, Philip Van Damme, James J. Crowley, Younes Mokrab, Valentina Escott-Price, Jesus S. Mora, Stanley V. Catts, David St Clair, Bernhard Landwehrmeyer, John Hardy, Kristin K. Nicodemus, Dominique Campion, Juha Veijola, Wim Robberecht, Thomas Meyer, Peter Lichtner, Christos Pantelis, Markus Weber, Nilo Riva, Jin P. Szatkiewicz, Michele T. Pato, Cinzia Bertolin, Frank P. Diekstra, Simon Arcuti, Bryan J. Mowry, Hon-Cheong So, Adriano Chiò, Viviana Pensato, Yunjung Kim, Jean-François Dartigues, Zita Ausrele Kucinskiene, Inez Myin-Germeys, Jaana Suvisaari, Sophie E. Legge, Roel A. Ophoff, Philippe Corcia, Gerald Nestadt, Stephan Ripke, Kuang Lin, Paola Giusti-Rodríguez, Michael John Owen, Chris C. A. Spencer, Safa Saker-Delye, Robert W. McCarley, Kimberley D. Chambert, Brandon Wormley, Isabella Fogh, Mamede de Carvalho, Pamela J. Shaw, Tõnu Esko, Ronald Y. L. Chan, Jianjun Liu, Tim B. Bigdeli, Christian R. Andres, David M. Hougaard, Michael Gill, Ammar Al-Chalabi, Colm O'Dushlaine, Rick A.A. van der Spek, Gary Donohoe, Tao Li, Jonathan D. Glass, Christopher Shaw, Draga Toncheva, Leonard H. van den Berg, Liene Nikitina-Zake, Morten Mattingsdal, François Salachas, Andrey Khrunin, Line Olsen, Jochen H. Weishaupt, Jo Knight, Katie Sidle, Filip Eftimov, Massimiliano Filosto, Russell L. McLaughlin, Pak C. Sham, Joshua L. Roffman, Thomas Hansen, Naser Durmishi, Deborah A. Nertney, Juha Karjalainen, Robert Swingler, Ditte Demontis, Vaidutis Kučinskas, Jennifer L. Moran, Leo McCluskey, Donald W. Black, Eric F.C. Cheung, Qiang Wang, Olli Pietilainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Annelie Nordin, Wolfgang Maier, Bradley N. Smith, Ettore Beghi, Rosa Capozzo, Garth A. Nicholson, Markus M. Nöuthen, Jordan W. Smoller, Eric Y.H. Chen, Joseph D. Buxbaum, Letizia Mazzini, Andrea Malaspina, Antonio Julià, Stephanie Williams, Tracey L. Petryshen, Christine Payan, Johan G. Eriksson, Carmel M. Loughland, Elodie Drapeau, Lieuwe de Haan, Martin Begemann, Lukas Tittmann, Franziska Degenhardt, Mark Reimers, Jurgen Del Favero, Jacqueline I. Goldstein, Annelot M. Dekker, Sergi Papiol, Svetlana A. Limborska, René S. Kahn, Shuna Colville, Kelly L. Williams, Pamela Sklar, Diana O. Perkins, Lili Milani, Ayman H. Fanous, Nicola Ticozzi, Fernando Rivadeneira, Marianne de Visser, P. Nigel Leigh, James T.R. Walters, Josef Frank, Aiden Corvin, Silviu Alin Bacanu, John L. Waddington, Stephanie H. Witt, Tiina Paunio, Margot Albus, Catherine Lomen-Hoerth, Sara Marsal, Per Hoffmann, David Curtis, Cindy Maurel, Todd Lencz, Orietta Pansarasa, Manuel Mattheisen, Anneke J. van der Kooi, A. Hofman, Dermot Walsh, Hailiang Huang, Ann Olincy, Anders D. Børglum, Ricardo Rojas-García, William Sproviero, Albert C. Ludolph, Edward M. Scolnick, Danielle Posthuma, George N. Papadimitriou, Michael A. van Es, Fritz Zimprich, F. Anthony O'Neill, Lude Franke, Jouko Lönnqvist, Daniel G. Bradley, Sven Cichon, Susanna Abdulla, Kristel R. van Eijk, Ingrid Agartz, Elisabetta Pupillo, Milica Pejovic-Milovancevic, Antonia Ratti, Henrik B. Rasmussen, Kari Stefansson, Brendan Bulik-Sullivan, Béla Melegh, Stéphanie Millecamps, Janis Klovins, Enrico Domenici, Michael Sendtner, Kai-How Farh, Randy L. Buckner, Albert Hofman, Benjamin M. Neale, Naomi R. Wray, An Goris, Kang Sim, Lauren Elman, Giulio Genovese, Jens R. Wendland, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Sandra D'Alfonso, Cristina Moglia, Carlos N. Pato, Sena Karachanak-Yankova, Nicholas John Craddock, Richard W. Orrell, Richard Bruggeman, Kenneth S. Kendler, Alan M. Pittman, Robin M. Murray, Richard E. Straub, Cathryn M. Lewis, Srdjan Djurovic, Vincent Meininger, Jeffrey A. Lieberman, Bertram Müller-Myhsok, Phil Lee, David J. Kavanagh, Srihari Gopal, Igor Nenadic, Matthew C. Keller, Christian R. Schubert, Jacob Gratten, Alexandra Durr, Roger Pamphlett, Douglas F. Levinson, Luba Kalaydjieva, Chiara Zecca, Anil K. Malhotra, Andre Franke, Vaughan J. Carr, Steven A. McCarroll, C. Robert Cloninger, Judit Bene, Ina Giegling, Wei Cheng, Hualin Simon Xi, Thomas Werge, Eric Strengman, Susanne Petri, Engilbert Sigurdsson, Mark Hansen, Patrick F. Sullivan, Kieran C. Murphy, Inge Joa, Complex Trait Genetics, McLaughlin, Russell L, Schijven, Dick, Van Rheenen, Wouter, Van Eijk, Kristel R, O'Brien, Margaret, Kahn, René S, Ophoff, Roel A, Goris, An, Bradley, Daniel G, Al-Chalabi, Ammar, Van Den Berg, Leonard H, Luykx, Jurjen J, Hardiman, Orla, Veldink, Jan H, Lee, S Hong, Project MinE GWAS Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Other departments, Neurology, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Schizophrenia Working Group of the Psychiatric Genomics Consortiumz, Germeys, Inez, Robberecht, Wim, and Van Damme, Philip
Subjects: 0301 basic medicine, Oncology, Genetics and Molecular Biology (all), Linkage disequilibrium, Multifactorial Inheritance, General Physics and Astronomy, Genome-wide association study, Comorbidity, VARIANTS, Neurodegenerative, Biochemistry, DISEASE, 3124 Neurology and psychiatry, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, Genetics research, Odds Ratio, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, ARCHITECTURE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Multidisciplinary, Chemistry (all), Motor neuron disease, Schizophrenia, BIPOLAR DISORDER, Single Nucleotide, Serious Mental Illness, 3. Good health, Mental Health, RC0346, motor neuron disease, Project MinE GWAS Consortium, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Science, European Continental Ancestry Group, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, Physics and Astronomy (all), Rare Diseases, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, MD Multidisciplinary, mental disorders, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Family, Bipolar disorder, GENOME-WIDE ASSOCIATION, Polymorphism, Biology, METAANALYSIS, business.industry, Amyotrophic Lateral Sclerosis, Human Genome, Case-control study, 3112 Neurosciences, Neurosciences, General Chemistry, Odds ratio, medicine.disease, R1, Brain Disorders, 030104 developmental biology, genetics research, Case-Control Studies, RC0321, Linear Models, PLEIOTROPY, Human medicine, 3111 Biomedicine, Biochemistry, Genetics and Molecular Biology (all), ALS, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
Published: 2017
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19. SU72. Abnormal Frontal Synaptic Gain Mediating the P300 in Patients With Psychosis and Their Unaffected Relatives

Author: Álvaro Díez, Dimitris A. Pinotsis, Mei-Hua Hall, Siri Ranlund, Angel Nevado, Madiha Shaikh, Elvira Bramon, Stella Calafato, Muriel Walshe, Rick A. Adams, and Karl J. Friston
Subjects: Psychosis, medicine.diagnostic_test, Functional integration (neurobiology), business.industry, Cognition, Electroencephalography, medicine.disease, Psychiatry and Mental health, Abstracts, medicine, GABAergic, In patient, Left superior, Genetic risk, business, Neuroscience, Cognitive psychology
Abstract: Background: The “dysconnection hypothesis” of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. We investigated intrinsic (self-)connectivity in a cortical hierarchy during a P300 experiment. We used Dynamic Causal Modeling to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Methods: Twenty-four patients with psychosis, 24 unaffected relatives, and 25 controls underwent EEG recordings during an auditory oddball paradigm. We analyzed 16 frontoparietal models (primary auditory, superior parietal, and superior frontal sources) and identified an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition. Results: The winning model included changes in connectivity at all 3 hierarchical levels. Patients showed decreased self-inhibition (ie, increased cortical excitability) in left superior frontal gyrus across task conditions, compared to unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets, relative to standard tones. Conclusion: We confirmed that both subjects with psychosis and their relatives show a context-independent loss of synaptic gain control at the highest levels of the hierarchy. The relatives also showed abnormal gain modulation responses to task-relevant stimuli. These may be caused by NMDA-receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis.
Published: 2017

20. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author: Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences
Subjects: Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Published: 2016
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21. Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

Author: Olivia Sousa, Stephen Sawcer, Janusz Jankowski, Serge Dronov, Aiden Corvin, Panos Deloukas, Leena Peltonen, Damjan Vukcevic, Cordelia Langford, Nicholas W. Wood, Nubia N. Pontes, Campbell S. Witt, Richard C. Trembath, Gloria R. Monteiro, Anshuman Mishra, Peter Donnelly, Audrey Duncanson, Matthew A. Brown, Heather J. Cordell, Mary E. Wilson, Elvira Bramon, Selma M. B. Jeronimo, Sarah E. Hunt, Sarah Edkins, Ananth C. Viswanathan, Christopher G. Mathew, Colin Freeman, Gavin Band, Chris C. A. Spencer, Henio G. Lacerda, Eleni Giannoulatou, Frank T. Christiansen, A. Strange, Hugh S. Markus, Céline Bellenguez, Michaela Fakiola, Zhan Su, Jenefer M. Blackwell, Matti Pirinen, Shyam Sundar, Robert Plomin, Shri Prakash Singh, Sanjana Mehrotra, L.K. Smith, Madhukar Rai, Emma Gray, Richard G. Pearson, E. Nancy Miller, Colin N. A. Palmer, Juan P. Casas, and Anna Rautanen
Subjects: Genotype, India, Genome-wide association study, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Article, HLA-DQ alpha-Chains, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetics, medicine, Genetic predisposition, Odds Ratio, Humans, Genetic Predisposition to Disease, Allele frequency, HLA-DRB1, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, Electrophoresis, Agar Gel, 0303 health sciences, Leishmaniasis, Odds ratio, medicine.disease, Visceral leishmaniasis, Haplotypes, Linear Models, Leishmaniasis, Visceral, Brazil, 030215 immunology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P(combined) = 2.76 × 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
Published: 2016
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22. Reduced mismatch negativity predates the onset of psychosis

Author: Anirban Dutt, Elvira Bramon, Paolo Fusar-Poli, Julia Lappin, Louise Johns, Muriel Walshe, Oliver D. Howes, James Woolley, Robin M. Murray, Madiha Shaikh, Fern Day, Matthew R. Broome, Paul Tabraham, Philip McGuire, Lucia Valmaggia, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: Adult, Male, Psychosis, medicine.medical_specialty, Mismatch negativity, Neuropsychological Tests, Audiology, Electroencephalography, behavioral disciplines and activities, law.invention, ARMS, Randomized controlled trial, Predictive Value of Tests, law, Event-related potential, medicine, Humans, Longitudinal Studies, EEG, Psychiatry, Biological Psychiatry, MMN, medicine.diagnostic_test, Sensory memory, Case-control study, At risk mental state, Biomarker, medicine.disease, Psychiatry and Mental health, Psychotic Disorders, Prodromal, Case-Control Studies, Evoked Potentials, Auditory, Female, Psychology, psychological phenomena and processes
Abstract: Background Individuals with an “At Risk Mental State” have a 20–30% chance of developing a psychotic disorder within two years; however it is difficult to predict which individuals will become ill on the basis of their clinical symptoms alone. We examined whether mismatch negativity (MMN) could help to identify those who are particularly likely to make a transition to psychosis. Method 41 cases meeting PACE criteria for the At Risk Mental State (ARMS) and 50 controls performed a duration-deviant passive auditory oddball task whilst their electroencephalogram was recorded. The amplitude of the MMN wave was compared between groups using linear regression. The ARMS subjects were then followed for 2 years to determine their clinical outcome. Results The MMN amplitude was significantly reduced in the ARMS group compared to controls. Of the at-risk subjects who completed followed up (n = 41), ten (24% of baseline sample) subsequently developed psychosis. The MMN amplitude in this subgroup was significantly smaller across all three recording sites (FZ, F3 and F4) than in the ARMS individuals who did not become psychotic. Conclusion: Among those with the ARMS, MMN amplitude reduction is associated with an increased likelihood of developing frank psychosis.
Published: 2016
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23. What causes the onset of psychosis?

Author: Carmine M. Pariante, Robin M. Murray, Louise Johns, Matthew R. Broome, Elvira Bramon, Graham K. Murray, James Woolley, Paul Tabraham, and Philip McGuire
Subjects: Psychosis, Substance-Related Disorders, media_common.quotation_subject, Population, Culture, Social Environment, Developmental psychology, Prodrome, Social psychiatry, medicine, Humans, Psychology, Social isolation, education, Biological Psychiatry, media_common, education.field_of_study, Social environment, Brain, medicine.disease, Anomalous experiences, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, medicine.symptom
Abstract: It has become increasingly clear that the simple neurodevelopmental model fails to explain many aspects of schizophrenia including the timing of the onset, and the nature of the abnormal perceptions. Furthermore, we do not know why some members of the general population have anomalous experiences but remain well, while others enter the prodrome of psychosis, and a minority progress to frank schizophrenia. We suggest that genes or developmental damage result in individuals vulnerable to dopamine deregulation. In contemporary society, this is often compounded by abuse of drugs such as amphetamines and cannabis, which then propel the individual into a state of dopamine-induced misinterpretation of the environment. Certain types of social adversity such as migration and social isolation, as well as affective change can also contribute to this. Thereafter, biased cognitive appraisal processes result in delusional interpretation of the abnormal perceptual experiences. Thus, a plausible model of the onset of psychosis needs to draw not only on neuroscience, but also on the insights of social psychiatry and cognitive psychology.
Published: 2016

24. Spatial working memory in individuals at high risk for psychosis: Longitudinal fMRI study

Author: James Woolley, Matthew R. Broome, Steven Williams, Paolo Fusar-Poli, Lucia Valmaggia, Paul Tabraham, Philip McGuire, Pall Matthiasson, Elvira Bramon, Louise Johns, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: Adult, Male, Psychosis, medicine.medical_specialty, Prodromal psychosis, Precuneus, Neuropsychological Tests, Audiology, Spatial memory, ARMS, Young Adult, Cognition, Risk Factors, Image Processing, Computer-Assisted, medicine, Humans, Longitudinal Studies, Psychiatry, Biological Psychiatry, Analysis of Variance, Brain Mapping, Working memory, fMRI, Parietal lobe, Brain, At risk mental state, medicine.disease, Magnetic Resonance Imaging, Oxygen, Psychiatry and Mental health, Memory, Short-Term, medicine.anatomical_structure, Psychotic Disorders, Schizophrenia, Female, Cognition Disorders, Mental Status Schedule, Psychology, Neurocognitive
Abstract: Background: Neurocognitive impairments in executive and mnemonic domains are already evident in the pre-psychotic phases. The longitudinal dynamic course of the neurofunctional abnormalities underlying liability to psychosis and their relation to clinical outcomes is unknown. Methods: In this study we used functional magnetic resonance imaging (fMRI) in a cohort of subjects at ultra high clinical risk for psychosis (with an "At Risk Mental State", ARMS) and in healthy controls. Images were acquired at baseline and again after one year on a 1.5 Tesla Signa, while patients were performing a visuospatial working memory task. Psychopathological assessment of the prodromal symptoms was conducted at the same time points by using the CAARMS and the PANSS instruments. Results: There were no significant differences between the ARMS and control groups with respect to age or IQ Although both groups performed the PAL task with a high degree of accuracy, the ARMS showed an increased latency in answers during the most demanding level of the task. At baseline, such cognitive impairment was associated with reduced activation in the left precuneus, left superior parietal lobule, right middle temporal gyrus in the ARMS as compared to controls. In addition, the ARMS failed to activate parietal areas with increasing difficulty of the task. Between presentation and follow-up the overall clinical status of the ARMS sample improved, despite 2 out of the 15 subjects having developed a full-blown psychosis: the CAARMS (perceptual disorder and thought disorder subscales) and the PANNS general scores decreased, while the GAF score increased. Such clinical amelioration was associated with a longitudinal compensatory increase in occipitoparietal regions. Conclusions: The prodromal phase of psychosis is associated with functional alterations in parietal and temporal networks subserving visuospatial working memory which are more evident under high cognitive loads. The clinical improvement at one year is associated with a compensatory increase in occipitoparietal regions. (C) 2010 Elsevier B.V. All rights reserved.
Published: 2010

25. Schizophrenia risk from complex variation of complement component 4

Author: Andrew Pocklington, Ole Mors, Tune Pers, Rolf Adolfsson, Andrew McQuillin, Vanessa Van Doren, James Walters, Hon-Cheong So, Joseph Buxbaum, Douglas Ruderfer, Lili Milani, Markus Nöthen, Joanne Knight, Silviu-Alin Bacanu, Avery Davis Bell, Samuel Rose, Danielle Posthuma, Inez Myin-Germeys, Francis Anthony O'Neill, Robert Handsaker, Antonio Julià Cano, Peter Visscher, Morten Mattingsdal, Thomas Folkmann Hansen, Esben Agerbo, Nolan Kamitaki, Benedicto Crespo-Facorro, Petr Slominsky, Sara Marsal, Joshua Roffman, Jingqin Wu, Ditte Demontis, David Collier, Jaana Suvisaari, Enrico Domenici, Fritz Zimprich, Hannelore Ehrenreich, Richard Bruggeman, Elvira Bramon, Sarah Bergen, Erik Jönsson, Bryan Mowry, Patrik Magnusson, Lude Franke, Srdjan Djurovic, Katherine Tooley, Matthew Baum, Peter Holmans, Murray Cairns, Kang Sim, Anders Børglum, Brian Kelly, Jennifer Moran, Sophie Legge, Sergi Papiol, Bradley Webb, Elisabeth Stögmann, Universidad de Cantabria, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Other departments, ANS - Complex Trait Genetics, Adult Psychiatry, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: 0301 basic medicine, Synaptic pruning, Messenger, Gene Dosage, Poison control, Major Histocompatibility Complex, Synapse, Mice, 0302 clinical medicine, Models, Risk Factors, Alleles, Amino Acid Sequence, Animals, Axons, Base Sequence, Brain, Complement C4, Complement Pathway, Classical, Dendrites, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Models, Animal, Neuronal Plasticity, Polymorphism, Single Nucleotide, RNA, Messenger, Schizophrenia, Synapses, Genetics, Complement component 4, Multidisciplinary, biology, Single Nucleotide, medicine.anatomical_structure, Major histocompatibility complex, Article, 03 medical and health sciences, mental disorders, medicine, Polymorphism, Allele, Genetic association, Animal, C4A, Classical, 030104 developmental biology, Complement Pathway, biology.protein, RNA, 030217 neurology & neurosurgery
Abstract: Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia. This work was supported by R01 HG 006855 (to S.A.M), by the Stanley Center for Psychiatric Research (to S.A.M and B.S.), by R01 MH077139 (to the PGC), and by T32 GM007753 (to A.S. and M.B.).
Published: 2016
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26. Cerebral metabolism in major depressive disorder:A voxel-based meta-analysis of positron emission tomography studies

Author: Yiyun Cai, Liang Su, Yifeng Xu, Anirban Dutt, Elvira Bramon, and Shenxun Shi
Subjects: Blood Glucose, Male, medicine.medical_specialty, Positron emission tomography, Thalamus, Activation likelihood estimation, Major depressive disorder, behavioral disciplines and activities, Basal Ganglia, Limbic system, Gyrus, Fluorodeoxyglucose F18, Internal medicine, Basal ganglia, mental disorders, Limbic System, medicine, Humans, Cerebral Cortex, Depressive Disorder, Major, Likelihood Functions, Putamen, medicine.disease, Psychiatry and Mental health, Meta-analysis, medicine.anatomical_structure, nervous system, Cerebral cortex, Positron-Emission Tomography, Cardiology, Radiopharmaceuticals, Psychology, Neuroscience, Insula, Research Article
Abstract: Background: Major depressive disorder (MDD) is a common mental illness with high lifetime prevalence close to 20%. Positron emission tomography (PET) studies have reported decreased prefrontal, insular and limbic cerebral glucose metabolism in depressed patients compared with healthy controls. However, the literature has not always been consistent. To evaluate current evidence from PET studies, we conducted a voxel-based meta-analysis of cerebral metabolism in MDD. Method: Data were collected from databases including PubMed and Web of Science, with the last report up to April 2013. Voxel-based meta-analyses were performed using the revised activation likelihood estimation (ALE) software. Results: Ten whole-brain-based FDG-PET studies in MDD were included in the meta-analysis, comprising 188 MDD patients and 169 healthy controls. ALE analyses showed the brain metabolism in bilateral insula, left lentiform nucleus putamen and extra-nuclear, right caudate and cingulate gyrus were significantly decreased. However, the brain activity in right thalamus pulvinar and declive of posterior lobe, left culmen of vermis in anterior lobe were significantly increased in MDD patients. Conclusion: Our meta-analysis demonstrates the specific brain regions where possible dysfunctions are more consistently reported in MDD patients. Altered metabolism in insula, limbic system, basal ganglia, thalamus, and cerebellum and thus these regions are likely to play a key role in the pathophysiology of depression.
Published: 2014
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27. Spatial working memory ability in individuals at ultra high risk for psychosis

Author: Matthew R. Broome, James Woolley, Oliver D. Howes, Majella Byrne, Louise Johns, Paul Tabraham, C Brett, Philip McGuire, Elvira Bramon, Lucia Valmaggia, and Vina M. Goghari
Subjects: Adult, Male, medicine.medical_specialty, Psychosis, Adolescent, Intelligence, Neuropsychological Tests, Spatial memory, Article, Young Adult, medicine, Humans, Young adult, Psychiatry, Biological Psychiatry, Intelligence Tests, Intelligence quotient, Working memory, Discriminant Analysis, medicine.disease, Psychiatry and Mental health, Memory, Short-Term, Psychotic Disorders, Cognitive remediation therapy, Schizophrenia, Space Perception, Female, sense organs, Psychology, Neurocognitive, Clinical psychology
Abstract: The goal of this investigation was to clarify the nature of spatial working memory difficulties in individuals at ultra high risk (UHR) for psychosis. We evaluated spatial working memory and intelligence in 96 individuals at UHR for psychosis, 28 patients with first episode psychosis (FEP), and 23 healthy controls. Fourteen UHR individuals developed a psychotic disorder during follow-up. Compared to controls, the UHR group was impaired in both the short-term maintenance of material and in the effective use of strategy, but not more immediate memory. These impairments were not as severe as those in the FEP group, as the UHR group performed better than the FEP group. A similar pattern of results was found for the intelligence measures. Discriminant function analyses demonstrated short-term maintenance of material significantly differentiated the UHR and healthy control groups even when accounting for full scale intelligence quotient (IQ); whereas full scale IQ significantly differentiated the UHR and FEP groups and FEP and control groups. Notably, within the UHR group, impaired spatial working memory performance was associated with lower global functioning, but not full scale IQ. The subgroup of UHR individuals who later developed psychosis was not significantly more impaired on any aspect of working memory performance than the group of UHR individuals who did not develop psychosis. Given, the relationship between spatial working memory deficits and functional outcome, these results indicate that cognitive remediation could be useful in individuals at UHR for psychosis to potentially improve functioning. © 2013 Elsevier Ltd. All rights reserved.
Published: 2014

28. Biological insights from 108 schizophrenia-associated genetic loci

Author: Svetlana A. Limborska, Panos Roussos, Benjamin M. Neale, Naser Durmishi, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Alexander Richards, Margot Albus, Lyudmila Georgieva, Sandra Meier, Ulrich Schall, Giulio Genovese, Pak C. Sham, Kai-How Farh, Randy L. Buckner, Qingqin S. Li, Jubao Duan, Carlos N. Pato, Sena Karachanak-Yankova, Nicholas John Craddock, Ole Mors, Chris C. A. Spencer, Miaoxin Li, Jim van Os, Richard Bruggeman, Antonio Julià, Srinivas Thirumalai, Vahram Haroutunian, Michael Davidson, Rodney J. Scott, George N. Papadimitriou, Noa Carrera, Nelson B. Freimer, Michele T. Pato, Mads V. Hollegaard, Hon-Cheong So, Annette M. Hartmann, Ole A. Andreassen, Rolf Adolfsson, Milica Pejovic-Milovancevic, Sarah E. Bergen, S. Hong Lee, Kang Sim, Steven A. McCarroll, Sarah Tosato, Milan Macek, Béla Melegh, Qiang Wang, Ina Giegling, Wei Cheng, Mari Nelis, Assen Jablensky, Jens R. Wendland, Christian Hammer, Paola Giusti-Rodríguez, Jonathan Pimm, Petr Slominsky, Raymond C.K. Chan, Thomas Werge, Jaana Suvisaari, Shaun Purcell, Tõnu Esko, Masashi Ikeda, Bryan J. Mowry, Janis Klovins, C. Robert Cloninger, Mark Hansen, Wiepke Cahn, Olli Pietiläinen, Naomi R. Wray, John L. Waddington, Xuebin Zheng, Eric F.C. Cheung, Madeline Alexander, Jordan W. Smoller, Jacqueline I. Goldstein, Veikko Salomaa, Gary Donohoe, Enrico Domenici, Colm McDonald, Martilias S. Farrell, Stanley V. Catts, Stacy Steinberg, Stephanie Williams, Carmel M. Loughland, Jo Knight, Zita Ausrele Kucinskiene, Jin P. Szatkiewicz, Stephan Ripke, Robert W. McCarley, Yunjung Kim, David St Clair, David Curtis, Todd Lencz, Michael John Owen, Srdjan Djurovic, Nancy G. Buccola, Frans Henskens, Michael Gill, Joshua L. Roffman, Dan Rujescu, Danielle Posthuma, Tao Li, Phil Lee, Thomas Hansen, Wolfgang Maier, Judit Bene, Michael Conlon O'Donovan, Josef Frank, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Kenneth L. Davis, Sophie E. Legge, Roel A. Ophoff, Gerald Nestadt, Claudine Laurent, Pamela Sklar, Diana O. Perkins, Stefan Herms, Fritz Zimprich, Juha Karjalainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Ann Olincy, Anders D. Børglum, Andrey Khrunin, Jianjun Liu, Bettina Konte, Guiqing Cai, Henrik B. Rasmussen, René S. Kahn, Lili Milani, John Powell, Srihari Gopal, Johan G. Eriksson, David Cohen, Eric Y.H. Chen, James L. Kennedy, Thomas G. Schulze, Richard A. Belliveau, Colm O'Dushlaine, Peter M. Visscher, Valentina Escott-Price, Hana Kuzelova-Ptackova, Stephanie Godard, Martin Begemann, Morten Mattingsdal, Sara Marsal, Alan R. Sanders, Kari Stefansson, Brendan Bulik-Sullivan, Andres Metspalu, Per Hoffmann, Erik Söderman, James T.R. Walters, Hannelore Ehrenreich, Marion Friedl, Brion S. Maher, Teimuraz Silagadze, Annelie Nordin, Raquelle I. Mesholam-Gately, Ingrid Melle, Peter Eichhammer, Dragan M. Svrakic, A. Hofman, Kenneth S. Kendler, Laura Nisenbaum, Hailiang Huang, Sang-Yun Oh, Alkes L. Price, Mark Weiser, Preben Bo Mortensen, J. Mallet, Robin M. Murray, Bradley T. Webb, Vihra Milanova, Ayman H. Fanous, Vaidutis Kučinskas, Jennifer L. Moran, Donald W. Black, Elodie Drapeau, Nadine Cohen, George Kirov, Daniel R. Weinberger, Andrew McQuillin, Patrik K. E. Magnusson, Elvira Bramon, Tune H. Pers, Jianxin Shi, Richard E. Straub, Aiden Corvin, Jimmy Lee Chee Keong, Tiina Paunio, Brien P. Riley, Douglas Blackwood, Juha Veijola, Peter Holmans, Larry J. Seidman, Ronald Y.L. Chen, Pablo V. Gejman, Digby Quested, Erik G. Jönsson, Jeffrey A. Lieberman, Emily H. M. Wong, Tracey L. Petryshen, Franziska Degenhardt, Mark Reimers, Jurgen Del Favero, Markus M. Noethen, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Aaron R. Wolen, Abraham Reichenberg, T. Scott Stroup, Elizabeth Bevilacqua, Silviu Alin Bacanu, Aarno Palotie, Robert Freedman, Patricia T. Michie, David M. Hougaard, F. Anthony O'Neill, Kung-Yee Liang, Jouko Lönnqvist, Inez Myin-Germeys, Draga Toncheva, Liene Nikitina-Zake, David J. Kavanagh, Rita M. Cantor, Kimberly Chambert, James J. Crowley, Ann E. Pulver, Ariel Darvasi, Christina M. Hultman, Brandon Wormley, Dai Wang, Deborah A. Nertney, Menachem Fromer, Younes Mokrab, Marcella Rietschel, Christos Pantelis, Dimitris Dikeos, Jan Lubinski, Laurent Essioux, Lieuwe de Haan, Eadbhard O'Callaghan, James A. Knowles, William Byerley, Manuel Mattheisen, Edward M. Scolnick, Line Olsen, Ingrid Agartz, Jana Strohmaier, Siow Ann Chong, Eli A. Stahl, David A. Collier, Farooq Amin, Joel N. Hirschhorn, Timothy G. Dinan, Elisabeth Stögmann, Hreinn Stefansson, Inge Joa, Dieter B. Wildenauer, Marian L. Hamshere, Frank Dudbridge, Sibylle G. Schwab, Esben Agerbo, Bernard Lerer, Andrew M. McIntosh, Carin J. Meijer, Stephanie H. Witt, Dermot Walsh, Lude Franke, Sven Cichon, Kristin K. Nicodemus, Dominique Campion, Tim B. Bigdeli, Ditte Demontis, Sergi Papiol, Hualin Simon Xi, Eric Strengman, Engilbert Sigurdsson, Patrick F. Sullivan, Kieran C. Murphy, Bertram Mueller-Myhsok, Vaughan J. Carr, Igor Nenadic, Matthew C. Keller, Christian R. Schubert, Jacob Gratten, Douglas F. Levinson, Luba Kalaydjieva, Anil K. Malhotra, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, Myin-Germeys, Inez, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Complex Trait Genetics, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Lee, S Hong, O'Donovan, Michael C, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case-Control Consortium, NCA - Brain mechanisms in health and disease, Human genetics, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, Medical Oncology, Epidemiology, Pharmacy, Clinical Genetics, and Child and Adolescent Psychiatry / Psychology
Subjects: Multifactorial Inheritance, Glutamatergic system, Genome-wide association study, Disease, heritability, genetic risk, Synaptic Transmission, Conferring risk, drugs, DISEASE, glutamatergic neurotransmission, Odds Ratio, 2.1 Biological and endogenous factors, GWAS, Aetiology, Psychiatric genetics, Genetics, Complement component 4, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Multidisciplinary, Genome-wide association, PSYCHIATRIC-DISORDERS, Brain, BIPOLAR DISORDER, Single Nucleotide, Serious Mental Illness, 3. Good health, Multidisciplinary Sciences, Mental Health, Enhancer Elements, Genetic, Schizophrenia, Biological plausibility, Engineering sciences. Technology, Mutations, Enhancer Elements, General Science & Technology, Glutamic Acid, schizophrenia, Genome-Wide Association Study, Biology, Polymorphism, Single Nucleotide, Genetic, medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, METAANALYSIS, Alleles, Genetic association, IDENTIFICATION, Prevention, Common variants, Human Genome, Neurosciences, Immunity, medicine.disease, FRAMEWORK, Brain Disorders, immune system, Genetic Loci, genome-wide association studies, Mutation
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. ispartof: Nature vol:511 issue:7510 pages:421-7 ispartof: location:England status: published
Published: 2014
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29. A 'Candidate-Interactome' Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Author: Federica Esposito, Arianna FORNASIERO, Helmut Butzkueven, Eleni Giannoulatou, Marcin Mycko, Trevor Kilpatrick, Françoise Clerget-Darpoux, Juliane Winkelmann, James Walters, Sandra D'Alfonso, Simon Foote, Richard Reynolds, Paola Cavalla, Laura Piccio, Vito A. G. Ricigliano, Silvia Romano, Matthew S. Gillman, Dianna Murray, Aiden Corvin, Joseph Glessner, Nicholas Wood, Jeannette Lechner-Scott, Izaura Lima Bomfim, Daniela Galimberti, Colin Palmer, Pablo Villoslada, Allan Kermode, Marie D'hooghe, JUSTIN RUBIO, Maurizio Leone, Robert Plomin, Christian Schulze, Matti Pirinen, Xavier Montalban, Rosella Mechelli, Sergio Baranzini, Fabio Macciardi, Jianjun Liu, Lars Alfredsson, Anna Rapa, Céline Bellenguez, Finn Sellebjerg, Loukas Moutsianas, Jenny Link, Erika Salvi, Anne Cross, Anna-Maija Sulonen, Ingrid Kockum, Krzysztof Selmaj, Jim Stankovich, Struan Grant, Per Soelberg Sorensen, Janusz Jankowski, Anne Spurkland, Frauke Zipp, Elvira Bramon, Giovanni RISTORI, Maria Chiara Buscarinu, Janna Saarela, Nikolaos Patsopoulos, Jacob McCauley, Refujia Gomez, Rodney Scott, An Goris, Filippo Martinelli boneschi, Manuel Comabella Lopez, James Wason, Tomas Olsson, Renato Umeton, Mechelli, R, Umeton, R, Policano, C, Annibali, V, Coarelli, G, Ricigliano, Va, Vittori, D, Fornasiero, A, Buscarinu, Mc, International Multiple Sclerosis Genetics, Consortium, Wellcome Trust Case Control, Consortium, Comi, Giancarlo, Romano, S, Salvetti, M, Ristori, G., MDC Library, Zhang, Luwen, Donnelly, P, University of St Andrews. School of Medicine, and University of Zurich
Subjects: Epidemiology, JC virus, lcsh:Medicine, Genome-wide association study, Neurodegenerative, medicine.disease_cause, Interactome, Major Histocompatibility Complex, 0302 clinical medicine, RA0421, RA0421 Public health. Hygiene. Preventive Medicine, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Aetiology, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, Statistics, Genomics, 3. Good health, Host-Pathogen Interaction, Infectious Diseases, Neurology, Medicine, Wellcome Trust Case Control Consortium, Function and Dysfunction of the Nervous System, Infection, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Biotechnology, Protein Binding, Research Article, Multiple Sclerosis, Genotype, General Science & Technology, Hepatitis C virus, Immunology, Aromatic hydrocarbon receptor, 610 Medicine & health, 570 Life Sciences, 1100 General Agricultural and Biological Sciences, Biology, Biostatistics, Autoimmune Disease, Microbiology, Virus, Environmental Epidemiology, Autoimmune Diseases, 610 Medical Sciences, Medicine, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 1300 General Biochemistry, Genetics and Molecular Biology, Genome Analysis Tools, medicine, Genome-Wide Association Studies, Humans, 030304 developmental biology, 1000 Multidisciplinary, Population Biology, Multiple sclerosis, Prevention, lcsh:R, Human Genome, Neurosciences, Computational Biology, medicine.disease, R1, Epstein–Barr virus, Demyelinating Disorders, 10040 Clinic for Neurology, International Multiple Sclerosis Genetics Consortium, Brain Disorders, Good Health and Well Being, Emerging Infectious Diseases, RC0321, Genetic Polymorphism, lcsh:Q, Clinical Immunology, 030217 neurology & neurosurgery, Population Genetics, Mathematics, Genome-Wide Association Study
Abstract: This work was funded by Italian Multiple Sclerosis Foundation grants (2007/R/17 and 2011/R/31) to MS. Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. Publisher PDF
Published: 2013
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30. Effect of DISC1 on the P300 waveform in psychosis

Author: Kuang Li, Maria Arranz, Anirban Dutt, Fruhling Rijsdijk, David A. Collier, John Powell, Katja Schulze, Matthew R. Broome, Robin M. Murray, Marco Picchioni, Miguel Constante, Timothea Toulopoulou, Elvira Bramon, Ian Williams, Daniel Stahl, Madiha Shaikh, Mei-Hua Hall, and Muriel Walshe
Subjects: Adult, Male, Psychosis, Candidate gene, Bipolar Disorder, Nerve Tissue Proteins, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, DISC1, medicine, Humans, Single-Blind Method, Allele, Genetics, biology, Haplotype, Electroencephalography, Regular Article, Middle Aged, medicine.disease, Brain Waves, Event-Related Potentials, P300, Psychiatry and Mental health, Haplotypes, Psychotic Disorders, Schizophrenia, Endophenotype, biology.protein, Female, Psychology
Abstract: Introduction: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. Methods: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. Results: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. Discussion: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.
Published: 2013

31. Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

Author: Robin M. Murray, Marco Picchioni, Elvira Bramon, Katja Schulze, Eugenia Kravariti, Mei-Hua Hall, Andrew Makoff, Fruhling Rijsdijk, Philip Asherson, Muriel Walshe, Rachel H Flomen, Timothea Toulopoulou, and Madiha Shaikh
Subjects: Adult, Male, Psychosis, Adolescent, alpha7 Nicotinic Acetylcholine Receptor, Biology, Receptors, Nicotinic, Population stratification, White People, Article, Young Adult, Gene Frequency, Gene Duplication, Genetics, medicine, Diseases in Twins, Humans, Copy-number variation, Allele, Allele frequency, Genetics (clinical), Genetic association, Aged, Aged, 80 and over, Chromosomes, Human, Pair 15, Sensory gating, Polymorphism, Genetic, Electroencephalography, Transmission disequilibrium test, Middle Aged, Sensory Gating, medicine.disease, medicine.anatomical_structure, Psychotic Disorders, Case-Control Studies, Female, Chromosome Deletion
Abstract: There is considerable evidence implicating the 15q13.3 region in neuropsychiatric disorders, with the α7 nicotinic receptor gene CHRNA7 the most plausible candidate. This region has multiple duplications and many copy number variants (CNVs). A common CNV involves a partial duplication of CHRNA7 (CHRFAM7A), which occurs in either orientation. We examined the distribution of these alternative genomic arrangements in a large cohort of psychiatric patients, their relatives and controls using the 2-bp deletion polymorphism as a marker for the orientation of CHRFAM7A. We investigated three common alleles for association with psychosis and with the P50 sensory gating deficit, which is strongly associated with psychosis and strongly linked to 15q13.3. We found significant within-family association with P50 (empirical P=0.004), which is robust to population stratification. Most of the effect came from the 2-bp deletion allele, which tags the variant of CHRFAM7A in the same orientation as CHRNA7. This allele is associated with the presence of the P50 sensory gating deficit (empirical P=0.0006). Tests comparing within-family and between-family components of association suggest considerable population stratification in the sample. We found no evidence for association with psychosis, but this may reflect lower power using this phenotype. Four out of six previous association studies found association of different psychiatric phenotypes with the same 2-bp deletion allele.European Journal of Human Genetics advance online publication, 16 May 2012; doi:10.1038/ejhg.2012.81., link_to_OA_fulltext
Published: 2012

32. Risk variant of oligodendrocyte lineage transcription factor 2 is associated with reduced white matter integrity

Author: Diana P, Prata, Richard A, Kanaan, Gareth J, Barker, Sukhwinder, Shergill, James, Woolley, Lyudmila, Georgieva, Marco M, Picchioni, Eugenia, Kravariti, Muriel, Walshe, Matt, Allin, Timothea, Toulopoulou, Elvira, Bramon, Colm, McDonald, Vincent, Giampietro, Robin M, Murray, Michael, Brammer, Michael, O'Donovan, and Philip, McGuire
Subjects: Adult, Male, Adolescent, Genotype, Brain, Nerve Tissue Proteins, Middle Aged, Oligodendrocyte Transcription Factor 2, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Young Adult, Diffusion Tensor Imaging, Risk Factors, Basic Helix-Loop-Helix Transcription Factors, Image Processing, Computer-Assisted, Schizophrenia, Humans, Female, Genetic Predisposition to Disease, Corrigendum, Research Articles
Abstract: The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity. Hum Brain Mapp 34:2025–2031, 2013. © 2011 Wiley Periodicals, Inc.
Published: 2012

33. The Association between COMT, BDNF, and NRG1 and Premorbid Social Functioning in Patients with Psychosis, Their Relatives, and Controls

Author: Timothea Toulopoulou, Robin M. Murray, Marco Picchioni, David A. Collier, Colm McDonald, Evangelos Vassos, Madiha Shaikh, Muriel Walshe, and Elvira Bramon
Subjects: medicine.medical_specialty, Candidate gene, Psychosis, Bipolar I disorder, Article Subject, lcsh:Medicine, Context (language use), behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, SNP, Allele, Psychiatry, lcsh:Science, General Environmental Science, lcsh:R, medicine.disease, 030227 psychiatry, Genetic epidemiology, Schizophrenia, lcsh:Q, General Agricultural and Biological Sciences, Psychology, 030217 neurology & neurosurgery, Research Article
Abstract: We investigated the influences of putative candidate genes for psychosis on premorbid social adjustment and on premorbid schizoid-schizotypal traits. A family-based sample was used including 177 patients with schizophrenia or bipolar I disorder with a history of psychotic symptoms, 86 of their unaffected relatives, and 116 unrelated healthy controls. Association analyses on the combined sample were conducted using the Statistical Analysis for Genetic Epidemiology software (SAGE) and adjusting for age, sex, clinical group, and the family-based nature of the data. The COMT Val158Met and BDNF Val66Met polymorphisms showed no evidence of association with either phenotype. The SNP rs221533 of the NRG1 gene was significantly associated with premorbid adjustment in adolescence with TT homozygous subjects having a poorer performance than C allele carriers. In the context of neurodevelopmental disorders such as schizophrenia and other psychoses, this finding is plausible; however, it is preliminary and requires replication in an independent sample. In a broader sense, the use of intermediate quantitative phenotypes such as the ones presented in this study may be of help to understand the mechanism of action of genetic risk factors.
Published: 2012

34. Striatal Dopamine Transporter Availability in Drug-Naive Patients With Schizophrenia: A Case-Control SPECT Study With [99mTc]-TRODAT-1 and a Meta-Analysis

Author: Oliver D. Howes, Po See Chen, Nan Tsing Chiu, Kao Chin Chen, Ru Band Lu, Anthony S. David, Tzung Lieh Yeh, I. Hui Lee, Yen Kuang Yang, Sabine Landau, and Elvira Bramon
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Young Adult, Sex Factors, Dopamine, Internal medicine, Basal ganglia, medicine, Humans, Dopamine transporter, Tomography, Emission-Computed, Single-Photon, Dopamine Plasma Membrane Transport Proteins, biology, Dopaminergic, Case-control study, Regular Article, Organotechnetium Compounds, Middle Aged, medicine.disease, Neostriatum, Psychiatry and Mental health, Drug-naïve, Endocrinology, Schizophrenia, Meta-analysis, Case-Control Studies, biology.protein, Female, Radiopharmaceuticals, Psychology, Neuroscience, medicine.drug, Tropanes
Abstract: Central dopaminergic hyperactivity has been one of the main hypotheses of the pathophysiology of schizophrenia since the 1970s. Excess dopamine (DA) neurotransmission in the striatum is hypothesized to alter the processing of information and result in psychotic symptoms in schizophrenia. Single photon emission computerized tomography (SPECT) provides in vivo indices of DA neurotransmission. Our study aimed to compare dopamine transporter (DAT) availability between drug-naive patients with schizophrenia and controls using SPECT. DAT availability through [(99m)Tc]-TRODAT-1 SPECT was compared between 47 drug-naive patients with recent-onset schizophrenia and 112 healthy controls. We also conducted a random-effects meta-analysis of the available literature synthesizing the results of 6 comparable published articles as well as our current data. The mean specific striatal binding showed a statistical trend for a reduction among the patients compared with controls (estimated difference = 0.071; 95% CI -0.01, 0.15; P = .08). There was an effect of gender, whereby females had a higher ratio of specific striatal binding than males. Age was negatively correlated with the ratio of specific striatal binding, both in patients and controls. The meta-analysis provided a pooled standardized effect size (Cohen's d) of -0.07 (95% CI -0.31, 0.18; P = .60) for the patient vs control comparison in TRODAT binding, with no evidence of heterogeneity between studies or publication bias. Our findings suggest that striatal DAT levels are not altered in the early stages of schizophrenia before medication is introduced. We identified gender differences and aging effects that could have significance for future studies.
Published: 2011

35. Altered brain function directly related to structural abnormalities in people at ultra high risk of psychosis: longitudinal VBM-fMRI study

Author: Scr Williams, Louise Johns, Paolo Fusar-Poli, James Woolley, Matthew R. Broome, Lucia Valmaggia, Paul Tabraham, Philip McGuire, Elvira Bramon, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: Adult, Male, medicine.medical_specialty, Psychosis, Prodromal psychosis, Neuropsychological Tests, Audiology, Brain mapping, ARMS, Young Adult, Supramarginal gyrus, Image Processing, Computer-Assisted, medicine, Humans, Longitudinal Studies, Psychiatry, VBM, Biological Psychiatry, Psychiatric Status Rating Scales, Brain Mapping, Memory Disorders, medicine.diagnostic_test, Working memory, High risk, Thought disorder, fMRI, Brain, Inferior parietal lobule, medicine.disease, Magnetic Resonance Imaging, Oxygen, Psychiatry and Mental health, Emotional lateralization, Cross-Sectional Studies, Memory, Short-Term, Psychotic Disorders, Female, medicine.symptom, Psychology, Functional magnetic resonance imaging
Abstract: Background Several studies have indicated that people with prodromal signs of psychosis show alterations in the structure and function of the brain when they first present to clinical services. However, the longitudinal course of these abnormalities, and how they relate to subsequent clinical and functional outcome is relatively unclear. Methods A cohort of subjects at ultra high risk of psychosis were studied using functional magnetic resonance imaging (fMRI) in conjunction with the N-Back task, and volumetric MRI at first clinical presentation and again after one year. Levels of psychopathology and global functioning were assessed at the same time points using the CAARMS, PANSS, and the GAF scale. Results At baseline, the high risk group showed reduced activation during the task in the left middle frontal gyrus, supramarginal gyrus and inferior parietal lobule, and reduced gray matter volume in the left middle and medial frontal gyri, left insula and the right anterior cingulate gyrus. Within the high-risk group, there was a positive correlation between the magnitude of the functional and structural alterations in the left middle frontal gyrus. Between presentation and follow up, the severity of perceptual disorder and thought disorder (rated by the CAARMS), and of general psychopathology (rated by the PANSS general score) decreased, and the level of global functioning improved. This clinical and functional improvement was associated with a longitudinal increase in activation in the anterior cingulate and right parahippocampal gyrus. The change in anterior cingulate response was directly correlated with the improvement in the GAF score. Conclusions In subjects presenting with prodromal signs of psychosis, reduced prefrontal activation during a working memory task is associated with a reduction in gray matter volume in the same area. Changes in anterior cingulate activation were correlated with functional improvement in this group, consistent with the role of this region in multiple cognitive and social processes.
Published: 2011

36. Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

Author: Chris C. A. Spencer, Panos Deloukas, Sarah Edkins, Amy Strange, Gavin Hudson, John Hardy, Aiden Corvin, Mark I. McCarthy, Karen E. Morrison, Robert Plomin, Nigel W. Williams, Patrick F. Chinnery, Simon C. Potter, Hannah Blackburn, Coro Paisán-Ruiz, Richard C. Trembath, Stephen Sawcer, Carl E Clarke, Juan-Pablo Casas, Gavin Band, Leena Peltonen, Matti Pirinen, Matthew A. Brown, Anna Rautanen, Martin A. Brown, Nicholas W. Wood, Cordelia Langford, Janusz Jankowski, David J. Burn, Kailash P. Bhatia, Roger A. Barker, Michelle Gardner, Peter Donnelly, J. P. Pearson, Sarah E. Hunt, Nicholas John Craddock, J.M. Evans, Elvira Bramon, Hugh S. Markus, Zhan Su, Colin Freeman, Colin N. A. Palmer, Andrew J. Lees, Christopher G. Mathew, Emma Gray, Vincent Plagnol, Huw R. Morris, Ananth C. Viswanathan, Jennie M. Blackwell, and Céline Bellenguez
Subjects: Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Genetics, SNP, Humans, Genetic Predisposition to Disease, Age of Onset, Molecular Biology, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Haplotype, Case-control study, Parkinson Disease, General Medicine, Articles, LRRK2, 3. Good health, Haplotypes, Case-Control Studies, Sample Size, alpha-Synuclein, Age of onset, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.
Published: 2011

37. Expanding the range of ZNF804A variants conferring risk of psychosis

Author: Robin M. Murray, Vera Golimbet, Sven Cichon, M. Rietschel, D St Clair, Andres Ingason, Thomas Hansen, Sarah Tosato, Ole Mors, Omar Gustafsson, Ragnheidur Fossdal, J. Yoon, Olli Pietiläinen, Annette M. Hartmann, Augustine Kong, Lavinia Athanasiu, Unnur Thorsteinsdottir, Srdjan Djurovic, Tao Li, Elvira Bramon, Markus M. Nöthen, Dan Rujescu, Erik G. Jönsson, Leena Peltonen, Jan-Erik Lönnqvist, Mette Nyegaard, Annamari Tuulio-Henriksson, Hannes Petursson, Birte Glenthøj, János Réthelyi, Nelson B. Freimer, Ingrid Melle, David M. Hougaard, M. Mattheisen, Lilia I. Abramova, Stacy Steinberg, Preben Bo Mortensen, David A. Collier, Ingrid Agartz, Neil Walker, Lambertus A. Kiemeney, H.-J. Möller, Gillian Fraser, Hreinn Stefansson, Ina Giegling, Anders D. Børglum, René Breuer, Thorgeir E. Thorgeirsson, Evangelos Vassos, Gesche Jürgens, Thomas Werge, Iris H Gudjonsdottir, Pall I. Olason, Lars Terenius, Kari Stefansson, Thordur Sigmundsson, Merete Nordentoft, Yvonne Böttcher, Bent Nørgaard-Pedersen, Tiina Paunio, Rita M. Cantor, Roel A. Ophoff, Henrik B. Rasmussen, Kaleda Vg, István Bitter, Jaana Suvisaari, Timothea Toulopoulou, Mirella Ruggeri, Eric Strengman, Engilbert Sigurdsson, Muriel Walshe, Ole A. Andreassen, deCODE genetics, Reykjavik, Iceland., Educational Neuroscience, Clinical Child and Family Studies, LEARN! - Brain, learning and development, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, ANS - Amsterdam Neuroscience, and Adult Psychiatry
Subjects: Psychosis, Bipolar Disorder, DNA Copy Number Variations, genetics [DNA Copy Number Variations], CNV, Kruppel-Like Transcription Factors, genetics [Anxiety Disorders], Genome-wide association study, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Reference Values, mental disorders, medicine, Humans, genetics [Schizophrenia], Genetic Predisposition to Disease, ddc:610, Bipolar disorder, Molecular Biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Genetic association, Genetics, bipolar disorder, 0303 health sciences, biology, genetics [Kruppel-Like Transcription Factors], Case-control study, association, Odds ratio, medicine.disease, Anxiety Disorders, schizophrenia, Psychiatry and Mental health, Schizophrenia, ZNF804A, Case-Control Studies, ZNF804A protein, human, biology.protein, Psychology, genetics [Bipolar Disorder], 030217 neurology & neurosurgery, Zinc finger protein 804A, Genome-Wide Association Study
Abstract: A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P5 × 10 8) associated with schizophrenia earlier. However, one variant, rs1344706T, had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10 7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10 8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR1.08, P0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N609, OR1.09, P0.00065). Furthermore, as it has been proposed that variants such as rs1344706Tcommon and with low relative riskmay also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P0.0016 for association with the larger set of psychiatric disorders). © 2011 Macmillan Publishers Limited All rights reserved., link_to_OA_fulltext
Published: 2011
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38. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Author: Nicholas W. Wood, Chris C. A. Spencer, Ewan R. Pearson, Richard C. Trembath, Christopher Schofield, Christopher G. Mathew, Roger Tavendale, Jenefer M. Blackwell, Cordelia Langford, Sarah E. Hunt, Kaixin Zhou, Sarah Edkins, Colin N. A. Palmer, Helen M. Colhoun, Matthew A. Brown, Anna Rautanen, D. G. Hardie, Robert Plomin, Joachim Jankowski, Lindsay Burch, Peter Donnelly, Amanda J. Bennett, Panos Deloukas, Amy Strange, Simon A. Hawley, N. Craddock, Ruth L. Coleman, Stephen Sawcer, Rury R. Holman, Elvira Bramon, Emma Gray, Fiona Carr, Hugh S. Markus, Lorna W. Harries, Alex S. F. Doney, Aiden Corvin, Serge Dronov, Colin Freeman, Christopher J. Groves, Juan P. Casas, Andrew T. Hattersley, Leena Peltonen, Calum Sutherland, Ananth C. Viswanathan, Céline Bellenguez, Andrew D. Morris, Mark I. McCarthy, Nilesh J. Samani, Louise A. Donnelly, and A. Duncanson
Subjects: 0303 health sciences, medicine.medical_specialty, DNA repair, Genome-wide association study, Type 2 diabetes, Biology, medicine.disease, Article, 3. Good health, Metformin, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, 030220 oncology & carcinogenesis, Diabetes mellitus, Internal medicine, Ataxia-telangiectasia, Genetics, medicine, Protein kinase A, 030304 developmental biology, Glycemic, medicine.drug
Abstract: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.
Published: 2011
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39. Neural correlates of visuospatial working memory in the 'at-risk mental state'

Author: Matthew R. Broome, Fernando Zelaya, Scr Williams, Paolo Fusar-Poli, Pall Matthiasson, James Woolley, Elvira Bramon, Paul Tabraham, Philip McGuire, Louise Johns, Mick Brammer, Xavier Chitnis, Lucia Valmaggia, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: Adult, Male, Psychosis, medicine.medical_specialty, Posterior parietal cortex, Audiology, Spatial memory, behavioral disciplines and activities, ARMS, memory, Young Adult, visuospatial, Visual memory, Parietal Lobe, Task Performance and Analysis, medicine, Humans, psychosis, Applied Psychology, First episode, medicine.diagnostic_test, Working memory, imaging, At risk mental state, medicine.disease, Magnetic Resonance Imaging, prodrome, Frontal Lobe, Psychiatry and Mental health, Memory, Short-Term, Case-Control Studies, Schizophrenia, Female, Schizophrenic Psychology, Functional magnetic resonance imaging, Psychology, Neuroscience, RC
Abstract: BackgroundImpaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia.MethodfMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object–location paired-associate memory task, with experimental manipulation of mnemonic load.ResultsIn all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS.ConclusionsAbnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.
Published: 2010
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40. The relationship between visual memory and the P300 in families with schizophrenia

Author: Alexandra Pentaraki, Robin M. Murray, Daniel Stahl, Elvira Bramon, Timothea Toulopoulou, and Eugenia Kravariti
Subjects: Psychosis, medicine.medical_specialty, Recall, business.industry, lcsh:RC435-571, Neuropsychology, Wechsler Adult Intelligence Scale, medicine.disease, Psychiatry and Mental health, Visual memory, Endophenotype, lcsh:Psychiatry, Meeting Abstract, Medicine, Family history, business, Psychiatry, Neurocognitive
Abstract: BackgroundPatients with schizophrenia and their unaffected rela-tives exhibit significant P300 amplitude and latencyabnormalities in conjunction with neurocognitive defi-cits. Both the deficits in the P300 and neurocognitionsuggest that these indexes may be potential endopheno-types of the disorder. Few studies have examined therelationship between the P300 and neuropsychologicalmeasurements of sustained attention, visual memoryand current intellectual ability in schizophrenia andthese studies provide inconsistent results. The aim ofthepresentstudyis(a)toexaminewhichcognitiveimpairments the P300 reflects in schizophrenia and (b)to investigate the relationship between neurocognitionand the P300 in families with schizophrenia in order toexamine if these may be potential endophenotypes ofthe disorder.Materials and methods95 patients with schizophrenia (35 females, 60 males),149 of their non-psychotic unaffected first-degree rela-tives (91 females, 57 males) and 69 unrelated healthycontrols with no personal family history of psychosis(39 females, 30 males) were assessed both in a P300oddball paradigm and neuropsychological measure-ments such as the WAIS-R (Wechsler, 1981), responsetendency of the Conner’s Continuous PerformanceTest (Conners, 1995), immediate and delayed visualrecall of The Wechsler Memory Scale-Russell’sversion(Russell, 1975). STATA 9.0 (STATA Corporation, Col-lege Station, TX) was used for the statistical analysis ofdata.ResultsSignificant P300 amplitude reductions and prolongedlatencies were found in patients and their unaffectedrelatives independent of current general intellectual abil-ity, education and age. There was a significant effect ofsustained attention (response tendency), on the P300amplitude reductions of patients and their unaffectedrelatives. Immediate visual recall had a significant effecton the P300 amplitude reduction of patients and theirunaffected relatives, while there was no effect of delayedvisual recall. There was no significant effect of immedi-ate and delayed visual recall on the P300 prolongedlatencies of patients and their unaffected relatives.Sustained attention did not have a significant effect onthe P300 latency, but after controlling for its effect thedifferences between the groups disappeared.ConclusionsThe findings of the present study suggest that the P300amplitude reduction that patients and their unaffectedrelatives exhibited reflected impairments in effortfulattention and in the use of short-memory processes (e.g.encoding) that involve the visual modality. The findingsalso suggest a dissociation between the P300 anddelayed visual recall in patients and their unaffectedrelatives. Although it is less clear from the present find-ings, the prolonged P300 latency does not seem toreflect impairments in sustained attention and visualmemory processes in either patients with schizophreniaor their unaffected relatives. The P300 amplitude reduc-tion seems to be a potential endophenotype ofschizophrenia
Published: 2010

41. Economic impact of early intervention in people at high risk of psychosis

Author: Corinne Prescott, Matthew R. Broome, Elvira Bramon, Paddy Power, Martin Knapp, Lucia Valmaggia, Julia Lappin, Paul McCrone, Paul Tabraham, Philip McGuire, James Woolley, and Louise Johns
Subjects: Gerontology, Male, Psychosis, medicine.medical_specialty, Time Factors, Referral, Cost effectiveness, Cost-Benefit Analysis, Young Adult, Risk Factors, Intervention (counseling), London, medicine, Humans, Psychiatry, Applied Psychology, health care economics and organizations, Cost–benefit analysis, business.industry, Social environment, At risk mental state, medicine.disease, Mental health, Psychiatry and Mental health, Psychotic Disorders, Female, business
Abstract: Background: Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis.Method: The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model.Results: Over the initial 12 months from presentation, the costs of the OASIS intervention were £1872 higher than CAU. However, after 24 months they were £961 less than CAU.Conclusions: This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.
Published: 2009
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42. Neural correlates of executive function and working memory in the 'at-risk mental state'

Author: Louise Johns, James Woolley, Paul Tabraham, Philip McGuire, Matthew R. Broome, Michael Brammer, Xavier Chitnis, Lucia Valmaggia, Pall Matthiasson, Paolo Fusar-Poli, Elvira Bramon, and Steven Williams
Subjects: Adult, Male, Psychosis, medicine.medical_specialty, Posterior parietal cortex, Audiology, Neuropsychological Tests, Gyrus Cinguli, behavioral disciplines and activities, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, medicine, Verbal fluency test, Humans, 030212 general & internal medicine, Prefrontal cortex, Psychiatry, First episode, Memory Disorders, Working memory, Verbal Behavior, At risk mental state, medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, Psychiatry and Mental health, Cross-Sectional Studies, Treatment Outcome, Psychotic Disorders, Schizophrenia, Case-Control Studies, Female, Psychology
Abstract: Background and Aims: People with ‘prodromal’ symptoms have a very high risk of developing psychosis. We used functional MRI to examine the neurocognitive basis of this vulnerability. Method: Cross-sectional comparison of subjects with an ARMS (n=17), first episode schizophreniform psychosis (n=10) and healthy volunteers (n=15). Subjects were studied using functional MRI while they performed an overt verbal fluency task, a random movement generation paradigm and an N-Back working memory task. Results: During an N-Back task the ARMS group engaged inferior frontal and posterior parietal cortex less than controls but more than the first episode group. During a motor generation task, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than the first episode group. During verbal fluency using ‘Easy’ letters, the ARMS group demonstrated intermediate activation in the left inferior frontal cortex, with first episode groups showing least, and controls most, activation. When processing ‘Hard’ letters, differential activation was evident in two left inferior frontal regions. In its dorsolateral portion, the ARMS group showed less activation than controls but more than the first episode group, while in the opercular part of the left inferior frontal gyrus / anterior insula activation was greatest in the first episode group, weakest in controls and intermediate in the ARMS group. Conclusions: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have just developed psychosis but less severe.
Published: 2009

43. Elevated striatal dopamine function linked to prodromal signs of schizophrenia

Author: Paul M. Grasby, Lucia Valmaggia, Matthew R. Broome, Robin M. Murray, Andrew J. Montgomery, Paul Tabraham, Philip McGuire, M.-C. Asselin, Isabel Valli, Louise Johns, Oliver D. Howes, and Elvira Bramon-Bosch
Subjects: Adult, Male, medicine.medical_specialty, Psychosis, Dopamine, Context (language use), Neuropsychological Tests, Schizotypal Personality Disorder, Young Adult, Neurochemical, Arts and Humanities (miscellaneous), Reference Values, Risk Factors, Internal medicine, Image Processing, Computer-Assisted, medicine, Humans, Dominance, Cerebral, Psychiatry, Psychiatric Status Rating Scales, Brain Mapping, Dopaminergic, medicine.disease, Schizotypal personality disorder, Corpus Striatum, Dihydroxyphenylalanine, Diagnostic and Statistical Manual of Mental Disorders, Psychiatry and Mental health, Schizophrenia, Positron-Emission Tomography, Female, Cognition Disorders, Psychology, Neurocognitive, medicine.drug
Abstract: CONTEXT: A major limitation on the development of biomarkers and novel interventions for schizophrenia is that its pathogenesis is unknown. Although elevated striatal dopamine activity is thought to be fundamental to schizophrenia, it is unclear when this neurochemical abnormality develops in relation to the onset of illness and how this relates to the symptoms and neurocognitive impairment seen in individuals with prodromal symptoms of schizophrenia. OBJECTIVES: To determine whether striatal dopamine function is elevated in individuals with prodromal symptoms of schizophrenia before the onset of psychosis and to assess how this relates to the symptoms and neurocognitive impairment. DESIGN: Case-control study of in vivo striatal dopaminergic function. SETTING: Academic research. Patients Patients were recruited from a community mental health service. Twenty-four patients having prodromal symptoms of schizophrenia were compared with 7 patients having schizophrenia and with 12 matched healthy control subjects from the same community. Main Outcome Measure Striatal 6-fluoro-l-dopa F 18-dopa uptake measured using positron emission tomographic (18)F-dopa imaging. RESULTS: Striatal (18)F-dopa uptake was elevated in patients with prodromal symptoms of schizophrenia (effect size, 0.75) to an intermediate degree compared with that in patients with schizophrenia (effect size, 1.25). The elevation was localized in the associative striatum in both groups. Moreover, striatal (18)F-dopa uptake in patients with prodromal symptoms of schizophrenia was correlated with the severity of prodromal psychopathologic and neuropsychological impairment but not with the severity of anxiety or depressive symptoms. CONCLUSIONS: These findings indicate that dopamine overactivity predates the onset of schizophrenia in individuals with prodromal psychotic symptoms, is predominantly localized in the associative striatum, and is correlated with the severity of symptoms and neurocognitive dysfunction.
Published: 2009

44. Outreach and support in south London (OASIS): implementation of a clinical service for prodromal psychosis and the at risk mental state

Author: Matthew R. Broome, Lucia Valmaggia, Rafael Gafoor, Louise Johns, Elvira Bramon, Paul Tabraham, James Woolley, and Philip McGuire
Subjects: Adult, Male, medicine.medical_specialty, Health Services Accessibility, 03 medical and health sciences, 0302 clinical medicine, Patient satisfaction, Risk Factors, Intervention (counseling), London, Urban Health Services, Humans, Medicine, 030212 general & internal medicine, Psychiatry, Referral and Consultation, First episode, Primary Health Care, business.industry, Public health, Primary care physician, Social environment, At risk mental state, Mental health, Community Mental Health Services, Community-Institutional Relations, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Socioeconomic Factors, Patient Satisfaction, Feasibility Studies, Female, business
Abstract: BackgroundWhile recent research points to the potential benefits of clinical intervention before the first episode of psychosis, the logistical feasibility of this is unclear.AimsTo assess the feasibility of providing a clinical service for people with prodromal symptoms in an inner city area where engagement with mental health services is generally poor.MethodsFollowing a period of liaison with local agencies to promote the service, referrals were assessed and managed in a primary care setting. Activity of the service was audited over 30 months.ResultsPeople with prodromal symptoms were referred by a range of community agencies and seen at their local primary care physician practice. Over 30 months, 180 clients were referred; 58 (32.2%) met criteria for an at risk mental state, most of whom (67.2%) had attenuated psychotic symptoms. Almost 30% were excluded due to current or previous psychotic illness, of which two-thirds were in the first episode of psychosis. The socio-demographic composition of the 'at risk' group reflected that of the local population, with an over-representation of clients from an ethnic minority. Over 90% of suitable clients remained engaged with the service after 1 year.ConclusionIt is feasible to provide a clinical service for people with prodromal symptoms in a deprived inner city area with a large ethnic minority population.
Published: 2005

45. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Author: Paul A. Weston, Emma Gray, Robert W. Ike, Sarah Rogers, Wolfgang Weger, Justin Paschall, Andreas Ruether, Anthony W. Ryan, James T. Elder, Robert Andrews, Ciara Coleman, Amy Perlmutter, Marin Aurand, Eva Riveira-Muñoz, Kati Kainu, G. Mark Lathrop, Per Hoffmann, Peter C.M. van de Kerkhof, Suzannah Bumpstead, Thomas Illig, Matthew W. Gillman, Gavin Band, Enno Christophers, Agnieszka Zawirska, Giuseppe Novelli, Jenefer M. Blackwell, Wilson Liao, Christopher G. Mathew, Steven J. Schrodi, Henry W. Lim, Sara Widaa, Lena Samuelsson, Cordelia Langford, Sari Suomela, Andre Franke, Jonathan Barker, Lotus Mallbris, Leena Peltonen, Ross McManus, Judith G.M. Bergboer, Radhi Ravindrarajah, Colin N. A. Palmer, O. T. McCann, Ggoncalo R. Abecasis, Ravi Hiremagalore, Tiziana Lepre, Rajan P. Nnair, Garrett Hellenthal, Brian Kirby, Richard D. Pearson, Linda E. Campbell, Stefan Schreiber, Eva Ellinghaus, Michael E. Weale, Sampath Prahalad, Stephen L. Guthery, Johann E. Gudjonsson, Janusz Jankowski, Simon C. Potter, Judith Fischer, Werner Kurrat, Michael J. Cork, Sean Ennis, Åsa Torinsson Naluai, Peter Donnelly, Raimund Erbel, Gosia Trynka, Audrey Duncanson, Martin den Heijer, Cindy Helms, Christian Gieger, Markward Ständer, Ulrike Hüffmeier, Mark I. McCarthy, Wolfgang Salmhofer, Yanming Li, Juan P. Casas, Nilesh J. Samani, Ramon M. Pujol, Peter Wolf, James Tt Eelder, Joost Schalkwijk, Katarina Wolk, Matthew Waller, Alan D. Irvine, Petra Badorf, Gemma Martin-Ezquerra, Dafna D. Gladman, Rotraut Mössner, Matthew A. Brown, Patrick L.J.M. Zeeuwen, Jonathan Nn Barker, Anne Barton, H.-Erich Wichmann, Hannah Blackburn, Emiliano Giardina, Wolfgang Küster, Heiko Traupe, Richard B. Warren, Aiden Corvin, Jennifer M. Gardner, Joe McPartlin, Alan Menter, Anna Rautanen, Jane Worthington, John J. Voorhees, Andrew Henschel, Külli Kingo, Proton Rahman, Jennifer Liddle, Hugh S. Markus, Catherine H. Smith, Cisca Wijmenga, Vinod Chandran, Richard Ttrembath, Ananth C. Viswanathan, Hyun Min Kang, David E. Goldgar, Fawnda Pellett, Joyce Leman, Jesús Lascorz, M. Perez, Sarah Edkins, Ulpu Saarialho-Kere, Alexandros Onoufriadis, Stephan Weidinger, Amy Strange, Funda Schürmeier-Horst, Michael H. Allen, Angelika Hofer, Lam C. Tsoi, Karl-Heinz Jöckel, Jun Ding, Adrian Hayday, Trilokraj Tejasvi, Mary J. Malloy, Susanne Moebus, Kristina Callis Duffin, Rachid Tazi-Ahnini, Zhan Su, Gerald G. Krueger, Trevor Markham, Richard C. Trembath, Philip E. Stuart, Gonçalo R. Abecasis, Nicholas Craddock, Céline Bellenguez, Serge Dronov, Clive R. Pullinger, Eleni Giannoulatou, A. David Burden, Damjan Vukcevic, Andrew Miner, Cheryl F. Rosen, L. Barnes, Sarah L. Spain, Mona Ståhle, Naomi Hammond, Rhian Gwilliam, Sarah E. Hunt, Frank O. Nestle, Xavier Estivill, Panos Deloukas, Phil Gallagher, Annica Inerot, Judith Conroy, Helen S. Young, Stephen J. Sawcer, Bruce F. Bebo, Isis Ricaño-Ponce, Juha Kere, Pamela Whittaker, John P. Kane, Anne M. Bowcock, Christopher E.M. Griffiths, W.H. Irwin McLean, Tilo Henseler, Juliane Winkelmann, Michael Weichenthal, Tõnu Esko, Ulrich Mrowietz, Jo Knight, Bing Jian Feng, André Reis, Sulev Kõks, Elvira Bramon, Nicholas W. Wood, Alagurevathi Jayakumar, Colin Freeman, Carlo Perricone, Yun Li, Chris C. A. Spencer, Pui Kwok, Robert Plomin, Ann B. Begovich, Francesca Capon, Carol Wise, Andres Metspalu, Caitriona Cusack, Oliver FitzGerald, Matti Pirinen, Michelle Ricketts, Rajan P. Neir, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Candidate gene, T-Lymphocytes, Genome-wide association study, Disease, DEAD-box RNA Helicases, 0302 clinical medicine, T-CELL DEVELOPMENT, Receptors, Immunologic, MULTIPLE COMMON, Oligonucleotide Array Sequence Analysis, Skin, GENE-EXPRESSION, Genetics, 0303 health sciences, GTPase-Activating Proteins, CELIAC-DISEASE, COMMON VARIANTS, 3. Good health, 030220 oncology & carcinogenesis, DEAD Box Protein 58, STAT3 Transcription Factor, Biology, Polymorphism, Single Nucleotide, White People, Article, TH17 DIFFERENTIATION, SIGNALING PATHWAYS, 03 medical and health sciences, Psoriasis, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Genetic association, Innate immune system, INTERFERON-GAMMA, Membrane Proteins, Pathogenesis and modulation of inflammation Infection and autoimmunity [N4i 1], NEGATIVE REGULATOR, medicine.disease, Immunity, Innate, Genetic architecture, CARD Signaling Adaptor Proteins, Core Binding Factor Alpha 3 Subunit, Settore MED/03 - Genetica Medica, Genetic Loci, Guanylate Cyclase, Genome-Wide Association Study
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. © 2012 Nature America, Inc. All rights reserved.
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