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1. Upregulation of the Renin–Angiotensin System Is Associated with Patient Survival and the Tumour Microenvironment in Glioblastoma

Author

Mathew Lozinski, Eugenie R. Lumbers, Nikola A. Bowden, Jennifer H. Martin, Michael F. Fay, Kirsty G. Pringle, and Paul A. Tooney

Subjects
glioblastoma, prorenin, angiotensinogen, hypoxia, chemoradiation, Cytology, QH573-671
Abstract

Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin–angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (ATP6AP2, AGTR1, AGTR2, ACE, AGT, and REN) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, ATP6AP2, AGTR1, ACE, and AGT had consistent expressions across samples, while AGTR2 and REN were lowly expressed. High expression of AGTR1 was independently associated with lower progression-free survival (PFS) (p = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis (p = 0.095). The combined expression of RAS receptors (ATP6AP2, AGTR1, and AGTR2) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, ATP6AP2 and AGTR1 were upregulated after chemoradiotherapy and correlated with an increase in HIF1A expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes.

Published
2024
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2. Characteristics of vasculogenic mimicry and tumour to endothelial transdifferentiation in human glioblastoma: a systematic review

Author

Kelsey Maddison, Nikola A. Bowden, Moira C. Graves, and Paul A. Tooney

Subjects
Glioblastoma, Vasculogenic mimicry, Transdifferentiation, Tumour-derived vasculature, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Glioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tumour vascularisation have also been reported in glioblastoma, including the formation of tumour cell-derived vessels by vasculogenic mimicry (VM) or the transdifferentiation of tumour cells to endothelial cells. VM and endothelial transdifferentiation have frequently been reported as distinct processes, however, the use of both terms to describe a single process of vascularisation also occurs. Some overlapping characteristics have also been reported when identifying each process. We therefore aimed to determine the markers consistently attributed to VM and endothelial transdifferentiation in the glioblastoma literature. Methods Ovid MEDLINE and Ovid Embase were searched for studies published between January 1999 and July 2021 that assessed VM or tumour to endothelial transdifferentiation in human glioblastoma. The online systematic review tool Covidence was used for screening and data extraction. Extracted data included type of tumour-derived vasculature reported, methods and techniques used, and markers investigated. Studies were grouped based on type of vasculature reported for further assessment. Results One hundred and thirteen of the 419 unique records identified were included for analysis. VM was reported in 64/113 studies, while tumour to endothelial transdifferentiation was reported in 16/113 studies. The remaining studies used both terms to describe a single process, did not define the process that occurred, or concluded that neither VM nor endothelial transdifferentiation occurred. Absence of CD34 and/or CD31 in vascular structures was the most common indicator of VM, while expression of CD34 and/or CD31, in addition to various other endothelial, stem cell or tumour cell markers, indicated tumour to endothelial transdifferentiation. Conclusion Cells derived from tumour to endothelial transdifferentiation express typical endothelial markers including CD34 and CD31, while tumour cells contributing to VM lack CD34 and CD31 expression. Additional tumour markers are required to identify transdifferentiation in glioblastoma tissue, and this process requires further characterisation.

Published
2023
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3. Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex

Author

Danielle M. Santarelli, Adam P. Carroll, Heath M. Cairns, Paul A. Tooney, and Murray J. Cairns

Subjects
Schizophrenia, MicroRNA, Dorsolateral prefrontal cortex, Network, Neuropathology, Biology (General), QH301-705.5, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA (miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex (BA 46) (n = 74 matched pairs of schizophrenia, schizoaffective, and control samples) was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92a, miR-495, and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that miRNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.

Published
2019
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4. Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment

Author

Mathew Lozinski, Nikola A. Bowden, Moira C. Graves, Michael Fay, Bryan W. Day, Brett W. Stringer, and Paul A. Tooney

Subjects
glioblastoma, DNA damage response, treatment resistance, temozolomide, radiation, Cytology, QH573-671
Abstract

Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RT-treated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition.

Published
2022
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5. 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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6. 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

7. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

James McKay, Frank Bellivier, Mark A. Frye, Bertram Müller-Myhsok, Fermín Mayoral, I. Nicol Ferrier, Marion Leboyer, Fabian Streit, Dan J. Stein, James L. Kennedy, Christine Søholm Hansen, Scott D. Gordon, Beata Świątkowska, Valentina Escott-Price, Michael Bauer, Lina Martinsson, Donald J. MacIntyre, Oleksandr Frei, Daniel J. Smith, Sara A. Paciga, Takeo Saito, Jennifer L. Moran, Verneri Antilla, C Pantelis, Tomas Olsson, Swapnil Awasthi, Lena Backlund, Eirini Maratou, Martin Schalling, John B. Vincent, Niamh Mullins, Sarah E. Bergen, Niamh L. O'Brien, Marco P. Boks, Carsten Bøcker Pedersen, Mikael Landén, Franziska Degenhardt, Hang Zhou, Margarita Rivera, Andrew M. McIntosh, Manuel Mattheisen, Shawn Levy, Roy H. Perlis, John P. Rice, Sigurdur H. Magnusson, Amanda Dobbyn, Michael Conlon O'Donovan, Julien Bryois, Wolfgang Maier, John-Anker Zwart, J. Raymond DePaulo, Martin Alda, Laura G. Sloofman, Friederike Sophie David, James A. Knowles, Aiden Corvin, Thomas G. Schulze, Markus M. Nöthen, Nolan Kamitaki, Nina Dalkner, Brandon J. Coombes, Gustavo Turecki, Allan H. Young, Caroline M. Nievergelt, Patricia T. Michie, Ingrid Agartz, Towfique Raj, Diego Albani, Maria Grigoroiu-Serbanescu, Bernhard T. Baune, Kyooseob Ha, Vincent Millischer, Engilbert Sigurdsson, Eva C. Beins, Nicholas G. Martin, Gulja Babadjanova, Josef Frank, Eva Z. Reininghaus, Patrick F. Sullivan, Ian R. Gizer, Guy A. Rouleau, Carmel M. Loughland, Christine Lochner, Thorsten M. Kranz, Amy Perry, Arne E. Vaaler, Mariam M. Al Eissa, Simon Xi, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Ketil J. Oedegaard, Helmut Vedder, Carol A. Mathews, Panagiotis Ferentinos, Tim B. Bigdeli, Derek W. Morris, Per Hoffmann, Mark Hyman Rapaport, Peter P. Zandi, Michael John Owen, Douglas M. Ruderfer, Anders D. Børglum, Catharina Lavebratt, Thorgeir E. Thorgeirsson, Paul A. Tooney, Michiaki Kubo, Steven A. Kushner, Jan Hillert, Loes M. Olde Loohuis, Anastasia Antoniou, Murielle Brum, Chikashi Terao, Nathaniel W. McGregor, Fabio Rivas, James B. Potash, Kevin S. O’Connell, Susanne Lucae, Brian M. Schilder, Katrin Gade, Stephan Ripke, Kristina Adorjan, Kari Stefansson, Tiffany A. Greenwood, Panos Roussos, Sarah Kittel-Schneider, Steven A. McCarroll, Sergi Papiol, Heon Jeong Lee, Assen Jablensky, Liliya Abramova, Dennis Hellgren, Jonas Bybjerg-Grauholm, Martin Lundberg, Hong-Hee Won, William Byerley, Lars Alfredsson, Joel Gelernter, Andrew McQuillin, Claire Slaney, Marta Ribasés, Stephanie H. Witt, Yoichiro Kamatani, Kyung Sue Hong, Marie Bækvad-Hansen, María Soler Artigas, Julie M. Cunningham, Fanny Senner, Stacy Steinberg, Paul D. Shilling, Nakao Iwata, Eystein Stordal, Armin Birner, Sarah E. Medland, Miquel Casas, Ben Michael Brumpton, Erlend Bøen, Bryan J. Mowry, Jolanta Lissowska, Francis J. McMahon, Howard J. Edenberg, Grant W. Montgomery, John I. Nurnberger, Stéphane Jamain, Claudio Toma, Ney Alliey-Rodriguez, Ole Mors, Micha Gawlik, David Curtis, Catrin Lewis, Evangelia-Eirini Tsermpini, Georgia Panagiotaropoulou, Marcella Rietschel, Jessica Yang, Ian Jones, Eduard Vieta, Ole A. Andreassen, Richard M. Myers, Dimitris Dikeos, Melissa J. Green, Janet L. Sobell, Maria Koromina, Piotr M. Czerski, Lilijana Oruc, Sven Cichon, Udo Dannlowski, Bruno Etain, Monika Budde, Alessia Fiorentino, Naomi R. Wray, Qingqin S. Li, Murray J. Cairns, Jonathan R. I. Coleman, Jose Guzman-Parra, Andreas J. Forstner, Hannah Young, Alfredo B. Cuellar-Barboza, Julian Roth, Torbjørn Elvsåshagen, Zhen Qiao, Thomas Werge, Athanassios Douzenis, Cristiana Cruceanu, Rolf Adolfsson, Peter Holmans, Vaughan J. Carr, Thomas W. Weickert, Masashi Ikeda, Joanna M. Biernacka, Lea Sirignano, Adam X. Maihofer, Ralph W. Kupka, John Strauss, Anders M. Dale, Elliot S. Gershon, Jakob Grove, Arianna Di Florio, Helena Medeiros, Ingrid Melle, Preben Bo Mortensen, Kristi Krebs, Saskia P. Hagenaars, Liz Forty, Stanley V. Catts, David M. Hougaard, Marianne Giørtz Pedersen, Andreas Reif, Toni-Kim Clarke, Anne T. Spijker, Danielle Posthuma, Manolis Kogevinas, Michael Boehnke, Rosa Bosch, Gerome Breen, Benjamin M. Neale, Jessica S. Johnson, Katherine Gordon-Smith, Cristina Sánchez-Mora, Alexander W. Charney, Henry R. Kranzler, Digby Quested, René S. Kahn, Lili Milani, Merete Nordentoft, Nathalie Brunkhorst-Kanaan, Laura M. Huckins, James T.R. Walters, Sigrid Børte, Antonio F. Pardiñas, Kristian Hveem, Julie Garnham, Jacob Lawrence, Vassily Trubetskoy, Rodney J. Scott, Nicholas Bass, Carlos N. Pato, Andrea Pfennig, Wei Xu, Calwing Liao, Nicholas John Craddock, Thomas Damm Als, Christina M. Hultman, Fernando S. Goes, Adebayo Anjorin, Evgenia Porichi, Frans Henskens, Nelson B. Freimer, Janice M. Fullerton, Cathryn M. Lewis, Srdjan Djurovic, Roel A. Ophoff, Phil Lee, Peter McGuffin, Gunnar Morken, George P. Patrinos, Alessandro Serretti, Cynthia Shannon Weickert, Pablo Cervantes, Bendik S. Winsvold, Tatiana Foroud, Tõnu Esko, Ulrich Schall, Michele T. Pato, Ji Hyun Baek, John R. Kelsoe, Olav B. Smeland, Janos Kalman, Eva C. Schulte, Joanna Hauser, Urs Heilbronner, Magnús Haraldsson, Martin Hautzinger, Lea Zillich, Eline J. Regeer, Douglas Blackwood, Laura J. Scott, Jordan W. Smoller, Michael J. Gandal, Marquis P. Vawter, Philip B. Mitchell, Ole Kristian Drange, Peter R. Schofield, Susanne Bengesser, Stefan Herms, George Kirov, Markus Leber, Louise Frisén, Thomas W. Mühleisen, Susan L. McElroy, Irwin D. Waldman, Wade H. Berrettini, Sally I. Sharp, Minsoo Kim, Lisa Jones, Eli A. Stahl, Hreinn Stefansson, Esben Agerbo, Dolores Malaspina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Mullins N., Forstner A.J., O'Connell K.S., Coombes B., Coleman J.R.I., Qiao Z., Als T.D., Bigdeli T.B., Borte S., Bryois J., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Kim M., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Steinberg S., Trubetskoy V., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Agerbo E., Al Eissa M., Albani D., Alliey-Rodriguez N., Anjorin A., Antilla V., Antoniou A., Awasthi S., Baek J.H., Baekvad-Hansen M., Bass N., Bauer M., Beins E.C., Bergen S.E., Birner A., Bocker Pedersen C., Boen E., Boks M.P., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cairns M., Casas M., Cervantes P., Clarke T.-K., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Degenhardt F., Djurovic S., Dobbyn A.L., Douzenis A., Elvsashagen T., Escott-Price V., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frank J., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Giortz Pedersen M., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Herms S., Hoffmann P., Holmans P.A., Huckins L., Jamain S., Johnson J.S., Kalman J.L., Kamatani Y., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Lawrence J., Leber M., Lee H.-J., Lee P.H., Levy S.E., Lewis C., Liao C., Lucae S., Lundberg M., MacIntyre D.J., Magnusson S.H., Maier W., Maihofer A., Malaspina D., Maratou E., Martinsson L., Mattheisen M., McCarroll S.A., McGregor N.W., McGuffin P., McKay J.D., Medeiros H., Medland S.E., Millischer V., Montgomery G.W., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Potash J.B., Quested D., Raj T., Rapaport M.H., DePaulo J.R., Regeer E.J., Rice J.P., Rivas F., Rivera M., Roth J., Roussos P., Ruderfer D.M., Sanchez-Mora C., Schulte E.C., Senner F., Sharp S., Shilling P.D., Sigurdsson E., Sirignano L., Slaney C., Smeland O.B., Smith D.J., Sobell J.L., Soholm Hansen C., Soler Artigas M., Spijker A.T., Stein D.J., Strauss J.S., Swiatkowska B., Terao C., Thorgeirsson T.E., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Walters J.T.R., Witt S.H., Xi S., Xu W., Yang J.M.K., Young A.H., Young H., Zandi P.P., Zhou H., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Babadjanova G., Backlund L., Baune B.T., Bellivier F., Bengesser S., Berrettini W.H., Blackwood D.H.R., Boehnke M., Borglum A.D., Breen G., Carr V.J., Catts S., Corvin A., Craddock N., Dannlowski U., Dikeos D., Esko T., Etain B., Ferentinos P., Frye M., Fullerton J.M., Gawlik M., Gershon E.S., Goes F.S., Green M.J., Grigoroiu-Serbanescu M., Hauser J., Henskens F., Hillert J., Hong K.S., Hougaard D.M., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Jones I., Jones L.A., Kahn R.S., Kelsoe J.R., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Lochner C., Loughland C., Martin N.G., Mathews C.A., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Michie P., Milani L., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Mowry B., Muller-Myhsok B., Myers R.M., Neale B.M., Nievergelt C.M., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Olsson T., Owen M.J., Paciga S.A., Pantelis C., Pato C., Pato M.T., Patrinos G.P., Perlis R.H., Posthuma D., Ramos-Quiroga J.A., Reif A., Reininghaus E.Z., Ribases M., Rietschel M., Ripke S., Rouleau G.A., Saito T., Schall U., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Scott R.J., Serretti A., Shannon Weickert C., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Streit F., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Waldman I.D., Weickert T.W., Werge T., Wray N.R., Zwart J.-A., Biernacka J.M., Nurnberger J.I., Cichon S., Edenberg H.J., Stahl E.A., McQuillin A., Di Florio A., Ophoff R.A., Andreassen O.A., IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etain, Bruno

Subjects
Multifactorial Inheritance, Bipolar Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Genome-wide association study, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Bipolar Disorder, Chromosomes, Human, Spectrum disorder, Genetics, 0303 health sciences, Bipolar Disorder/genetics, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Schizophrenia, Synaptic signaling, Case-Control Studie, Human, Quantitative Trait Loci, Biology, MESH: Phenotype, MESH: Chromosomes, Human, Article, 03 medical and health sciences, MESH: Major Histocompatibility Complex, SDG 3 - Good Health and Well-being, ddc:570, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Multifactorial Inheritance/genetics, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, Genome, Human, Risk Factor, Chromosomes, Human/genetics, Mental illness, medicine.disease, MESH: Quantitative Trait Loci, Human genetics, Psychologie, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, Expression quantitative trait loci, MESH: Multifactorial Inheritance, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021
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8. Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

Author

Raquel E. Gur, Geor Bakker, Erick J. Canales-Rodríguez, Edith Pomarol-Clotet, Cynthia Shannon Weickert, Neda Jahanshad, Ulrich Schall, Theodore D. Satterthwaite, Vince D. Calhoun, Aleix Solanes, Frans Henskens, Antonin Skoch, Sara Llufriu, Anthony A. James, Michael Stäblein, Aurora Bonvino, Kun Yang, Cyril Höschl, Christos Pantelis, Carlos López-Jaramillo, Stefan Ehrlich, S. Sarró, Stefan Kaiser, Udo Dannlowski, Fengmei Fan, Wenhao Jiang, Paul E. Rasser, Patricia T. Michie, Julian A Pineda-Zapata, Zhiren Wang, Russell T. Shinohara, Eduard Vieta, Rodney J. Scott, Tilo Kircher, Andrea Weideman, Melissa J. Green, Nicola G. Cascella, Jason M. Bruggemann, Dominik Grotegerd, Viola Oertel, Janice M. Fullerton, Theo G.M. van Erp, Stanley V. Catts, Hong Xiang, Murray J. Cairns, Jingxu Chen, Paul M. Thompson, Adrian Preda, Elisabeth Solana, Fleur M. Howells, Godfrey D. Pearlson, Anne Uhlmann, Peter Kochunov, Christian Knöchel, Fabrizio Piras, Fude Yang, Je-Yeon Yun, Yunlong Tan, Henk Temmingh, Covadonga M. Díaz-Caneja, Peter J. McKenna, Carmel M. Loughland, Alexander Tomyshev, Kang Sim, Joost Janssen, Kaleda Vg, Ruben C. Gur, Akira Sawa, Ana M. Díaz-Zuluaga, Annabella Di Giorgio, Nerisa Banaj, Jessica A. Turner, Vanessa Cropley, Gavin Cooper, Raymond Salvador, Marc L. Seal, Rhoshel K. Lenroot, Stefan S. du Plessis, Yoichiro Takayanagi, Federica Piras, Jun Soo Kwon, Dan J. Stein, Anton Albajes-Eizagirre, David C. Glahn, Vaughan J. Carr, Thomas W. Weickert, Francesca Assogna, Lydia Fortea, Joaquim Radua, Igor Nenadic, Alessandro Bertolino, Margaret D. King, Eloy Martinez-Heras, Gianfranco Spalletta, Paul A. Tooney, Tim Hahn, Hua Guo, Stefan Borgwardt, Yann Quidé, Bryan J. Mowry, Shuping Tan, Axel Krug, Therese van Amelsvoort, Elliot Hong, Irina V. Lebedeva, David Tomecek, Daniel H. Wolf, Celso Arango, Clara Alloza, Matthias Kirschner, Dana Nguyen, Kaiser, Stefan, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), and RS: MHeNs - R2 - Mental Health

Subjects
Male, Computer science, Image Processing, Medical and Health Sciences, 0302 clinical medicine, Computer-Assisted, Image Processing, Computer-Assisted, ENIGMA Consortium collaborators, Cerebral Cortex, 05 social sciences, Brain, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Mental Health, Neurology, Schizophrenia, Biomedical Imaging, Female, Algorithms, Adult, medicine.medical_specialty, Mega-analysis, Cognitive Neuroscience, Neuroimaging, SURFACE-BASED ANALYSIS, 050105 experimental psychology, Article, Cortical thickness, lcsh:RC321-571, 03 medical and health sciences, Young Adult, Physical medicine and rehabilitation, Meta-Analysis as Topic, medicine, Humans, 0501 psychology and cognitive sciences, Cortical surface, ddc:610, Gray matter, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neurology & Neurosurgery, Volume, Psychology and Cognitive Sciences, Neurosciences, medicine.disease, Brain Disorders, Data set, 030217 neurology & neurosurgery, Diagnosis of schizophrenia
Abstract

Altres ajuts: SRB: The Australian Schizophrenia Research Bank (ASRB) was supported by the National Health and Medical Research Council of Australia (NHMRC) (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief Investigators for ASRB were Carr, V., Schall, U., Scott, R., Jablensky, A., Mowry, B., Michie, P., Catts, S., Henskens, F., Pantelis, C. We thank Loughland, C., the ASRB Manager, and acknowledge the help of Jason Bridge for ASRB database queries. CP was supported by NHMRC Senior Principal Research Fellowships (IDs: 628386 & 1105825); GC was supported by the Schizophrenia Research Institute utilizing infrastructure funding from the New South Wales Ministry of Health and New South Wales Ministry of Trade and Investment (Australia); JMF was supported by NHMRC project grant (1063960) and the Janette Mary O'Neil Research Fellowship; MJG was supported by NHMRC as an R.D. Wright Biomedical Career Development Fellow (1061875). MJC was supported by NHMRC Senior Research Fellowship (1121474). CASSI: CSW is funded by the NSW Ministry of Health, Office of Health and Medical Research. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). CIAM: The CIAM study (FMH - PI) was supported by the University Research Committee, University of Cape Town and South African funding bodies National Research Foundation and Medical Research Council. COBRE: The COBRE dataset and investigators were supported by NIH grants R01EB006841 & P20GM103472, as well as NSF grant 1539067. JT (senior author) and VDC are supported by 5R01MH094524. JMS is supported by R01 AA021771 and P50 AA022534. EONCKS: This work was supported by a New Partnership for Africa's Development (NEPAD) grant through the Department of Science and Technology of South Africa, the Medical Research Council of South Africa (grant number 65174). ESO: The ESO study was funded by NPU I - LO1611 and Ministry of Health, Czech Republic - Conceptual Development of Research Organization 00023001 (IKEM). FIDMAG/Project: This work was supported by the Catalan Government and several grants from the Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, 'Investing in your future'): Miguel Servet Research Contracts and Research Project Grants. FOR2107 Marburg: The FOR2107 Marburg study was funded by the German Research Foundation (DFG), Tilo Kircher (speaker FOR2107; DFG grant numbers KI588/14-1, KI588/14-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). FOR2107 Muenster: The FOR2107 Muenster study was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). TH was supported by grants from the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). Frankfurt: MRI was performed at the Frankfurt Brain Imaging Center, supported by the German Research Council (DFG) and the German Ministry for Education and Research (BMBF; Brain Imaging Center Frankfurt/Main, DLR 01GO0203). GIPSI: This study was supported by Colciencias PRISMA-U.T. Huilong1 & Huilong2: This study was funded by the National Natural Science Foundation of China (81761128021; 31671145; 81401115; 81401133), Beijing Municipal Science and Technology Commission grant (Z141107002514016) and Beijing Natural Science Foundation(7162087, Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding (XMLX201609; zylx201409). IGP: This study was funded by Project Grants from the Australian National Health and Medical Research Council of Australia (NHMRC; APP630471 and APP1081603), the Macquarie University's Australian Research Council Centre of Excellence in Cognition and its Disorders (CE110001021). Johns Hopkins: Supported by National Institutes of Health Grant Nos. MH-092443, MH-094268 (Silvio O. Conte Center), MH-105660, and MH-107730; foundation grants from Stanley, RUSK/S-R, and NARSAD/Brain and Behavior Research Foundation. Madrid: Supported by the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III, co-financed by ERDF Funds from the European Commission, "A way of making Europe", CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds and European Union Seventh Framework Program and H2020 Program; Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. MPRC1 & MPRC2: Support was received from NIH grants U01MH108148, 2R01EB015611, R01MH112180, R01DA027680, R01MH085646, P50MH103222 and T32MH067533, a State of Maryland contract (M00B6400091) and NSF grant (1620457). OLIN: The Olin study was supported by NIH grants R37MH43375 and R01MH074797. Oxford: The Oxford study MRC G0500092. SLF Rome: Support from the Italian Ministry of Health grants RC-12-13-14-15-16-17-18-19/A. RSCZ: RSCZ data collection was supported by RFBR 15-06-05758 grant. SCORE: This study was supported in part by grant 3232BO_119382 from the Swiss National Science Foundation. We thank the FePsy (Frueherkennung von Psychosen; early detection of psychosis) Study Group from the University of Basel, Department of Psychiatry, Switzerland, for the recruitment of the study participants. The FePsy Study was supported in part by grant No. SNF 3200-057216/1, ext./2, ext./3. Singapore: This study was supported by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/11003), and the Singapore Bioimaging Consortium (RP C-009/2006) research grants awarded to KS. SNUH: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (Grant no. 2013R1A2A1A03071089 and 2017M3C7A1029610). UCISZ: The UCISZ study was supported by the National Institutes of Mental Health grant number R21MH097196 to TGMvE. UCISZ data were processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. UNIBA: The UNIBA study was supported by grant funding from the Italian Ministry of Health (PE-2011-02347951). UNIMAAS: The study was supported by Dutch Organization for Health Research and Development (ZonMw 91112002) and a personal grant to Thérèse van Amelsvoort (ZonMw-VIDI: 91712394). The data was collected in a clinical trial registered in the Dutch clinical trial registry under ID: NTR5094 (http://www.trialregister.nl). UPenn: This study was supported by the National Institute of Mental Health grants MH064045, MH 60722, MH019112, MH085096 (DHW), and R01MH112847 (RTS and TDS). Zurich: This study was supported by the Swiss National Science Foundation (105314_140351 to S.K.). Matthias Kirschner acknowledges support from the National Bank Fellowship (McGill University) and the Swiss National Foundation (P2SKP3_178175). Research reported in this publication was also supported by the following National Institutes of Health grants: U54 EB020403 to PMT, R01 MH116147, U24 RR21992, R21MH097196, and TR000153 to TGMvE, S10 OD023696 and R01EB015611 to PK, T32 AG058507and 5T32 MH073526 to CRKC, R01 MH117601 to NJ, ENIGMA's NIH Big Data to Knowledge (BD2K) initiative U54 EB020403, ENIGMA Sex Differences R01MH116147, and ENIGMA-COINSTAC: Advanced World-wide Transdiagnostic Analysis of Valence System Brain Circuits R01MH121246. A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Published
2020

9. Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort

Author

Vaughan J. Carr, Rodney J. Scott, Melissa J. Green, Assen Jablensky, Bryan J. Mowry, Frans Henskens, Murray J. Cairns, Ulrich Schall, Xiaoman Liu, Alan V. Boddy, Paul A. Tooney, Siew-Kee Low, Heath M. Cairns, Carmel M. Loughland, Jing Qin Wu, William R. Reay, Joshua R. Atkins, Patricia T. Michie, Stan Catts, Christos Pantelis, Liu, Xiaoman, Low, Siew Kee, Atkins, Joshua R., Wu, Jing Qin, Reay, William R., Cairns, Heath M., Green, Melissa J., Schall, Ulrich, Jablensky, Assen, Mowry, Bryan, Michie, Patricia T., Catts, Stan V., Henskens, Frans, Pantelis, Christos, Loughland, Carmel, Boddy, Alan V, Tooney, Paul A, Scott, Rodney J, Carr, Vaughan J, and Cairns, Murray J

Subjects
FZD1, Genetics, 0303 health sciences, Schizophrenia (object-oriented programming), Wnt Receptor Gene, Genome-wide association study, General Medicine, Biology, Genetic analysis, Genome, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Cohort, 030217 neurology & neurosurgery, 030304 developmental biology, SNP array
Abstract

Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories. Methods: We performed a case–control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome. Results: The strongest finding ( p = 2.01 × 10−6, odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance ( p = 2.78 × 10−6). Conclusion: The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.

Published
2020

10. M99. INVESTIGATING THE BEST PREDICTIVE CLINICAL FEATURES OF ANTI-N-METHYL-D-ASPARTATE RECEPTOR (NMDAR) ENCEPHALITIS IN THE 2010 AUSTRALIAN NATIONAL SURVEY OF HIGH IMPACT PSYCHOSIS (SHIP) COHORT

Author

Vera A. Morgan, Carol Harvey, Cyndi Shannon Weickert, Denny Meyer, Cherrie Galletly, Paul A. Tooney, Andrea Phillipou, David J. Castle, and Susan L. Rossell

Subjects
D aspartate, Oncology, Psychosis, medicine.medical_specialty, Poster Session II, business.industry, AcademicSubjects/MED00810, medicine.disease, Psychiatry and Mental health, Internal medicine, Cohort, mental disorders, medicine, Nmdar encephalitis, business, Receptor
Abstract

Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, a recently reported autoimmune disorder, can be mistakenly diagnosed as a psychotic disorder, especially schizophrenia, as patients can present with prominent psychotic symptoms, in particular persecutory ideation, hallucinations and disturbed speech. In this study we used machine learning of the clinical data in a large cohort of persons with a positive psychosis history to ascertain whether we could predict NMDAR-positive cases, and which variables most accurately distinguished between NMDAR-positive and -negative cases. Methods SHIP collected nationally representative data from 1825 individuals with a psychotic illness. Plasma samples were available for n=472. To investigate the prevalence of NMDAR autoantibodies a recombinant indirect immunofluorescence test was performed (EuroImmun AG, Lübeck, Germany), with NMDAR transfected human embryonic kidney (HEK) 293 cells quantified using NIS Elements software. NMDAR-positive cases were estimated. Gradient boosting machine learning (the data were randomly split: 60% for initial ascertainment and 40% for validation) was subsequently performed using the clinical data available: 120 variables in total across various domains of sociodemographic, medical history, psychiatric diagnosis and current psychiatric symptoms. Only the variables found to have significant (or near significant) association with being NMDAR-positive were used to develop rules for identifying cases. Results There were 38 NMDAR-positive cases. They were more likely to be associated with a schizophrenia /schizoaffective and a depressive psychosis diagnosis, and less likely to be associated with a bipolar diagnosis, than antibody-negative cases. They were also more likely to be associated with a single episode with good recovery, and with anxiety symptoms and dizziness in the prior 12 months (which included light headedness, feeling faint and unsteady). For the present state symptoms, restricted affect was more likely to be present whereas poverty of speech was rare. Initial insomnia and a medical history that included epilepsy were not present for any of the NMDAR-positive cases. The machine learning algorithm was able to successfully classify 94% of cases to the correct antibody group. Discussion In this significant Australian epidemiological cohort, we have identified key clinical features associated with anti-NMDAR encephalitis, including diagnosis, and symptoms and clinical course. The novel and insightful analyses afforded by using machine learning should be replicated in other samples to confirm the important clinical findings reported in the current work.

Published
2020

11. TMIC-41. PROSTATE SPECIFIC MEMBRANE ANTIGEN EXPRESSION IN PRIMARY AND RECURRENT GLIOBLASTOMA

Author

Michael Fay, Nikola A. Bowden, Moira C. Graves, Mathew Lozinski, and Paul A. Tooney

Subjects
Primary Glioblastoma, Cancer Research, Primary (chemistry), business.industry, Recurrent glioblastoma, Tissue membrane, medicine.disease, urologic and male genital diseases, medicine.anatomical_structure, Oncology, Antigen, Prostate, Cancer research, Glutamate carboxypeptidase II, Tumor Microenvironment, Medicine, Neurology (clinical), business, Glioblastoma
Abstract

Patients with glioblastoma almost always suffer a recurrence of an aggressive treatment resistant tumour and succumb within months highlighting the need to develop treatment options for recurrent glioblastoma. One potential target is prostate specific membrane antigen (PSMA) expressed on the new vessels in primary glioblastoma tumours. This study compared the expression of PSMA in primary and recurrent glioblastoma tumours. Formalin-fixed paraffin-embedded sections of primary and matched recurrent tumours from 13 patients with glioblastoma were processed for PSMA immunohistochemical labelling. PSMA expression was scored from digitally scanned sections using a categorical system (Total PSMA expression = PSMA label intensity (0–3) x percent PSMA-positive blood vessels). Little PSMA labelling was observed in any adjacent ‘unaffected’ brain tissue. PSMA was localised to blood vessels including those displaying microvascular proliferation in 12/13 primary and 9/13 recurrent glioblastoma tumours. Total PSMA expression scores ranged from 0 – 230 (maximum score = 300) and was divided into low and high expression based on a median split (median = 57) of PSMA expression across all tumours. Regression analysis showed a significant difference in PSMA expression between primary and recurrent glioblastoma (p = 0.04) with PSMA being highly expressed in ~70% of primary and only 31% of recurrent glioblastoma. Three cases displayed high expression in both primary and recurrent glioblastoma and one case had no PSMA expression at all. In conclusion, whilst higher expression of PSMA was detected in more primary tumours, 70%+ of all primary and recurrent tumours expressed PSMA to some extent adding evidence that this may be a useful target for treatment of glioblastoma. Larger cohorts and other techniques for detecting PSMA are needed to provide further evidence for PSMA’s utility as a target and to further define which glioblastoma patients are most likely to benefit from this approach.

Published
2019

12. 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. McElroy, Stephan Zipfel, Peter P. Zandi, Cathryn M. Lewis, Lars Klareskog, Martin Begemann, Phil Lee, Richard Anney, Mark A. Bellgrove, Lisa Jones, Andreas J. Forstner, Agnieszka Słopień, Hilary Coon, Dong Li, Alessandro Serretti, Carsten Horn, Christos Pantelis, Ryan L. Collins, David M. Howard, Lucía Colodro-Conde, Pippa A. Thomson, Martin Hautzinger, Alysa E. Doyle, Julie Hagstrøm, Oliver S. P. Davis, Karen S. Mitchell, Jordan W. Smoller, Michael Strober, John I. Nurnberger, Andrea G. Ludolph, Monika Budde, Anna Maaser, Lambertus Klei, Aribert Rothenberger, Yulia Worbe, Fabian Streit, James L. Kennedy, Barbara E. Stranger, Ashley Dumont, Jianxin Shi, Dale R. Nyholt, Craig Johnson, Jonna Kuntsi, Yun-Joo Koh, Loes M. Olde Loohuis, Robert B. Freedman, Anke Hinney, Susanne Walitza, Enrico Domenici, Margarita Rivera, Sodahm Kook, Erica Greenberg, Tetyana Zayats, Josef Frank, Gary A. Heiman, Andrew McQuillin, Abraham Reichenberg, Piotr M. Czerski, Humberto Nicolini, Lee P.H., Anttila V., Won H., Feng Y.-C.A., Rosenthal J., Zhu Z., Tucker-Drob E.M., Nivard M.G., Grotzinger A.D., Posthuma D., Wang M.M.-J., Yu D., Stahl E.A., Walters R.K., Anney R.J.L., Duncan L.E., Ge T., Adolfsson R., Banaschewski T., Belangero S., Cook E.H., Coppola G., Derks E.M., Hoekstra P.J., Kaprio J., Keski-Rahkonen A., Kirov G., Kranzler H.R., Luykx J.J., Rohde L.A., Zai C.C., Agerbo E., Arranz M.J., Asherson P., Baekvad-Hansen M., Baldursson G., Bellgrove M., Belliveau R.A., Buitelaar J., Burton C.L., Bybjerg-Grauholm J., Casas M., Cerrato F., Chambert K., Churchhouse C., Cormand B., Crosbie J., Dalsgaard S., Demontis D., Doyle A.E., Dumont A., Elia J., Grove J., Gudmundsson O.O., Haavik J., Hakonarson H., Hansen C.S., Hartman C.A., Hawi Z., Hervas A., Hougaard D.M., Howrigan D.P., Huang H., Kuntsi J., Langley K., Lesch K.-P., Leung P.W.L., Loo S.K., Martin J., Martin A.R., McGough J.J., Medland S.E., Moran J.L., Mors O., Mortensen P.B., Oades R.D., Palmer D.S., Pedersen C.B., Pedersen M.G., Peters T., Poterba T., Poulsen J.B., Ramos-Quiroga J.A., Reif A., Ribases M., Rothenberger A., Rovira P., Sanchez-Mora C., Satterstrom F.K., Schachar R., Artigas M.S., Steinberg S., Stefansson H., Turley P., Walters G.B., Werge T., Zayats T., Arking D.E., Bettella F., Buxbaum J.D., Christensen J.H., Collins R.L., Coon H., De Rubeis S., Delorme R., Grice D.E., Hansen T.F., Holmans P.A., Hope S., Hultman C.M., Klei L., Ladd-Acosta C., Magnusson P., Naerland T., Nyegaard M., Pinto D., Qvist P., Rehnstrom K., Reichenberg A., Reichert J., Roeder K., Rouleau G.A., Saemundsen E., Sanders S.J., Sandin S., St Pourcain B., Stefansson K., Sutcliffe J.S., Talkowski M.E., Weiss L.A., Willsey A.J., Agartz I., Akil H., Albani D., Alda M., Als T.D., Anjorin A., Backlund L., Bass N., Bauer M., Baune B.T., Bellivier F., Bergen S.E., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boen E., Budde M., Bunney W., Burmeister M., Byerley W., Byrne E.M., Cichon S., Clarke T.-K., Coleman J.R.I., Craddock N., Curtis D., Czerski P.M., Dale A.M., Dalkner N., Dannlowski U., Degenhardt F., Di Florio A., Elvsashagen T., Etain B., Fischer S.B., Forstner A.J., Forty L., Frank J., Frye M., Fullerton J.M., Gade K., Gaspar H.A., Gershon E.S., Gill M., Goes F.S., Gordon S.D., Gordon-Smith K., Green M.J., Greenwood T.A., Grigoroiu-Serbanescu M., Guzman-Parra J., Hauser J., Hautzinger M., Heilbronner U., Herms S., Hoffmann P., Holland D., Jamain S., Jones I., Jones L.A., Kandaswamy R., Kelsoe J.R., Kennedy J.L., Joachim O.K., Kittel-Schneider S., Kogevinas M., Koller A.C., Lavebratt C., Lewis C.M., Li Q.S., Lissowska J., Loohuis L.M.O., Lucae S., Maaser A., Malt U.F., Martin N.G., Martinsson L., McElroy S.L., McMahon F.J., McQuillin A., Melle I., Metspalu A., Millischer V., Mitchell P.B., Montgomery G.W., Morken G., Morris D.W., Muller-Myhsok B., Mullins N., Myers R.M., Nievergelt C.M., Nordentoft M., Adolfsson A.N., Nothen M.M., Ophoff R.A., Owen M.J., Paciga S.A., Pato C.N., Pato M.T., Perlis R.H., Perry A., Potash J.B., Reinbold C.S., Rietschel M., Rivera M., Roberson M., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Sigurdsson E., Smeland O.B., Stordal E., Streit F., Strohmaier J., Thorgeirsson T.E., Treutlein J., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Wang Y., Witt S.H., Zandi P., Adan R.A.H., Alfredsson L., Ando T., Aschauer H., Baker J.H., Bencko V., Bergen A.W., Birgegard A., Perica V.B., Brandt H., Burghardt R., Carlberg L., Cassina M., Clementi M., Courtet P., Crawford S., Crow S., Crowley J.J., Danner U.N., Davis O.S.P., Degortes D., DeSocio J.E., Dick D.M., Dina C., Docampo E., Egberts K., Ehrlich S., Espeseth T., Fernandez-Aranda F., Fichter M.M., Foretova L., Forzan M., Gambaro G., Giegling I., Gonidakis F., Gorwood P., Mayora M.G., Guo Y., Halmi K.A., Hatzikotoulas K., Hebebrand J., Helder S.G., Herpertz-Dahlmann B., Herzog W., Hinney A., Imgart H., Jimenez-Murcia S., Johnson C., Jordan J., Julia A., Kaminska D., Karhunen L., Karwautz A., Kas M.J.H., Kaye W.H., Kennedy M.A., Kim Y.-R., Klareskog L., Klump K.L., Knudsen G.P.S., Landen M., Le Hellard S., Levitan R.D., Li D., Lichtenstein P., Maj M., Marsal S., McDevitt S., Mitchell J., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., O'Toole J.K., Padyukov L., Pantel J., Papezova H., Rabionet R., Raevuori A., Ramoz N., Reichborn-Kjennerud T., Ricca V., Roberts M., Rujescu D., Rybakowski F., Scherag A., Schmidt U., Seitz J., Slachtova L., Slof-Op't Landt M.C.T., Slopien A., Sorbi S., Southam L., Strober M., Tortorella A., Tozzi F., Treasure J., Tziouvas K., van Elburg A.A., Wade T.D., Wagner G., Walton E., Watson H.J., Wichmann H.-E., Woodside D.B., Zeggini E., Zerwas S., Zipfel S., Adams M.J., Andlauer T.F.M., Berger K., Binder E.B., Boomsma D.I., Castelao E., Colodro-Conde L., Direk N., Docherty A.R., Domenici E., Domschke K., Dunn E.C., Foo J.C., de. Geus E.J.C., Grabe H.J., Hamilton S.P., Horn C., Hottenga J.-J., Howard D., Ising M., Kloiber S., Levinson D.F., Lewis G., Magnusson P.K.E., Mbarek H., Middeldorp C.M., Mostafavi S., Nyholt D.R., Penninx B.W., Peterson R.E., Pistis G., Porteous D.J., Preisig M., Quiroz J.A., Schaefer C., Schulte E.C., Shi J., Smith D.J., Thomson P.A., Tiemeier H., Uher R., van der Auwera S., Weissman M.M., Alexander M., Begemann M., Bramon E., Buccola N.G., Cairns M.J., Campion D., Carr V.J., Cloninger C.R., Cohen D., Collier D.A., Corvin A., DeLisi L.E., Donohoe G., Dudbridge F., Duan J., Freedman R., Gejman P.V., Golimbet V., Godard S., Ehrenreich H., Hartmann A.M., Henskens F.A., Ikeda M., Iwata N., Jablensky A.V., Joa I., Jonsson E.G., Kelly B.J., Knight J., Konte B., Laurent-Levinson C., Lee J., Lencz T., Lerer B., Loughland C.M., Malhotra A.K., Mallet J., McDonald C., Mitjans M., Mowry B.J., Murphy K.C., Murray R.M., O'Neill F.A., Oh S.-Y., Palotie A., Pantelis C., Pulver A.E., Petryshen T.L., Quested D.J., Riley B., Sanders A.R., Schall U., Schwab S.G., Scott R.J., Sham P.C., Silverman J.M., Sim K., Steixner A.A., Tooney P.A., van Os J., Vawter M.P., Walsh D., Weiser M., Wildenauer D.B., Williams N.M., Wormley B.K., Zhang F., Androutsos C., Arnold P.D., Barr C.L., Barta C., Bey K., Bienvenu O.J., Black D.W., Brown L.W., Budman C., Cath D., Cheon K.-A., Ciullo V., Coffey B.J., Cusi D., Davis L.K., Denys D., Depienne C., Dietrich A., Eapen V., Falkai P., Fernandez T.V., Garcia-Delgar B., Geller D.A., Gilbert D.L., Grados M.A., Greenberg E., Grunblatt E., Hagstrom J., Hanna G.L., Hartmann A., Hedderly T., Heiman G.A., Heyman I., Hong H.J., Huang A., Huyser C., Ibanez-Gomez L., Khramtsova E.A., Kim Y.K., Kim Y.-S., King R.A., Koh Y.-J., Konstantinidis A., Kook S., Kuperman S., Leventhal B.L., Lochner C., Ludolph A.G., Madruga-Garrido M., Malaty I., Maras A., McCracken J.T., Meijer I.A., Mir P., Morer A., Muller-Vahl K.R., Munchau A., Murphy T.L., Naarden A., Nagy P., Nestadt G., Nestadt P.S., Nicolini H., Nurmi E.L., Okun M.S., Paschou P., Piras F., Pittenger C., Plessen K.J., Richter M.A., Rizzo R., Robertson M., Roessner V., Ruhrmann S., Samuels J.F., Sandor P., Schlogelhofer M., Shin E.-Y., Singer H., Song D.-H., Song J., Spalletta G., Stein D.J., Stewart S.E., Storch E.A., Stranger B., Stuhrmann M., Tarnok Z., Tischfield J.A., Tubing J., Visscher F., Vulink N., Wagner M., Walitza S., Wanderer S., Woods M., Worbe Y., Zai G., Zinner S.H., Sullivan P.F., Franke B., Daly M.J., Bulik C.M., McIntosh A.M., O'Donovan M.C., Zheutlin A., Andreassen O.A., Borglum A.D., Breen G., Edenberg H.J., Fanous A.H., Faraone S.V., Gelernter J., Mathews C.A., Mattheisen M., Mitchell K.S., Neale M.C., Nurnberger J.I., Ripke S., Santangelo S.L., Scharf J.M., Stein M.B., Thornton L.M., Walters J.T.R., Wray N.R., Geschwind D.H., Neale B.M., Kendler K.S., Smoller J.W., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Epidemiology and Data Science, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, APH - Digital Health, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Kas lab, Adult Psychiatry, Child Psychiatry, ANS - Complex Trait Genetics, Aarno Palotie / Principal Investigator, Jaakko Kaprio / Principal Investigator, Centre of Excellence in Complex Disease Genetics, Genetic Epidemiology, Department of Public Health, University Management, Anna Keski-Rahkonen / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, HUS Psychiatry, Institute for Molecular Medicine Finland, Research Programs Unit, Genomics of Neurological and Neuropsychiatric Disorders, Biological Psychology, Complex Trait Genetics, APH - Methodology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Lee, P. H., Anttila, V., Won, H., Feng, Y. -C. A., Rosenthal, J., Zhu, Z., Tucker-Drob, E. M., Nivard, M. G., Grotzinger, A. D., Posthuma, D., Wang, M. M. -J., Yu, D., Stahl, E. A., Walters, R. K., Anney, R. J. L., Duncan, L. E., Ge, T., Adolfsson, R., Banaschewski, T., Belangero, S., Cook, E. H., Coppola, G., Derks, E. M., Hoekstra, P. J., Kaprio, J., Keski-Rahkonen, A., Kirov, G., Kranzler, H. R., Luykx, J. J., Rohde, L. A., Zai, C. C., Agerbo, E., Arranz, M. J., Asherson, P., Baekvad-Hansen, M., Baldursson, G., Bellgrove, M., Belliveau, R. A., Buitelaar, J., Burton, C. L., Bybjerg-Grauholm, J., Casas, M., Cerrato, F., Chambert, K., Churchhouse, C., Cormand, B., Crosbie, J., Dalsgaard, S., Demontis, D., Doyle, A. E., Dumont, A., Elia, J., Grove, J., Gudmundsson, O. O., Haavik, J., Hakonarson, H., Hansen, C. S., Hartman, C. A., Hawi, Z., Hervas, A., Hougaard, D. M., Howrigan, D. P., Huang, H., Kuntsi, J., Langley, K., Lesch, K. -P., Leung, P. W. L., Loo, S. K., Martin, J., Martin, A. R., Mcgough, J. J., Medland, S. E., Moran, J. L., Mors, O., Mortensen, P. B., Oades, R. D., Palmer, D. S., Pedersen, C. B., Pedersen, M. G., Peters, T., Poterba, T., Poulsen, J. B., Ramos-Quiroga, J. A., Reif, A., Ribases, M., Rothenberger, A., Rovira, P., Sanchez-Mora, C., Satterstrom, F. K., Schachar, R., Artigas, M. S., Steinberg, S., Stefansson, H., Turley, P., Walters, G. B., Werge, T., Zayats, T., Arking, D. E., Bettella, F., Buxbaum, J. D., Christensen, J. H., Collins, R. L., Coon, H., De Rubeis, S., Delorme, R., Grice, D. E., Hansen, T. F., Holmans, P. A., Hope, S., Hultman, C. M., Klei, L., Ladd-Acosta, C., Magnusson, P., Naerland, T., Nyegaard, M., Pinto, D., Qvist, P., Rehnstrom, K., Reichenberg, A., Reichert, J., Roeder, K., Rouleau, G. A., Saemundsen, E., Sanders, S. J., Sandin, S., St Pourcain, B., Stefansson, K., Sutcliffe, J. S., Talkowski, M. E., Weiss, L. A., Willsey, A. J., Agartz, I., Akil, H., Albani, D., Alda, M., Als, T. 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B., Brandt, H., Burghardt, R., Carlberg, L., Cassina, M., Clementi, M., Courtet, P., Crawford, S., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., Degortes, D., Desocio, J. E., Dick, D. M., Dina, C., Docampo, E., Egberts, K., Ehrlich, S., Espeseth, T., Fernandez-Aranda, F., Fichter, M. M., Foretova, L., Forzan, M., Gambaro, G., Giegling, I., Gonidakis, F., Gorwood, P., Mayora, M. G., Guo, Y., Halmi, K. A., Hatzikotoulas, K., Hebebrand, J., Helder, S. G., Herpertz-Dahlmann, B., Herzog, W., Hinney, A., Imgart, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Julia, A., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J. H., Kaye, W. H., Kennedy, M. A., Kim, Y. -R., Klareskog, L., Klump, K. L., Knudsen, G. P. S., Landen, M., Le Hellard, S., Levitan, R. D., Li, D., Lichtenstein, P., Maj, M., Marsal, S., Mcdevitt, S., Mitchell, J., Monteleone, P., Monteleone, A. M., Munn-Chernoff, M. A., Nacmias, B., Navratilova, M., O'Toole, J. 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S., Paschou, P., Piras, F., Pittenger, C., Plessen, K. J., Richter, M. A., Rizzo, R., Robertson, M., Roessner, V., Ruhrmann, S., Samuels, J. F., Sandor, P., Schlogelhofer, M., Shin, E. -Y., Singer, H., Song, D. -H., Song, J., Spalletta, G., Stein, D. J., Stewart, S. E., Storch, E. A., Stranger, B., Stuhrmann, M., Tarnok, Z., Tischfield, J. A., Tubing, J., Visscher, F., Vulink, N., Wagner, M., Walitza, S., Wanderer, S., Woods, M., Worbe, Y., Zai, G., Zinner, S. H., Sullivan, P. F., Franke, B., Daly, M. J., Bulik, C. M., Mcintosh, A. M., O'Donovan, M. C., Zheutlin, A., Andreassen, O. A., Borglum, A. D., Breen, G., Edenberg, H. J., Fanous, A. H., Faraone, S. V., Gelernter, J., Mathews, C. A., Mattheisen, M., Mitchell, K. S., Neale, M. C., Nurnberger, J. I., Ripke, S., Santangelo, S. L., Scharf, J. M., Stein, M. B., Thornton, L. M., Walters, J. T. R., Wray, N. R., Geschwind, D. H., Neale, B. M., Kendler, K. S., and Smoller, J. W.

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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13. 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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14. Reply to:New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

Author

Theo G.M. van Erp, Esther Walton, Derrek P. Hibar, Lianne Schmaal, Wenhao Jiang, David C. Glahn, Godfrey D. Pearlson, Nailin Yao, Masaki Fukunaga, Ryota Hashimoto, Naohiro Okada, Hidenaga Yamamori, Vincent P. Clark, Bryon A. Mueller, Sonja M.C. de Zwarte, Roel A. Ophoff, Neeltje E.M. van Haren, Ole A. Andreassen, Tiril P. Gurholt, Oliver Gruber, Bernd Kraemer, Anja Richter, Vince D. Calhoun, Benedicto Crespo-Facorro, Roberto Roiz-Santiañez, Diana Tordesillas-Gutiérrez, Carmel Loughland, Stanley Catts, Janice M. Fullerton, Melissa J. Green, Frans Henskens, Assen Jablensky, Bryan J. Mowry, Christos Pantelis, Yann Quidé, Ulrich Schall, Rodney J. Scott, Murray J. Cairns, Marc Seal, Paul A. Tooney, Paul E. Rasser, Gavin Cooper, Cynthia Shannon Weickert, Thomas W. Weickert, Elliot Hong, Peter Kochunov, Raquel E. Gur, Ruben C. Gur, Judith M. Ford, Fabio Macciardi, Daniel H. Mathalon, Steven G. Potkin, Adrian Preda, Fengmei Fan, Stefan Ehrlich, Margaret D. King, Lieuwe De Haan, Dick J. Veltman, Francesca Assogna, Nerisa Banaj, Pietro de Rossi, Mariangela Iorio, Fabrizio Piras, Gianfranco Spalletta, Edith Pomarol-Clotet, Sinead Kelly, Simone Ciufolini, Joaquim Radua, Robin Murray, Tiago Reis Marques, Andrew Simmons, Stefan Borgwardt, Fabienne Schönborn-Harrisberger, Anita Riecher-Rössler, Renata Smieskova, Kathryn I. Alpert, Alessandro Bertolino, Aurora Bonvino, Annabella Di Giorgio, Emma Neilson, Andrew R. Mayer, Je-Yeon Yun, Dara M. Cannon, Irina Lebedeva, Alexander S. Tomyshev, Tolibjohn Akhadov, Vasily Kaleda, Helena Fatouros-Bergman, Lena Flyckt, Pedro G.P. Rosa, Mauricio H. Serpa, Marcus V. Zanetti, Cyril Hoschl, Antonin Skoch, Filip Spaniel, David Tomecek, Andrew M. McIntosh, Heather C. Whalley, Christian Knöchel, Viola Oertel-Knöchel, Fleur M. Howells, Dan J. Stein, Henk S. Temmingh, Anne Uhlmann, Carlos Lopez-Jaramillo, Danai Dima, Joshua I. Faskowitz, Boris A. Gutman, Neda Jahanshad, Paul M. Thompson, Jessica A. Turner, Lars Farde, Simon Cervenka, Ingrid Agartz, Karin Collste, Pauliina Victorsson, Göran Engberg, Sophie Erhardt, Lilly Schwieler, Anna Malmqvist, Mikael Hedberg, Funda Orhan, Fredrik Piehl, APH - Mental Health, Adult Psychiatry, Universidad de Cantabria, Child and Adolescent Psychiatry / Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Schizophrenia (object-oriented programming), Prefrontal Cortex, BF, Neuroimaging, Mega, Severity of Illness Index, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Medical imaging, Humans, Medical physics, Disease process, Age of Onset, Child, Biological Psychiatry, Aged, Brain Diseases, medicine.diagnostic_test, Brain, Magnetic resonance imaging, Middle Aged, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, 030104 developmental biology, Case-Control Studies, Linear Models, Schizophrenia, RC0321, Female, Biological psychiatry, Psychology, 030217 neurology & neurosurgery
Abstract

The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Published
2018
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15. 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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16. Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells

Author

Murray J. Cairns, Rodney J. Scott, Natalie J. Beveridge, Vaughan J. Carr, Paul A. Tooney, Erin Gardiner, Bing Liu, and Brian Kelly

Subjects
Adult, Male, mRNA, Down-Regulation, Gene Expression, Inflammation, Schizoaffective disorder, Expression, Biology, Peripheral blood mononuclear cell, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Immune system, Gene expression, medicine, Humans, RNA, Messenger, Gene, Biological Psychiatry, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Messenger RNA, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Australia, Middle Aged, medicine.disease, Microarray Analysis, 3. Good health, Up-Regulation, Gene expression profiling, Immune, Psychiatry and Mental health, Immunology, PBMCs, Schizophrenia, Leukocytes, Mononuclear, Female, medicine.symptom, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Peripheral blood mononuclear cells (PBMCs) represent an accessible tissue source for gene expression profiling in schizophrenia that could provide insight into the molecular basis of the disorder. This study used the Illumina HT_12 microarray platform and quantitative real time PCR (QPCR) to perform mRNA expression profiling on 114 patients with schizophrenia or schizoaffective disorder and 80 non-psychiatric controls from the Australian Schizophrenia Research Bank (ASRB). Differential expression analysis revealed altered expression of 164 genes (59 up-regulated and 105 down-regulated) in the PBMCs from patients with schizophrenia compared to controls. Bioinformatic analysis indicated significant enrichment of differentially expressed genes known to be involved or associated with immune function and regulating the immune response. The differential expression of 6 genes, EIF2C2 (Ago 2), MEF2D, EVL, PI3, S100A12 and DEFA4 was confirmed by QPCR. Genome-wide expression analysis of PBMCs from individuals with schizophrenia was characterized by the alteration of genes with immune system function, supporting the hypothesis that the disorder has a significant immunological component in its etiology.

Published
2012

17. Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells

Author

Rodney J. Scott, Natalie J. Beveridge, Vaughan J. Carr, Paul A. Tooney, Erin Gardiner, Murray J. Cairns, and Jing Qin Wu

Subjects
Adult, Male, Candidate gene, Adolescent, DNA Copy Number Variations, Down-Regulation, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, gene silencing, Genomic Imprinting, 0302 clinical medicine, microRNA, Gene expression, Gene silencing, Humans, Epigenetics, Molecular Biology, 14q32, 030304 developmental biology, Aged, Chromosomes, Human, Pair 14, 0303 health sciences, Microarray analysis techniques, Gene Expression Profiling, Middle Aged, Microarray Analysis, Molecular biology, Cell biology, Gene expression profiling, schizophrenia, Psychiatry and Mental health, MicroRNAs, Case-Control Studies, PBMCs, Leukocytes, Mononuclear, biomarker, Original Article, Female, Genomic imprinting, 030217 neurology & neurosurgery, Biomarkers
Abstract

MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and are important for coordinating nervous system development and neuronal function in the mature brain. We have recently identified schizophrenia-associated alteration of cortical miRNA biogenesis and expression in post-mortem brain tissue with implications for the dysregulation of schizophrenia candidate genes. Although these changes were observed in the central nervous system, it is plausible that schizophrenia-associated miRNA expression signatures may also be detected in non-neural tissue. To explore this possibility, we investigated the miRNA expression profile of peripheral blood mononuclear cells (PBMCs) from 112 patients with schizophrenia and 76 non-psychiatric controls. miRNA expression analysis of total RNA conducted using commercial miRNA arrays revealed that 33 miRNAs were significantly downregulated after correction for multiple testing with a false discovery rate (FDR) of 0%, which increased to 83 when we considered miRNA with an FDR

Published
2011

18. CX3CR1 is dysregulated in blood and brain from schizophrenia patients

Author

El Chérif Ibrahim, Florence Pelletier, Rodney J. Scott, Natalie J. Beveridge, Nishantha Kumarasinghe, Bing Liu, Eric Fakra, Olivier Blin, Murray J. Cairns, Paul A. Tooney, Raoul Belzeaux, José Boucraut, Aurélie Bergon, Magali Comte, Erin Gardiner, Mylène Hervé, Ulrich Schall, Vaughan J. Carr, Brian Kelly, Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Centre for Translational Neuroscience and Mental Health, The University of Newcastle, The Hunter Medical Research Institute, University of Newcastle, Kids Cancer Alliance, Cancer Institute NSW, Department of Psychiatry, Monash University [Clayton], Schizophrenia Research Institute [Sydney], Centre investigation clinique - Unité de pharmacologie clinique et d'évaluations thérapeutiques (CIC-UPCET), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Pôle de Psychiatrie, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), and Ibrahim, El Chérif

Subjects
Adult, Male, medicine.drug_class, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, CX3C Chemokine Receptor 1, Epigenetics of schizophrenia, Atypical antipsychotic, Down-Regulation, Inflammation, Bioinformatics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Real-Time Polymerase Chain Reaction, Cohort Studies, Chemokine receptor, CX3CR1, mental disorders, medicine, Humans, Biological Psychiatry, Microglia, business.industry, Microarray analysis techniques, Brain, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Middle Aged, medicine.disease, Microarray Analysis, 3. Good health, Psychiatry and Mental health, medicine.anatomical_structure, Schizophrenia, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, Receptors, Chemokine, medicine.symptom, business, Neuroscience, Biomarkers, Antipsychotic Agents
Abstract

International audience; The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by diverse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of sample types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N = 474) and non-psychiatric control (N = 485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N = 29) and matched controls (N = 31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia.

Published
2015
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19. Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia

Author

Natalie J. Beveridge, Murray J. Cairns, Rodney J. Scott, Vaughan J. Carr, Paul A. Tooney, Xi Wang, and Jing Qin Wu

Subjects
Male, Anatomy and Physiology, lcsh:Medicine, Social and Behavioral Sciences, Transcriptome, Exon, 0302 clinical medicine, Doublecortin-Like Kinases, RNA Isoforms, Psychology, lcsh:Science, Promoter Regions, Genetic, Genetics, Psychiatry, Cerebral Cortex, 0303 health sciences, Multidisciplinary, Intracellular Signaling Peptides and Proteins, Middle Aged, Mental Health, Medicine, Research Article, Adult, Adolescent, Sequence analysis, Biology, Protein Serine-Threonine Kinases, 03 medical and health sciences, Young Adult, Neuropsychology, Humans, RNA, Messenger, Gene, 030304 developmental biology, Aged, Base Sequence, Sequence Analysis, RNA, Gene Expression Profiling, lcsh:R, Alternative splicing, Reproducibility of Results, Promoter, Gene expression profiling, Alternative Splicing, Case-Control Studies, Genetics of Disease, Synapses, Schizophrenia, lcsh:Q, Physiological Processes, 030217 neurology & neurosurgery, Neuroscience
Abstract

Background: While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression. Methodology/Principal Findings: The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR

Published
2012

20. Alternative mRNA fates identified in microRNA-associated transcriptome analysis

Author

Nham Tran, Murray J. Cairns, Adam P. Carroll, and Paul A. Tooney

Subjects
lcsh:QH426-470, RNA-induced silencing complex, Bioinformatics, lcsh:Biotechnology, RNA Stability, Trans-acting siRNA, miR-181b, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, RNA interference, lcsh:TP248.13-248.65, Target identification, Cell Line, Tumor, Genetics, Gene silencing, Humans, Cell Lineage, RNA, Messenger, Post-transcriptional regulation, 030304 developmental biology, miRNA, 0303 health sciences, Binding Sites, Gene Expression Profiling, Non-coding RNA, RNA silencing, lcsh:Genetics, MicroRNAs, HEK293 Cells, E2F1, RNA editing, 030220 oncology & carcinogenesis, Hela Cells, Gene expression, E2F1 Transcription Factor, Biotechnology, Research Article, HeLa Cells
Abstract

Background MicroRNA (miRNA) are small non-coding RNA molecules which function as nucleic acid-based specificity factors in the universal RNA binding complex known as the RNA induced silencing complex (RISC). In the canonical gene-silencing pathway, these activated RISC particles are associated with RNA decay and gene suppression, however, there is evidence to suggest that in some circumstances they may also stabilise their target RNA and even enhance translation. To further explore the role of miRNA in this context, we performed a genome-wide expression analysis to investigate the molecular consequences of bidirectional modulation of the disease-associated miRNAs miR-181b and miR-107 in multiple human cell lines. Results This data was subjected to pathways analysis and correlated against miRNA targets predicted through seed region homology. This revealed a large number of both conserved and non-conserved miRNA target genes, a selection of which were functionally validated through reporter gene assays. Contrary to expectation we also identified a significant proportion of predicted target genes with both conserved and non-conserved recognition elements that were positively correlated with the modulated miRNA. Finally, a large proportion of miR-181b associated genes devoid of the corresponding miRNA recognition element, were enriched with binding motifs for the E2F1 transcription factor, which is encoded by a miR-181b target gene. Conclusions These findings suggest that miRNA regulate target genes directly through interactions with both conserved and non-conserved target recognition elements, and can lead to both a decrease and increase in transcript abundance. They also multiply their influence through interaction with transcription factor genes exemplified by the observed miR-181b/E2F1 relationship.

Published
2012

21. Preliminary evidence of an interaction between the FOXP2 gene and childhood emotional abuse predicting likelihood of auditory verbal hallucinations in schizophrenia

Author

Paul A. Tooney, Melissa J. Green, Rodney J. Scott, Christopher Oldmeadow, Murray J. Cairns, Vaughan J. Carr, Jing Qin Wu, and Simon McCarthy-Jones

Subjects
Adult, Male, Child abuse, Psychosis, medicine.medical_specialty, Genotype, Hallucinations, Emotions, Hearing voices, Logistic regression, Polymorphism, Single Nucleotide, Odds, Young Adult, medicine, Humans, Genetic Predisposition to Disease, Child Abuse, Child, Psychiatry, Psychological abuse, Set (psychology), Biological Psychiatry, Aged, Schizophrenia, Paranoid, Forkhead Transcription Factors, FOXP2, Middle Aged, medicine.disease, Psychiatry and Mental health, Psychotic Disorders, Genes, Schizophrenia, Auditory Perception, Speech Perception, Female, Gene-Environment Interaction, Psychology
Abstract

Objective The FOXP2 gene is involved in the development of speech and language. As some single nucleotide polymorphisms (SNPs) of FOXP2 have been found to be associated with auditory verbal hallucinations (AVHs) at trend levels, this study set out to undertake the first examination into whether interactions between candidate FOXP2 SNPs and environmental factors (specifically, child abuse) predict the likelihood of AVHs. Method Data on parental child abuse and FOXP2 SNPs previously linked to AVHs (rs1456031, rs2396753, rs2253478) were obtained from the Australian Schizophrenia Research Bank for people with schizophrenia-spectrum disorders, both with (n = 211) and without (n = 122) a lifetime history of AVHs. Results Genotypic frequencies did not differ between the two groups; however, logistic regression found that childhood parental emotional abuse (CPEA) interacted with rs1456031 to predict lifetime experience of AVH. CPEA was only associated with significantly higher levels of AVHs in people with CC genotypes (odds ratio = 4.25), yet in the absence of CPEA, people with TT genotypes had significantly higher levels of AVHs than people with CC genotypes (odds ratio = 4.90). This interaction was specific to auditory verbal hallucinations, and did not predict the likelihood of non-verbal auditory hallucinations. Conclusions Our findings offer tentative evidence that FOXP2 may be a susceptibility gene for AVHs, influencing the probability people experience AVHs in the presence and absence of CPEA. However, these findings are in need of replication in a larger study that addresses the methodological limitations of the present investigation.

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22. Gene Expression Profiling of Xeroderma Pigmentosum

Author

Rodney J. Scott, Nikola A. Bowden, and Paul A. Tooney

Subjects
Genetics, Xeroderma Pigmentosum, Xeroderma pigmentosum, lcsh:QH426-470, DNA repair, DNA damage, Research, Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, lcsh:RC254-282, Cyclobutane, Complementation, Gene expression profiling, lcsh:Genetics, Nucleotide excision repair, chemistry.chemical_compound, UV-light and neurological symptoms, Oncology, chemistry, gene expresion profiling, medicine, Gene, Genetics (clinical)
Abstract

Xeroderma pigmentosum (XP) is a rare recessive disorder that is characterized by extreme sensitivity to UV light. UV light exposure results in the formation of DNA damage such as cyclobutane dimers and (6-4) photoproducts. Nucleotide excision repair (NER) orchestrates the removal of cyclobutane dimers and (6-4) photoproducts as well as some forms of bulky chemical DNA adducts. The disease XP is comprised of 7 complementation groups (XP-A to XP-G), which represent functional deficiencies in seven different genes, all of which are believed to be involved in NER. The main clinical feature of XP is various forms of skin cancers; however, neurological degeneration is present in XPA, XPB, XPD and XPG complementation groups. The relationship between NER and other types of DNA repair processes is now becoming evident but the exact relationships between the different complementation groups remains to be precisely determined. Using gene expression analysis we have identified similarities and differences after UV light exposure between the complementation groups XP-A, XP-C, XP-D, XP-E, XP-F, XP-G and an unaffected control. The results reveal that there is a graded change in gene expression patterns between the mildest, most similar to the control response (XP-E) and the severest form (XP-A) of the disease, with the exception of XP-D. Distinct differences between the complementation groups with neurological symptoms (XP-A, XP-D and XP-G) and without (XP-C, XP-E and XP-F) were also identified. Therefore, this analysis has revealed distinct gene expression profiles for the XP complementation groups and the first step towards understanding the neurological symptoms of XP.

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24. Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia.

Author

Jing Qin Wu, Xi Wang, Natalie J Beveridge, Paul A Tooney, Rodney J Scott, Vaughan J Carr, and Murray J Cairns

Subjects
Medicine, Science
Abstract

While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR

Published
2012
Full Text
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