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1. Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Author

Ole Kristian Drange, Olav Bjerkehagen Smeland, Alexey A. Shadrin, Per Ivar Finseth, Aree Witoelar, Oleksandr Frei, Psychiatric Genomics Consortium Bipolar Disorder Working Group, Yunpeng Wang, Sahar Hassani, Srdjan Djurovic, Anders M. Dale, Ole A. Andreassen, Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Jonathan R I Coleman, Heìleìna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Friseìn, 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, Jakob Grove, Weihua Guan, Joseì Guzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Steìphane Jamain, Jessica S Johnson, Anders Jureìus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, 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, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, 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, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Ceìline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Saìnchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, ToÞnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, Reneì S Kahn, George Kirov, Mikael Landeìn, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribaseìs, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
Alzheimer’s disease, bipolar disorder, GWAS, pleiotropy, cognitive symptoms, affective symptoms, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

Published
2019
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2. 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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3. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author

Jonathan R.I. Coleman, Héléna A. Gaspar, Julien Bryois, Gerome Breen, Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Epidemiology, Erasmus MC other, Urology, Psychiatry, Internal Medicine, Medical Informatics, Immunology, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, Coleman J.R.I., Gaspar H.A., Bryois J., Byrne E.M., Forstner A.J., Holmans P.A., de Leeuw C.A., Mattheisen M., McQuillin A., Whitehead Pavlides J.M., Pers T.H., Ripke S., Stahl E.A., Steinberg S., Trubetskoy V., Trzaskowski M., Wang Y., Abbott L., Abdellaoui A., Adams M.J., Adolfsson A.N., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Anjorin A., Antilla V., Van der Auwera S., Awasthi S., Bacanu S.-A., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Beekman A.T.F., Belliveau R., Bergen S.E., Bigdeli T.B., Binder E.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Buttenschon H.N., Bybjerg-Grauholm J., Byerley W., Cai N., Casas M., Castelao E., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Christensen J.H., Churchhouse C., St Clair D., Clarke T.-K., Colodro-Conde L., Coryell W., Couvy-Duchesne B., Craig D.W., Crawford G.E., Cruceanu C., Czerski P.M., Dale A.M., Davies G., Deary I.J., Degenhardt F., Del-Favero J., DePaulo J.R., Derks E.M., Direk N., Djurovic S., Dobbyn A.L., Dolan C.V., Dumont A., Dunn E.C., Eley T.C., Elvsashagen T., Escott-Price V., Fan C.C., Finucane H.K., Fischer S.B., Flickinger M., Foo J.C., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Goes F.S., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Hall L.S., Hamshere M.L., Hansen C.S., Hansen T.F., Hautzinger M., Heilbronner U., van Hemert A.M., Herms S., Hickie I.B., Hipolito M., Hoffmann P., Holland D., Homuth G., Horn C., Hottenga J.-J., Huckins L., Ising M., Jamain S., Jansen R., Johnson J.S., de Jong S., Jorgenson E., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Hassan Kiadeh F.F., Kittel-Schneider S., Knowles J.A., Kogevinas M., Kohane I.S., Koller A.C., Kraft J., Kretzschmar W.W., Krogh J., Kupka R., Kutalik Z., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Li Y., Lind P.A., Liu C., Olde Loohuis L.M., Maaser A., MacIntyre D.J., MacKinnon D.F., Mahon P.B., Maier W., Maier R.M., Marchini J., Martinsson L., Mbarek H., McCarroll S., McGrath P., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Mehta D., Meng F., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mirza S.S., Mondimore F.M., Montgomery G.W., Morris D.W., Mostafavi S., Muhleisen T.W., Mullins N., Nauck M., Ng B., Nguyen H., Nievergelt C.M., Nivard M.G., Nwulia E.A., Nyholt D.R., O'Donovan C., O'Reilly P.F., Ori A.P.S., Oruc L., Osby U., Oskarsson H., Painter J.N., Parra J.G., Pedersen C.B., Pedersen M.G., Perry A., Peterson R.E., Pettersson E., Peyrot W.J., Pfennig A., Pistis G., Purcell S.M., Quiroz J.A., Qvist P., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Riley B.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schoevers R., Schork N.J., Schulte E.C., Shehktman T., Shen L., Shi J., Shilling P.D., Shyn S.I., Sigurdsson E., Slaney C., Smeland O.B., Smit J.H., Smith D.J., Sobell J.L., Spijker A.T., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Tansey K.E., Teismann H., Teumer A., Thompson R.C., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Uitterlinden A.G., Umbricht D., Vedder H., Viktorin A., Visscher P.M., Wang W., Watson S.J., Webb B.T., Weickert C.S., Weickert T.W., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Xu W., Yang J., Young A.H., Zandi P., Zhang P., Zhang F., Zollner S., Adolfsson R., Agartz I., Alda M., Arolt V., Backlund L., Baune B.T., Bellivier F., Berger K., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Boomsma D.I., Corvin A., Craddock N., Daly M.J., Dannlowski U., Domenici E., Domschke K., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., de Geus E.J.C., Gill M., Goes F., Grabe H.J., Grigoroiu-Serbanescu M., Hamilton S.P., Hauser J., Hayward C., Heath A.C., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kendler K.S., Kirov G., Kloiber S., Landen M., Leboyer M., Lewis G., Li Q.S., Lissowska J., Lucae S., Madden P.A.F., Magnusson P.K., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Pedersen N.L., Penninx B.W.J.H., Perlis R.H., Porteous D.J., Posthuma D., Potash J.B., Preisig M., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schaefer C., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Tiemeier H., Turecki G., Uher R., Vaaler A.E., Vieta E., Vincent J.B., Volzke H., Weissman M.M., Werge T., Andreassen O.A., Borglum A.D., Cichon S., Edenberg H.J., Di Florio A., Kelsoe J., Levinson D.F., Lewis C.M., Nurnberger J.I., Ophoff R.A., Scott L.J., Sklar P., Sullivan P.F., Wray N.R., and Breen G.

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genetic correlation, Genome-wide association study, Mood Disorder, Bipolar disorder, Population, BF, Genomics, Major depressive disorder, Affective disorder, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Animals, ddc:610, education, Depression (differential diagnoses), Biological Psychiatry, 030304 developmental biology, Genetic association, Genetics, Depressive Disorder, Major, 0303 health sciences, education.field_of_study, Animal, business.industry, Risk Factor, medicine.disease, 3. Good health, Affective disorders, 030104 developmental biology, Mood, Mood disorders, RC0321, Biological psychiatry, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

Published
2020
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4. Genome-wide significant locus for Research Diagnostic Criteria Schizoaffective Disorder Bipolar type

Author

Christine Fraser, Arianna Di Florio, Ian Jones, Michael Conlon O'Donovan, Lisa Jones, Liz Forty, Katherine Gordon-Smith, Nicholas John Craddock, Michael John Owen, George Kirov, Pamela Sklar, Alexander Richards, Shaun Purcell, Detelina Grozeva, Elaine K. Green, and Jennifer L. Moran

Subjects
Genetic Markers, 0301 basic medicine, Bipolar Disorder, Research Diagnostic Criteria, Schizoaffective disorder, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Genome, 03 medical and health sciences, Cellular and Molecular Neuroscience, Meta-Analysis as Topic, medicine, Humans, SNP, Genetic Predisposition to Disease, Bipolar disorder, Gene, Genetics (clinical), Genetics, medicine.disease, R1, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Schizophrenia, Genome-Wide Association Study
Abstract

Studies have suggested that Research Diagnostic Criteria for Schizoaffective disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP we have performed a replication study using independent RDC-SABP cases (n=144) and controls (n=6,559), focusing on the 10 loci that P-value

Published
2017
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5. Genotype-phenotype Correlations in Darier Disease - a Focus on the Neuropsychiatric Phenotype

Author

Sherine Tavadia, Katherine Gordon-Smith, Lisa Jones, Detelina Grozeva, Nicholas John Craddock, and Elaine K. Green

Subjects
Male, 0301 basic medicine, Gene isoform, Genotype, BF, Sarcoplasmic Reticulum Calcium-Transporting ATPases, 030207 dermatology & venereal diseases, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Darier Disease, ATP2A2, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Genotype-Phenotype Correlations, Gene, Genetic Association Studies, Genetics (clinical), Skin, Genetics, business.industry, Mental Disorders, medicine.disease, Phenotype, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Mutation, RC0321, Female, business
Abstract

Darier Disease (DD) is an autosomal dominant skin disorder caused by mutations in ATP2A2 encoding the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2). Evidence of a population-level association between DD and psychiatric disorders suggests that mutations in ATP2A2 may have pleiotropic effects on the brain as well as skin. Evidence of genotype-phenotype relationships between ATP2A2 mutations and neuropsychiatric phenotypes would further support this suggestion. \ud We investigated genotype-phenotype correlations between lifetime neuropsychiatric features and ATP2A2 mutation type (dichotomized into likely gene disrupting (LGD) or protein altering (PA)) in 75 unrelated individuals with DD. We also looked for evidence of clustering of mutations within SERCA2 according to neuropsychiatric features.\ud Combining our data with the existing literature, the rate of LGD mutations was found to be significantly higher among DD cases/families with bipolar disorder, schizophrenia or affective psychosis (p=0.011). We also found a significant relationship between mutations located in the S4-M4 region of the protein and the presence of a severe neuropsychiatric phenotype (p=0.032).\ud Our findings add support to the hypothesis that Darier-causing mutations in ATP2A2 confer susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness. This, together with evidence from research on common polymorphisms confirms ATP2A2 as a gene at which variation influences susceptibility to major psychiatric illness.

Published
2018

6. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author

Peter P. Zandi, Lisa Jones, Aartjan T.F. Beekman, Christine Fraser, Andreas J. Forstner, Nese Direk, Mark Lathrop, Jesper Krogh, Merete Nordentoft, Bradley T. Webb, Yihan Li, Michael Bauer, Qingqin S. Li, Daniel J. Smith, Carsten Horn, Robert C. Thompson, René Breuer, Eli A. Stahl, David A. Collier, Richard Williamson, Boomsma, Dorret, I, Céline S. Reinbold, Laura J. Scott, Manolis Kogevinas, Jacob Lawrence, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Wade H. Berrettini, John B. Vincent, Toni-Kim Clarke, Henry Voelzke, Stacy Steinberg, Hreinn Stefansson, Dean F. MacKinnon, Thorgeir E. Thorgeirsson, Niamh Mullins, Esben Agerbo, Rudolf Uher, Christina M. Hultman, Pamela A. F. Madden, Eva C. Schulte, Matthew Flickinger, Sebastian Zöllner, Kenneth S. Kendler, Urban Ösby, Enrique Castelao, Michael John Owen, Colm O'Dushlaine, Jens Treutlein, Joanna Hauser, Markus M. Noethen, Erin N. Smith, James McKay, Sandra Van der Auwera, Erin C. Dunn, Steven P. Hamilton, Martin Schalling, Helmut Vedder, Katherine Gordon-Smith, Fabio Rivas, Matthias Nauck, James B. Potash, Morten Mattingsdal, Ling Shen, Tim B. Bigdeli, Kimberly Chambert, Volker Arolt, Daniel L. Koller, Annelie Nordin Adolfsson, Na Cai, Nicholas G. Martin, Carlos N. Pato, Georg Homuth, Jonas Bybjerg-Grauholm, Alexander Teumer, Wesley K. Thompson, Hamel Patel, Jian Yang, Margit Burmeister, Frank Bellivier, Jodie N. Painter, Enda M. Byrne, Margarita Rivera, Nicholas John Craddock, Tatiana Foroud, Shaun Purcell, Paul D. Shilling, David Craig, Vanessa Kiyomi Ota, Michael Boehnke, Devin Absher, Stéphane Jamain, Anne Farmer, Yunpeng Wang, Ole Mors, William A. Scheftner, Jack D. Barchas, Robert Maier, Stanley J. Watson, Allan H. Young, Baptiste Couvy-Duchesne, Jakob Grove, Rick Jansen, John P. Rice, Gerome Breen, Eske M. Derks, Ingrid Melle, Tiffany A. Greenwood, Manuel Mattheisen, Bernard Ng, Edward M. Scolnick, Stefan Kloiber, Lili Milani, Yuri Milaneschi, Fermín Mayoral, Engilbert Sigurdsson, Sarah E. Medland, Wolfgang Maier, Alan F. Schatzberg, Myrna M. Weissman, Jun Li, John R. Kelsoe, Eric Jorgenson, Grant C.B. Sinnamon, Preben Bo Mortensen, Jana Strohmaier, William Byerley, Michel G. Nivard, Richard M. Myers, Evelin Mihailov, Gustavo Turecki, Benjamin S. Pickard, Ian J. Deary, Bernhard T. Baune, Marian L. Hamshere, Stephanie H. Witt, Patrick F. Sullivan, Jennifer L. Moran, Farnush Farhadi Hassan Kiadeh, Cathryn M. Lewis, Srdjan Djurovic, Ian B. Hickie, Hans J. Grabe, Helena Gaspar, Francis J. McMahon, Catherine Schaefer, Guy A. Rouleau, Sandra Meier, Derek W. Morris, Tõnu Esko, Wouter J. Peyrot, Markus Schwarz, Silviu-Alin Bacanu, Adam Wright, Melvin G. McInnis, Elaine K. Green, Douglas M. Ruderfer, Danielle Posthuma, Franziska Degenhardt, Per Qvist, Henriette N. Buttenschøn, Jolanta Lissowska, Stephan Ripke, Nicholas Bass, Giorgio Pistis, Emma M. Quinn, Shantel Weinsheimer, Howard J. Edenberg, Sintia Iole Belangero, Charles Curtis, Ashley R. Winslow, Tracy M. Air, Johannes H. Smit, Isaac S. Kohane, Wei Xu, Pamela B. Mahon, Neonila Szeszenia-Dabrowska, Gonneke Willemsen, Ivan Nikolov, Sven Cichon, Gregory E. Crawford, David M. Hougaard, E.J.C. de Geus, Klaus Berger, Evaristus A. Nwulia, Fernando S. Goes, Pablo Cervantes, Udo Dannlowski, Rolf Adolfsson, Thomas G. Schulze, Bruno Etain, Mark J. Adams, Thomas Hansen, Hugh Gurling, Fan Guo Meng, Judith A. Badner, Julien Bryois, Mateus Jose Abdalla Diniz, Rodrigo A. Bressan, Radhika Kandaswamy, Josef Frank, I. Nicol Ferrier, Bertram Mueller-Myhsok, Manuel A. R. Ferreira, Marion Leboyer, Futao Zhang, Valentina Moskvina, Patrik K. E. Magnusson, Laura M. Huckins, Douglas Blackwood, Michael Gill, Jianxin Shi, Dale R. Nyholt, Nancy L. Pedersen, André G. Uitterlinden, Henning Tiemeier, Vassily Trubetskoy, Scott D. Gordon, Ian Jones, Grant W. Montgomery, Martin Preisig, Cristiana Cruceanu, Sara A. Paciga, Lena Backlund, Abdel Abdellaoui, Andres Metspalu, Gunnar Morken, Marcus Ising, Sascha B. Fischer, Lilijana Oruc, Sian Caesar, Sarah Kittel-Schneider, Thalia C. Eley, Vihra Milanova, Thomas Werge, Andrew Heath, Katherine E. Tansey, Thomas W. Muehleisen, Jane H. Christensen, Chunyu Liu, Mikael Landén, Douglas F. Levinson, Julia Kraft, Juergen Wellmann, Coleman, Jonathan R., I, Peng Zhang, Glyn Lewis, Henning Teismann, Hamdi Mbarek, Carsten Bøcker Pedersen, Szabolcs Szelinger, Alexander Viktorin, Paul Brennan, Brenda W.J.H. Penninx, Maciej Trzaskowski, Yang Wu, Katharina Domschke, John Strauss, Hilary K. Finucane, Detelina Grozeva, Peter Holmans, Saira Saeed Mirza, Ole A. Andreassen, John I. Nurnberger, Lynsey S Hall, Till F. M. Andlauer, Sara Mostafavi, Andreas Reif, Joanna M. Biernacka, Christine Søholm Hansen, Hualin S. Xi, Stephen Newhouse, William E. Bunney, Andrew M. McIntosh, Anna Maaser, Enrico Domenici, Shyn, Stanley, I, Gail Davies, Warren W. Kretzschmar, Simone de Jong, Lucía Colodro-Conde, Pippa A. Thomson, Francis M. Mondimore, Martin Hautzinger, Cinnamon S. Bloss, Fabian Streit, James L. Kennedy, Erik Pettersson, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Johannes Schumacher, Kevin A. McGhee, Divya Mehta, Naomi R. Wray, Robert A. Schoevers, John A. Rice, Jordan W. Smoller, Anders D. Børglum, Susanne Lucae, Jorge A. Quiroz, Daniel Umbricht, Jouke-Jan Hottenga, Kari Stefansson, Marcella Rietschel, Zoltán Kutalik, Sarah E. Bergen, Paul F. O'Reilly, Amanda Dobbyn, Michael Conlon O'Donovan, Falk W. Lohoff, Caroline M. Nievergelt, David J. Porteous, Matthew Traylor, Brien P. Riley, Roy H. Perlis, J. Raymond DePaulo, Martin Alda, James A. Knowles, Cristiano Noto, Keith Matthews, Mark A. Frye, Patrick J. McGrath, Roseann E. Peterson, David St Clair, Roel A. Ophoff, William Coryell, Peter McGuffin, Andiara Calado Saloma Rodrigues, Elliot S. Gershon, Conor V. Dolan, Janice M. Fullerton, Weihua Guan, Niklas Långström, Pamela Sklar, Paul Lichtenstein, Per Hoffmann, Ary Gadelha, Alan W. McLean, Andrew McQuillin, Philip B. Mitchell, Huda Akil, Piotr M. Czerski, Michael Steffens, Hogni Oskarsson, Soumya Raychaudhuri, Marcos L. Santoro, Elisabeth B. Binder, Christel M. Middeldorp, Jose G. Para, Jurgen Del-Favero, Vishwajit L. Nimgaonkar, Peter R. Schofield, Stefan Herms, Marie Bækvad-Hansen, Andrea Pfennig, Albert M. van Hemert, Jutta Kammerer-Ciernioch, Adebayo Anjorin, Sara Paciga, William Lawson, George Kirov, Aiden Corvin, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Jonathan Marchini, Markus Leber, Maria Hipolito, Louise Frisén, Margitta Borrmann-Hassenbach, Amanda Elkin, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, TFM, Bacanu, S.A., Bækvad-Hansen, M., Beekman, ATF, Bigdeli, T.B., Binder, E.B., Blackwood, DHR, Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, JRI, Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, FFH, Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shyn, S.I., Sigurdsson, E., Sinnamon, GCB, Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., de Geus, EJC, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, PAF, Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Müller-Myhsok, B., Nordentoft, M., Nöthen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, BWJH, Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Völzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Børglum, A.D., Sullivan, P.F., Meier, S., Strauss, J., Xu, W., Vincent, J.B., Matthews, K., Ferreira, M., O'Dushlaine, C., Purcell, S., Raychaudhuri, S., Ruderfer, D.M., Sklar, P., Scott, L.J., Flickinger, M., Burmeister, M., Li, J., Guan, W., Absher, D., Thompson, R.C., Meng, F.G., Schatzberg, A.F., Bunney, W.E., Barchas, J.D., Watson, S.J., Myers, R.M., Akil, H., Boehnke, M., Chambert, K., Moran, J., Scolnick, E., Djurovic, S., Melle, I., Morken, G., Corvin, A., Anjorin, A., Kandaswamy, R., Lawrence, J., McLean, A.W., Pickard, B.S., Bergen, S.E., Nimgaonkar, V., Landén, M., Schalling, M., Osby, U., Backlund, L., Frisén, L., Langstrom, N., Stahl, E., Dobbyn, A., Jamain, S., Etain, B., Bellivier, F., Leber, M., Maaser, A., Fischer, S.B., Reinbold, C.S., Kittel-Schneider, S., Fullerton, J.M., Oruč, L., Para, J.G., Mayoral, F., Rivas, F., Czerski, P.M., Kammerer-Ciernioch, J., Vedder, H., Borrmann-Hassenbach, M., Pfennig, A., Brennan, P., McKay, J.D., Kogevinas, M., Schwarz, M., Schofield, P.R., Mühleisen, T.W., Schumacher, J., Bauer, M., Wright, A., Mitchell, P.B., Hautzinger, M., Kelsoe, J.R., Greenwood, T.A., Nievergelt, C.M., Shilling, P.D., Smith, E.N., Bloss, C.S., Edenberg, H.J., Koller, D.L., Gershon, E.S., Liu, C., Badner, J.A., Scheftner, W.A., Lawson, W.B., Nwulia, E.A., Hipolito, M., Coryell, W., Rice, J., Byerley, W., McMahon, F.J., Lohoff, F.W., Zandi, P.P., Mahon, P.B., McInnis, M.G., Zöllner, S., Zhang, P., Szelinger, S., St Clair, D., Caesar, S., Gordon-Smith, K., Fraser, C., Green, E.K., Grozeva, D., Hamshere, M.L., Kirov, G., Nikolov, I., Collier, D.A., Elkin, A., Williamson, R., Young, A.H., Ferrier, I.N., Milanova, V., Alda, M., Cervantes, P., Cruceanu, C., Rouleau, G.A., Turecki, G., Paciga, S., Winslow, A.R., Grigoroiu-Serbanescu, M., Ophoff, R., Adolfsson, R., Adolfsson, A.N., Del-Favero, J., Pato, C., Biernacka, J.M., Frye, M.A., Morris, D., Schork, N.J., Reif, A., Lissowska, J., Hauser, J., Szeszenia-Dabrowska, N., McGhee, K., Quinn, E., Moskvina, V., Holmans, P.A., Farmer, A., Kennedy, J.L., Andreassen, O.A., Mattingsdal, M., Bass, N.J., Gurling, H., McQuillin, A., Breuer, R., Hultman, C., Lichtenstein, P., Huckins, L.M., Leboyer, M., Lathrop, M., Nurnberger, J., Steffens, M., Foroud, T.M., Berrettini, W.H., Craig, D.W., Shi, J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Major Depressive Disorder Bipolar, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, Pediatric Surgery, Epidemiology, Child and Adolescent Psychiatry / Psychology, Psychiatry, and Internal Medicine

Subjects
Netherlands Twin Register (NTR), 0301 basic medicine, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Bipolar Disorder, SAMPLE, Medicine (miscellaneous), Pedigree chart, Disease, 0302 clinical medicine, SCHIZOPHRENIA, 2.1 Biological and endogenous factors, Medicine, Aetiology, ANTICIPATION, lcsh:QH301-705.5, Psychiatry, 0303 health sciences, Depression, ASSOCIATION, Serious Mental Illness, Mental Health, Schizophrenia, Major depressive disorder, General Agricultural and Biological Sciences, Engineering sciences. Technology, medicine.medical_specialty, Context (language use), Article, Psykiatri, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, AGE, SDG 3 - Good Health and Well-being, ddc:570, Behavioral and Social Science, Genetics, PLINK, Genetic Testing, Bipolar disorder, Biology, 030304 developmental biology, business.industry, Prevention, Human Genome, Assortative mating, medicine.disease, Brain Disorders, 030104 developmental biology, Mood, lcsh:Biology (General), Mood disorders, Anticipation (genetics), ONSET, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Simone de Jong et al. examine the balance of common and rare risk for psychiatric disorders in a large family with high incidence of Bipolar Disorder and Major Depressive Disorder. They find that increased polygenic risk over generations could be partially due to assortative mating, which may explain the observation of anticipation in mood disorders.

Published
2018
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7. Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases

Author

Christopher P. Morley, Jennifer L. Moran, Douglas S. Lehrer, Janet L. Sobell, Arianna Di Florio, Mikael Landén, Peter F. Buckley, Steven A. McCarroll, Elaine K. Green, Phil H. Lee, Jordan W. Smoller, Liz Forty, Katherine E. Burdick, Lena Backlund, Michele T. Pato, Martin Schalling, Jeffrey J. Rakofsky, Eli A. Stahl, Katherine Gordon-Smith, Carlos N. Pato, Ayman H. Fanous, Alexander W. Charney, Nicholas John Craddock, Sarah E. Bergen, James A. Knowles, Douglas M. Ruderfer, Laura J. Fochtmann, Stephen R. Marder, Shaun Purcell, Mark Hyman Rapaport, Humberto Nicolini, Ian Jones, Kimberly Chambert, Chia-Yen Chen, Michael Escamilla, Evelyn J. Bromet, Pamela Sklar, Paul Lichtenstein, Diana O. Perkins, Helena Medeiros, Anders Juréus, Christina A Hultman, Roy H. Perlis, Lisa Jones, Dolores Malaspina, and Richard A. Belliveau

Subjects
0301 basic medicine, Oncology, Multifactorial Inheritance, medicine.medical_specialty, Psychosis, Bipolar Disorder, Bipolar I disorder, DNA Copy Number Variations, BF, Schizoaffective disorder, Article, Cohort Studies, 03 medical and health sciences, Bipolar II disorder, 0302 clinical medicine, Gene Duplication, Internal medicine, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Biological Psychiatry, Depression (differential diagnoses), 030304 developmental biology, 0303 health sciences, business.industry, Not Otherwise Specified, Genomics, medicine.disease, 3. Good health, 030104 developmental biology, Psychotic Disorders, Schizophrenia, Case-Control Studies, RC0321, Disease Susceptibility, medicine.symptom, business, Mania, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BackgroundGenetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. BD subtypes schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I) and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania and depression. The factors contributing to the combination of symptoms within a given patient are poorly understood.MethodsRare, large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis], 1436 BD II, 579 SAB) and 8656 controls. Measures of CNV burden were integrated with polygenic risk scores (PRS) for schizophrenia (SCZ) to evaluate the relative contributions of rare and common variants to psychosis risk.ResultsCNV burden did not differ in BD relative to controls when treated as a single diagnostic entity. Burden in SAB was increased compared to controls (p-value = 0.001), BD I (p-value = 0.0003) and BD II (p-value = 0.0007). Burden and SCZ PRS were higher in SAB compared to BD I with psychosis (CNV p-value = 0.0007, PRS p-value = 0.004) and BD I without psychosis (CNV p-value = 0.0004, PRS p-value = 3.9 × 10−5). Within BD I, psychosis was associated with higher SCZ PRS (p-value = 0.005) but not with CNV burden.ConclusionsCNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Published
2018
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8. Systematic Analysis and Biomarker Study for Alzheimer's Disease

Author

Xinzhong, Li, Haiyan, Wang, Jintao, Long, Genhua, Pan, Taigang, He, Oleg, Anichtchik, Robert, Belshaw, Diego, Albani, Paul, Edison, Elaine K, Green, and James, Scott

Subjects
NF-kappa B, Brain, Nitric Oxide Synthase Type II, Sensitivity and Specificity, Article, Mitochondria, Machine Learning, Blood, Alzheimer Disease, Case-Control Studies, Humans, Cognitive Dysfunction, Ribosomes, Biomarkers, Genome-Wide Association Study, Signal Transduction
Abstract

Revealing the relationship between dysfunctional genes in blood and brain tissues from patients with Alzheimer’s Disease (AD) will help us to understand the pathology of this disease. In this study, we conducted the first such large systematic analysis to identify differentially expressed genes (DEGs) in blood samples from 245 AD cases, 143 mild cognitive impairment (MCI) cases, and 182 healthy control subjects, and then compare these with DEGs in brain samples. We evaluated our findings using two independent AD blood datasets and performed a gene-based genome-wide association study to identify potential novel risk genes. We identified 789 and 998 DEGs common to both blood and brain of AD and MCI subjects respectively, over 77% of which had the same regulation directions across tissues and disease status, including the known ABCA7, and the novel TYK2 and TCIRG1. A machine learning classification model containing NDUFA1, MRPL51, and RPL36AL, implicating mitochondrial and ribosomal function, was discovered which discriminated between AD patients and controls with 85.9% of area under the curve and 78.1% accuracy (sensitivity = 77.6%, specificity = 78.9%). Moreover, our findings strongly suggest that mitochondrial dysfunction, NF-κB signalling and iNOS signalling are important dysregulated pathways in AD pathogenesis.

Published
2018

9. Copy number variation in bipolar disorder

Author

George Kirov, Steven A. McCarroll, Giulio Genovese, Nicholas John Craddock, Stephan Ripke, Ian Jones, Liz Forty, Pamela Sklar, Elaine K. Green, K-G Smith, Kimberly Chambert, Michael John Owen, Elliott Rees, Jennifer L. Moran, James T.R. Walters, Lisa Jones, Detelina Grozeva, and Michael Conlon O'Donovan

Subjects
Male, 0301 basic medicine, Bipolar Disorder, DNA Copy Number Variations, Genotyping Techniques, MEDLINE, Biology, White People, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Text mining, medicine, Humans, Copy-number variation, Bipolar disorder, Molecular Biology, Genetics, Extramural, business.industry, Middle Aged, medicine.disease, R1, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, RC0321, Female, Original Article, business, 030217 neurology & neurosurgery
Abstract

Large (4100 kb), rare (o1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n = 2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P = 0.022), deletions at 3q29 (P = 0.03) and duplications at 16p11.2 (P = 2.3 × 10− 4). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (4500 kb) CNVs in BD compared with SZ, most notably for deletions 41Mb (P=9×10− 4).

Published
2015
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10. Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes

Author

Thomas G. Schulze, Eduard Vieta, Melissa J. Green, Jakob Grove, Ingrid Melle, Preben Bo Mortensen, Nicholas J. Schork, Thorgeir E. Thorgeirsson, Jonas Bybjerg-Grauholm, Margit Burmeister, Peter R. Schofield, Szabolcs Szelinger, Fermín Mayoral, Katherine Gordon-Smith, Qingqin S. Li, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Derek W. Morris, Douglas M. Ruderfer, Stefan Herms, Huckins Lm, Martin Hautzinger, Eline J. Regeer, Sebastian Zöllner, Gustavo Turecki, Christine Søholm Hansen, Helena Medeiros, Laura J. Scott, Annelie Nordin Adolfsson, Helmut Vedder, Thomas W. Weickert, Nelson B. Freimer, Céline S. Reinbold, James McKay, Cathryn M. Lewis, Eric R. Gamazon, Frank Bellivier, Marie B¾kvad-Hansen, Srdjan Djurovic, Chun Chieh Fan, Ole A. Andreassen, Solveig K. Sieberts, Jack D. Barchas, David Curtis, Elaine K. Green, Tatiana Foroud, Shaun Purcell, Mette A. Peters, Joanna M. Biernacka, Fabian Streit, Alan F. Schatzberg, James L. Kennedy, Tiffany A. Greenwood, Bertram Müller-Myhsok, Robin Kramer, Swapnil Awasthi, Jordan W. Smoller, Cristina Sánchez-Mora, George Kirov, Ulrik Fredrik Malt, Gabriel E. Hoffman, Liz Forty, Pablo Cervantes, Jose Guzman Parra, Nicholas G. Martin, William Byerley, J. Raymond DePaulo, Martin Alda, Anil P.S. Ori, Menachem Fromer, William E. Bunney, Valentina Escott-Price, Judith A. Badner, Danielle Posthuma, Judith Allardyce, M. Ribasés, Manolis Kogevinas, Stephanie H. Witt, Anne T. Spijker, James A. Knowles, Simon Xi, Jun Li, Francis J. McMahon, Nancy J. Cox, Marcella Rietschel, Markus Leber, Laura M. Huckins, John I. Nurnberger, M. Casas, Marco P. Boks, Maria Hipolito, Evaristus A. Nwulia, Gerome Breen, Franziska Degenhardt, Janice M. Fullerton, Carlos N. Pato, Urs Heilbronner, Piotr M. Czerski, Michael Steffens, Monika Budde, Nicholas John Craddock, Katrin Gade, Bernie Devlin, Sarah Kittel-Schneider, Enrico Domenci, Weihua Guan, Sarah E. Bergen, Fan Meng, Eystein Stordal, Janet L. Sobell, Naomi R. Wray, Engilbert Sigurdsson, Marion Leboyer, Sven Cichon, Pamela Sklar, Bruno Etain, Richard M. Myers, Melvin G. McInnis, Steve McCarroll, Nicholas Bass, Christine Fraser, Thomas W. Mühleisen, Anna Maaser, Patrick F. Sullivan, Mark A. Frye, Amanda Dobbyn, John P. Rice, Amy Perry, Wei Xu, Thomas Damm Als, Anders D. Børglum, Anna C. Koller, Michael Conlon O'Donovan, Pamela B. Mahon, Sara A. Paciga, Douglas Blackwood, Michael Bauer, Fernando S. Goes, Susanne Lucae, Markus M. Nöthen, Josef Frank, Grant W. Montgomery, Scott D. Gordon, Philip B. Mitchell, Hoang T. Nguyen, Huda Akil, Chunyu Liu, Stanley J. Watson, Allan H. Young, Roel A. Ophoff, Caroline M. Nievergelt, John B. Vincent, Robert Karlsson, Kari Stefansson, Thomas Werge, Niamh Mullins, William A. Scheftner, Elliot S. Gershon, Peter McGuffin, Ralph Kupka, Mikael Landén, Matthew Flickinger, Claudia Giambartolomei, Carsten Bøcker Pedersen, Michael John Owen, Diego Albani, Hae Kyung Im, Andres Metspalu, Gunnar Morken, Panos Roussos, Tõnu Esko, Andrew M. McIntosh, Vishwajit L. Nimgaonkar, Per Hoffmann, Olav B. Smeland, Stéphane Jamain, Ole Mors, Vahram Haroutunian, Anders Juréus, Shawn Levy, Roy H. Perlis, Whitney McFadden, James Boocock, Ney Alliey-Rodriguez, Stacy Steinberg, Paul D. Shilling, Arne E. Vaaler, David Craig, Sarah E. Medland, Donald J. MacIntyre, William Coryell, Jens Treutlein, Joanna Hauser, Cynthia Shannon Weickert, Jana Strohmaier, Guy A. Rouleau, Michele T. Pato, John R. Kelsoe, Arianna Di Florio, Radhika Kandaswamy, David M. Hougaard, Toni-Kim Clarke, Susan L. McElroy, Ian Jones, Sarah Knott, Tatyana Shehktman, Wade H. Berrettini, John Strauss, Anders M. Dale, Peter P. Zandi, Andreas Reif, Claire Slaney, Julie Garnham, Margarita Rivera, Michael Gill, Lisa Jones, Cristiana Cruceanu, Sascha B. Fischer, Marian L. Hamshere, Lilijana Oruc, Weiqing Wang, Eli A. Stahl, Wolfgang Maier, Peng Zhang, Hreinn Stefansson, Ingrid Agartz, Bernhard T. Baune, Esben Agerbo, Alessandro Serretti, Robert C. Thompson, Ketil J. Oedegaard, William Lawson, Merete Nordentoft, Jacob Lawrence, Fabio Rivas, James B. Potash, Aiden Corvin, Christina M. Hultman, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Michael Boehnke, René S. Kahn, Lili Milani, Jurgen Del-Favero, Veera M. Rajagopal, Jolanta Lissowska, Howard J. Edenberg, Udo Dannlowski, Rolf Adolfsson, Andrea Pfennig, Adebayo Anjorin, and Torbjørn Elvsåshagen

Subjects
Genotype, Expression quantitative trait loci, medicine, Genome-wide association study, Locus (genetics), Bipolar disorder, Computational biology, Biology, medicine.disease, Phenotype, Genetic architecture, Imputation (genetics)
Abstract

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

Published
2017
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11. Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

Author

Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R I Coleman, Héléna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Srdjan Djurovic, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Frisén, 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, Jakob Grove, Weihua Guan, JoséGuzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Stéphane Jamain, Jessica S Johnson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, 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, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, 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, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Céline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, Tõnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, RenéS Kahn, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, medicine.disease, European descent, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genomewide association, medicine, Bipolar disorder, medicine.symptom, Psychiatry, business, Mania, 030217 neurology & neurosurgery, Depression (differential diagnoses), 030304 developmental biology
Abstract

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

Published
2017
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12. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

Author

Pamela Sklar, Paul Lichtenstein, Diana O. Perkins, Douglas M. Ruderfer, Lena Backlund, Humberto Nicolini, Stephen R. Marder, Phil Lee, Elaine K. Green, Roy H. Perlis, Martin Schalling, Jeffrey J. Rakofsky, Steven A. McCarroll, Evelyn J. Bromet, Jordan W. Smoller, Liz Forty, Dolores Malaspina, Janet L. Sobell, Richard A. Belliveau, Katherine Gordon-Smith, Jennifer L. Moran, Ian Jones, Sarah E. Bergen, A. Di Florio, Laura J. Fochtmann, Michael Escamilla, Helena Medeiros, Alexander W. Charney, Mikael Landén, Panos Roussos, A. H. Fanous, Mark Hyman Rapaport, Shaun Purcell, Kimberly Chambert, James A. Knowles, Carlos N. Pato, Douglas S. Lehrer, Nicholas John Craddock, M. T. Pato, Christopher P. Morley, Anders Juréus, Lisa Jones, Eli A. Stahl, Peter F. Buckley, and Christina M. Hultman

Subjects
0301 basic medicine, Oncology, Bipolar Disorder, Genome-wide association study, Aminopeptidases, 0302 clinical medicine, 2.1 Biological and endogenous factors, Psychology, Pair 10, Aetiology, Genetics, Nuclear Proteins, Single Nucleotide, Serious Mental Illness, L-Type, 3. Good health, Psychiatry and Mental health, Phenotype, Mental Health, Schizophrenia, Public Health and Health Services, Major depressive disorder, Original Article, Human, Ankyrins, medicine.medical_specialty, Calcium Channels, L-Type, Genotype, Clinical Sciences, BF, Schizoaffective disorder, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Genetic correlation, Chromosomes, 03 medical and health sciences, Cellular and Molecular Neuroscience, Clinical Research, Internal medicine, medicine, Humans, Bipolar disorder, Allele, Polymorphism, Biological Psychiatry, Chromosomes, Human, Pair 10, Genetic heterogeneity, Human Genome, medicine.disease, R1, Brain Disorders, Cytoskeletal Proteins, 030104 developmental biology, Psychotic Disorders, Case-Control Studies, RC0321, Calmodulin-Binding Proteins, Calcium Channels, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10−8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Published
2017

13. Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia

Author

Stephan Ripke, A. Di Florio, Gustavo Turecki, N Bass, Ian Jones, Laura J. Scott, Lisa Hall, Martin Hautzinger, Tracy Air, Sarah Knott, Marcella Rietschel, Christel M. Middeldorp, Patrick J. Brennan, John Strauss, Nicholas G. Martin, Bertram Müller-Myhsok, Tony Davis, Andreas Reif, Katherine Gordon-Smith, Céline S. Reinbold, Urs Heilbronner, Anders Juréus, Stefan Kloiber, Andrew McQuillin, Dan Rujescu, N. Dahmen, Fermin Mayoral-Cleries, Richard M. Myers, Abdel Abdellaoui, Franck Bellivier, Gunnar Morken, Sarah E. Bergen, Manolis Kogevinas, Dorret I. Boomsma, Thomas G. Schulze, Arian Mobascher, Stefanie Heilmann-Heimbach, Sascha B. Fischer, Christine Fraser, Y. Milaneschi, Michael Conlon O'Donovan, Susan L. McElroy, Klaus Lieb, B.W.J.H. Penninx, Helmut Vedder, Fabian Streit, Piotr M. Czerski, Swapnil Awasthi, Lilijana Oruc, Caroline M. Nievergelt, Michael Bauer, Jana Strohmaier, Qingqin S. Li, Bernhard T. Baune, Roel A. Ophoff, S. E. Medland, Marco P. Boks, Gulja Babadjanova, Mark A. Frye, Christian Schmahl, M. M. Nöthen, Nicholas John Craddock, John B. Vincent, Douglas Blackwood, Marion Leboyer, Franziska Degenhardt, C. E. Schwarze, Henriette N. Buttenschøn, Tiffany A. Greenwood, Ole A. Andreassen, Toni-Kim Clarke, Loes M. Olde Loohuis, Scott D. Gordon, Björn H. Schott, Stephanie H. Witt, Stefan Roepke, John I. Nurnberger, S Van der Auwera, Lisa Jones, James D. McKay, André Tadić, Mikael Landén, Guy A. Rouleau, Monika Budde, Grant C.B. Sinnamon, Enda M. Byrne, Bruno Etain, Darja Schendel, Andreas J. Forstner, Cristiana Cruceanu, Srdjan Djurovic, Sara A. Paciga, Ney Alliey-Rodriguez, Joanna Hauser, Enrico Domenici, Peter Hoffmann, Elaine K. Green, Stéphane Jamain, Markus Schwarz, Marian L. Hamshere, Christian Witt, E.J.C. de Geus, Andrew M. McIntosh, Sven Cichon, Ole Mors, Jolanta Lissowska, Josef Frank, Pablo Cervantes, G. Kirov, Howard J. Edenberg, Ina Giegling, Grant W. Montgomery, Lydie Dietl, Martin Preisig, M. J. Owen, Martin Alda, David Curtis, Eli A. Stahl, Gonneke Willemsen, Udo Dannlowski, Rolf Adolfsson, Janice M. Fullerton, Jose Guzman-Parra, Elliot S. Gershon, Peter Holmans, Hans-Jörgen Grabe, Hualin S. Xi, Jens Treutlein, Fabio Rivas, James B. Potash, Martin Bohus, Naomi R. Wray, René S. Kahn, Katrin Gade, Sarah Kittel-Schneider, Anders D. Børglum, Susanne Lucae, Jouke-Jan Hottenga, Joanna M. Biernacka, Liz Forty, Margitta Borrmann-Hassenbach, Martin Jungkunz, Andrea Pfennig, Jutta Kammerer-Ciernioch, Maria Grigoroiu-Serbanescu, Peter R. Schofield, Stefan Herms, Amy Perry, Shashi Hitturlingappa, Markus Leber, Thomas W. Mühleisen, Philip B. Mitchell, Andrew Bethell, Huda Akil, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Environmental Policy Analysis, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Bipolar Disorders Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), and Duchange, Nathalie

Subjects
Netherlands Twin Register (NTR), Male, Linkage disequilibrium, Multifactorial Inheritance, Bipolar Disorder, FEATURES, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Genome-wide association study, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, MESH: Genotype, 0302 clinical medicine, Borderline Personality Disorder, MESH: Bipolar Disorder, Borderline personality disorder, Genetics, RISK, Psychiatry, MESH: Aged, MESH: Middle Aged, PSYCHOPATHOLOGY, MESH: Genetic Predisposition to Disease, Middle Aged, MESH: Case-Control Studies, 3. Good health, FAMILY, Psychiatry and Mental health, Schizophrenia, MESH: Young Adult, Female, Original Article, medicine.symptom, Psychology, SET, TRAITS, Adolescent, Adult, Aged, Bipolar Disorder/genetics, Borderline Personality Disorder/genetics, Case-Control Studies, Depressive Disorder, Major/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Schizophrenia/genetics, Young Adult, Clinical psychology, MESH: Depressive Disorder, Major, TWIN, BF, Impulsivity, Psykiatri, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Journal Article, ddc:610, Bipolar disorder, Biological Psychiatry, METAANALYSIS, MESH: Borderline Personality Disorder, MESH: Adolescent, Depressive Disorder, Major, MESH: Humans, MESH: Adult, medicine.disease, Comorbidity, MESH: Male, MESH: Schizophrenia, 030227 psychiatry, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, PATTERNS, RC0321, DPYD, MESH: Multifactorial Inheritance, COMORBIDITY, MESH: Female, 030217 neurology & neurosurgery
Abstract

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Published
2017
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14. Genome-wide association study identifies 30 loci associated with bipolar disorder

Author

Euijung Ryu, Danfeng Chen, Allan H. Young, Olav B. Smeland, James McKay, Frank Bellivier, Qingqin S. Li, Yunpeng Wang, Tõnu Esko, Bertram Müller-Myhsok, Weiqing Wang, Thomas W. Weickert, Joanna M. Biernacka, Ralph W. Kupka, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Marian L. Hamshere, Derek W. Morris, Douglas M. Ruderfer, Stephan Ripke, Nelson B. Freimer, Tatiana Foroud, Shaun Purcell, Ashley Dumont, Shawn Levy, Dominic Holland, Joanna Hauser, Anders D. Børglum, Liz Forty, Alan F. Schatzberg, Christine Fraser, Jennifer M. Whitehead Pavlides, William E. Bunney, Merete Nordentoft, Andres Metspalu, Gunnar Morken, Susanne Lucae, Roy H. Perlis, Anne T. Spijker, Richard A. Belliveau, Sarah E. Bergen, Fan Meng, Eduard Vieta, Cynthia Shannon Weickert, J. Raymond DePaulo, Martin Alda, Lina Martinsson, Melvin G. McInnis, Jacob Lawrence, Markus Leber, James A. Knowles, Franziska Degenhardt, Melissa J. Green, Jaqueline Goldstein, Amanda Dobbyn, Radhika Kandaswamy, Steve McCarroll, Katrin Gade, Jack D. Barchas, Christina M. Hultman, Sarah Kittel-Schneider, Martin Hautzinger, Maria Hipolito, Louise Frisén, Kari Stefansson, Michael Conlon O'Donovan, Markus M. Nöthen, Eline J. Regeer, Jens Treutlein, Robert Karlsson, Ian Jones, Nicholas G. Martin, William A. Scheftner, Caroline M. Nievergelt, Marta Ribasés, Simone de Jong, Szabolcs Szelinger, Thomas W. Mühleisen, Michele T. Pato, Manuel Mattheisen, Maciej Trzaskowski, Urs Heilbronner, Diane Gage, Jakob Grove, Ingrid Melle, Ole A. Andreassen, Claudia Giambartolomei, Kimberly Chambert, Arne E. Vaaler, William Coryell, Peter R. Schofield, Preben Bo Mortensen, Roel A. Ophoff, Fabian Streit, Manolis Kogevinas, Ingrid Agartz, John Strauss, James L. Kennedy, Anders M. Dale, Stefan Herms, Douglas Blackwood, Torbjørn Elvsåshagen, Bernhard T. Baune, Grant W. Montgomery, Andreas Reif, Fabio Rivas, Andrew McQuillin, Jordan W. Smoller, Chun Chieh Fan, James B. Potash, Jun Li, Ketil J. Oedegaard, David Curtis, Martin Schalling, John R. Kelsoe, Valentina Escott-Price, Sascha B. Fischer, Tatyana Shehktman, Jonathan R. I. Coleman, Stanley J. Watson, Donald J. MacIntyre, Tune H. Pers, Eystein Stordal, Richard M. Myers, Jose Guzman-Parra, Danielle Posthuma, John I. Nurnberger, William Lawson, Janet L. Sobell, Felecia Cerrato, Judith A. Badner, Elliot S. Gershon, Gerome Breen, Naomi R. Wray, Thomas Werge, Lilijana Oruc, Claire Slaney, Anil P.S. Ori, Alexander W. Charney, Marianne Giørtz Pedersen, Marie Bækvad-Hansen, Michael Boehnke, Marcella Rietschel, George Kirov, Aiden Corvin, Piotr M. Czerski, Peter Holmans, Michael Steffens, Margarita Rivera, Maria Grigoroiu-Serbanescu, René S. Kahn, Laura M. Huckins, Monika Budde, Michael Gill, Lili Milani, Christiaan de Leeuw, Peng Zhang, Nicholas Bass, Jana Strohmaier, John P. Rice, Wei Xu, Cristiana Cruceanu, Vassily Trubetskoy, Philip B. Mitchell, Helena Medeiros, Thomas Damm Als, Anna C. Koller, Huda Akil, Jessica S. Johnson, Toni-Kim Clarke, Janice M. Fullerton, Guy A. Rouleau, Fernando S. Goes, Weihua Guan, Wolfgang Maier, Pamela Sklar, Diego Albani, Laura J. Scott, Pamela B. Mahon, Anna Maaser, Katherine Gordon-Smith, Urban Ösby, Jurgen Del-Favero, Jolanta Lissowska, Howard J. Edenberg, Sven Cichon, Annelie Nordin Adolfsson, Julie Garnham, Josef Frank, Hoang T. Nguyen, Michael Bauer, Helmut Vedder, Vishwajit L. Nimgaonkar, Loes M. Olde Loohuis, Thomas G. Schulze, Cristina Sánchez-Mora, Udo Dannlowski, Rolf Adolfsson, Benjamin M. Neale, Verneri Antilla, Andrea Pfennig, John B. Vincent, Niamh Mullins, Per Hoffmann, Peter McGuffin, Erlend Bøen, Ney Alliey-Rodriguez, Adebayo Anjorin, Fermín Mayoral, Arianna Di Florio, Claire Churchhouse, David M. Hougaard, Nicholas J. Schork, Tiffany A. Greenwood, Carlos N. Pato, Thorgeir E. Thorgeirsson, Nicholas John Craddock, Stephanie H. Witt, Liam Abbott, Swapnil Awasthi, Miquel Casas, Jonas Bybjerg-Grauholm, Cathryn M. Lewis, Srdjan Djurovic, Bruno Etain, Margit Burmeister, Phil Lee, Elaine K. Green, Sara A. Paciga, Lena Backlund, Engilbert Sigurdsson, Patrick F. Sullivan, Amy Perry, Pablo Cervantes, Marco P. Boks, Catharina Lavebratt, Andrew M. McIntosh, Panos Roussos, Enda M. Byrne, Alexander Richards, Eli A. Stahl, Stéphane Jamain, Hreinn Stefansson, Ole Mors, Esben Agerbo, Susan L. McElroy, Wade H. Berrettini, Peter P. Zandi, Lisa Jones, Andreas J. Forstner, Alessandro Serretti, Céline S. Reinbold, Robert C. Thompson, Matthew Flickinger, William Byerley, Michael John Owen, Helena Gaspar, Francis J. McMahon, David St Clair, Mark A. Frye, Christine Søholm Hansen, Scott D. Gordon, Mikael Landén, Gustavo Turecki, Simon Xi, Evaristus A. Nwulia, Anders Juréus, James Boocock, Stacy Steinberg, Paul D. Shilling, David Craig, Mark J. Daly, Sarah E. Medland, Marion Leboyer, Chunyu Liu, Carsten Bøcker Pedersen, Sebastian Zöllner, APH - Mental Health, Psychiatry, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Stahl E.A., Breen G., Forstner A.J., McQuillin A., Ripke S., Trubetskoy V., Mattheisen M., Wang Y., Coleman J.R.I., Gaspar H.A., de Leeuw C.A., Steinberg S., Pavlides J.M.W., Trzaskowski M., Byrne E.M., Pers T.H., Holmans P.A., Richards A.L., Abbott L., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Anjorin A., Antilla V., Awasthi S., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Belliveau R., Bergen S.E., Pedersen C.B., Boen E., Boks M.P., Boocock J., Budde M., Bunney W., Burmeister M., Bybjerg-Grauholm J., Byerley W., Casas M., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Churchhouse C., Clarke T.-K., Coryell W., Craig D.W., Cruceanu C., Curtis D., Czerski P.M., Dale A.M., de Jong S., Degenhardt F., Del-Favero J., DePaulo J.R., Djurovic S., Dobbyn A.L., Dumont A., Elvsashagen T., Escott-Price V., Fan C.C., Fischer S.B., Flickinger M., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Pedersen M.G., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Guzman-Parra J., Hamshere M.L., Hautzinger M., Heilbronner U., Herms S., Hipolito M., Hoffmann P., Holland D., Huckins L., Jamain S., Johnson J.S., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koller A.C., Kupka R., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Liu C., Lucae S., Maaser A., MacIntyre D.J., Mahon P.B., Maier W., Martinsson L., McCarroll S., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Meng F., Milani L., Montgomery G.W., Morris D.W., Muhleisen T.W., Mullins N., Nguyen H., Nievergelt C.M., Adolfsson A.N., Nwulia E.A., O'Donovan C., Loohuis L.M.O., Ori A.P.S., Oruc L., Osby U., Perlis R.H., Perry A., Pfennig A., Potash J.B., Purcell S.M., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schork N.J., Shannon Weickert C., Shehktman T., Shilling P.D., Sigurdsson E., Slaney C., Smeland O.B., Sobell J.L., Soholm Hansen C., Spijker A.T., St Clair D., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Thompson R.C., Thorgeirsson T.E., Treutlein J., Vedder H., Wang W., Watson S.J., Weickert T.W., Witt S.H., Xi S., Xu W., Young A.H., Zandi P., Zhang P., Zollner S., Adolfsson R., Agartz I., Alda M., Backlund L., Baune B.T., Bellivier F., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Borglum A.D., Corvin A., Craddock N., Daly M.J., Dannlowski U., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., Gill M., Goes F., Grigoroiu-Serbanescu M., Hauser J., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Posthuma D., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Werge T., Nurnberger J.I., Wray N.R., Di Florio A., Edenberg H.J., Cichon S., Ophoff R.A., Scott L.J., Andreassen O.A., Kelsoe J., Sklar P., eQTLGen Consortium, BIOS Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, and Complex Trait Genetics

Subjects
Male, Bipolar Disorder, Bipolar I disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, VARIANTS, Bipolar II disorder, 0302 clinical medicine, SCHIZOPHRENIA, GWAS, Psychotic Disorders/genetics, Non-U.S. Gov't, RISK, Genetics, 0303 health sciences, HERITABILITY, Research Support, Non-U.S. Gov't, Systems Biology, Major/genetics, Single Nucleotide, 3. Good health, Schizophrenia, Major depressive disorder, Female, Case-Control Studie, Depressive Disorder, Major/genetics, Human, Psychosis, GENES, Biology, Psychotic Disorder, Research Support, Polymorphism, Single Nucleotide, Article, Bipolar Disorder/classification, N.I.H, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Journal Article, POLYGENICITY, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, METAANALYSIS, 030304 developmental biology, Intramural, Depressive Disorder, Major, Depressive Disorder, Genetic heterogeneity, Research Support, N.I.H., Intramural, medicine.disease, INDIVIDUALS, Psychotic Disorders, Genetic Loci, Case-Control Studies, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, Meta-Analysis
Abstract

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu)., Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P, This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch.

Published
2019
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15. Evidence that duplications of 22q11.2 protect against schizophrenia

Author

M. T. Pato, Michael Gill, Patrick F. Sullivan, Harald H H Göring, Kimberly Chambert, Alan R. Sanders, Christina M. Hultman, Francis A. O'Neill, Douglas F. Levinson, Aiden Corvin, Ian Jones, Pamela Sklar, Pablo V. Gejman, Michael John Owen, Sophie E. Legge, Geraint Davies, Winton Moy, Michael Conlon O'Donovan, Jennifer L. Moran, Elaine K. Green, Derek W. Morris, Paul Cormican, Alexander Richards, Jubao Duan, George Kirov, Elliott Rees, Steven A. McCarroll, Giulio Genovese, Carlos N. Pato, Jing Shi, Kenneth S. Kendler, Nicholas John Craddock, Jin P. Szatkiewicz, Colm O'Dushlaine, James T.R. Walters, and Brien P. Riley

Subjects
Male, DNA Copy Number Variations, Chromosomes, Human, Pair 22, CNV, Population, 22q11.2, Biology, Bioinformatics, medicine.disease_cause, Structural variation, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, DiGeorge syndrome, Chromosome Duplication, mental disorders, Gene duplication, DiGeorge Syndrome, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Copy-number variation, education, Molecular Biology, Genetics, education.field_of_study, Mutation, medicine.disease, Phenotype, schizophrenia, Psychiatry and Mental health, duplication, Schizophrenia, RC0321, Female, Immediate Communication, protective
Abstract

A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.

Published
2013
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16. NovelATP2A2mutations in a large sample of individuals with Darier disease

Author

Nicholoas Craddock, Katherine Gordon-Smith, Susan Burge, Sherine Tavadia, Colin S. Munro, Detelina Grozeva, Elaine K. Green, and Lisa Jones

Subjects
Male, Genetics, Dermatology, General Medicine, Biology, Polymerase Chain Reaction, Pedigree, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Large sample, Pathogenesis, Darier Disease, ATP2A2, Mutation, Humans, Coding region, Female, Genetic Predisposition to Disease
Abstract

Darier disease (DD) is a rare autosomal dominantly inherited skin disorder caused by mutations in ATP2A2, which is expressed in both the skin and the brain and encodes for SERCA2. We have screened the coding regions of ATP2A2 in a total of 95 unrelated individuals with DD to identify the pathogenic mutations. We identified 66 potentially pathogenic mutations in ATP2A2 for 74 of the 95 individuals with DD of which 45 (68%) are thought to be novel. Forty-nine (74%) are unique to an individual and 17 (26%) were found in more than one individual or overlap with previously identified variants. The results suggest that mutations in ATP2A2 may not be as family-specific as first thought. The spectrum of mutations identified will inform understanding of the pathogenesis of DD.

Published
2013
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17. Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype

Author

Katherine Gordon-Smith, Michael Conlon O'Donovan, E. Russell, Nicholas John Craddock, Damjan Vukcevic, Nadine Norton, Christine Fraser, I. N. Ferrier, Lisa Jones, Michael John Owen, Valentina Moskvina, Peter Donnelly, D. A. Collier, A. H. Young, Detelina Grozeva, Elaine K. Green, Peter Holmans, Anne Farmer, Sian Caesar, Peter McGuffin, Ivan Nikolov, George Kirov, Ian Jones, D. St Clair, G. D. Breen, and Marian L. Hamshere

Subjects
Adult, Male, Psychosis, Bipolar Disorder, Adolescent, Statistics as Topic, Population, GABRA5, GABRA4, Schizoaffective disorder, Genome-wide association study, Polymorphism, Single Nucleotide, Article, Young Adult, Cellular and Molecular Neuroscience, Gene Frequency, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, education, Molecular Biology, Aged, Genetics, education.field_of_study, biology, Middle Aged, Receptors, GABA-A, medicine.disease, Psychiatry and Mental health, Phenotype, Schizophrenia, biology.protein, Female, Chromosomes, Human, Pair 4, Psychology, Neuroscience, Genome-Wide Association Study
Abstract

Despite compelling evidence for a major genetic contribution to risk of bipolar mood disorder, conclusive evidence implicating specific genes or pathophysiological systems has proved elusive. In part this is likely to be related to the unknown validity of current phenotype definitions and consequent aetiological heterogeneity of samples. In the recent Wellcome Trust Case Control Consortium genome-wide association analysis of bipolar disorder (1868 cases, 2938 controls) one of the most strongly associated polymorphisms lay within the gene encoding the GABA(A) receptor beta1 subunit, GABRB1. Aiming to increase biological homogeneity, we sought the diagnostic subset that showed the strongest signal at this polymorphism and used this to test for independent evidence of association with other members of the GABA(A) receptor gene family. The index signal was significantly enriched in the 279 cases meeting Research Diagnostic Criteria for schizoaffective disorder, bipolar type (P=3.8 x 10(-6)). Independently, these cases showed strong evidence that variation in GABA(A) receptor genes influences risk for this phenotype (independent system-wide P=6.6 x 10(-5)) with association signals also at GABRA4, GABRB3, GABRA5 and GABRR3. [corrected] Our findings have the potential to inform understanding of presentation, pathogenesis and nosology of bipolar disorders. Our method of phenotype refinement may be useful in studies of other complex psychiatric and non-psychiatric disorders.

Published
2016
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18. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Morris J. Brown, Sanjeev S. Bhaskar, Alison J. Coffey, Suzanne Rafelt, Kirsten McLay, John Bowes, Francesca Bredin, Alastair Compston, John C. Mansfield, Elaine R. Nimmo, Kate Downes, Peter McGuffin, Neil Walker, Anthony J. Balmforth, Philip Howard, Detelina Grozeva, Helen Stevens, Kate L. Lee, Richard D. Pearson, Gerome Breen, T. Daniel Andrews, Sheila Seal, Anna Elliot, Beverley M. Shields, Andrew T. Hattersley, Sarah Edkins, Ann E. Morgan, Gil McVean, Julian Maller, Millicent A. Stone, Adam Auton, Carol Scott, Michael R. Stratton, Matthew Woodburn, John R. B. Perry, Michael Conlon O'Donovan, Nigel P. Carter, Vincent Plagnol, Stephen Sawcer, Sarah Hines, Mahim Jain, Allan H. Young, Steve Eyre, Elilan Somaskantharajah, Alexander J. Mentzer, Niall Cardin, Eleanor Howard, Inês Barroso, Stephen C. L. Gough, Toby Johnson, Deborah P M Symmons, Christopher Holmes, David St Clair, Patricia B. Munroe, Sue Shaw-Hawkins, Emma Gray, Stephen W. Scherer, Tariq Ahmad, Jaswinder Bull, Debbie Hughes, E. Russell, Timothy M. Frayling, Chris Clee, I. Nicol Ferrier, James Lee, Dominic P. Kwiatkowski, Husam Hebaishi, Anne Hinks, Simon Myers, Gareth Evans, Eleftheria Zeggini, Katarina Spanova, Michael L. Mimmack, David M. Reid, Amanda J. Bennett, Richard T. Scott, Armand Valsesia, Derek P. Jewell, Andrew P. Morris, Peter Donnelly, Mark J. Caulfield, Jake K. Byrnes, Lars Feuk, Pile Harrison, Anna F. Dominiczak, Cathryn Edwards, Andrew Dunham, Dalila Pinto, Inga Prokopenko, Ian Jones, Craig Mowat, Nigel R. Ovington, Willem H. Ouwehand, Edward Flynn, Jason D. Cooper, Louise V. Wain, Alistair Forbes, Bernadette Ebbs, Jennifer Jolley, Jonathan Marchini, Peter S. Braund, Ifejinelo Onyiah, Mark Walker, Adrian V. S. Hill, Cordelia Langford, Anne M. Phillips, George Kirov, David P. Strachan, Oliver S. Burren, Martin D. Tobin, Anthony G. Wilson, Ian N. Bruce, Hana Lango-Allen, Alistair S. Hall, Natalie J. Prescott, Charles Lee, Clare Turnbull, Cecilia M. Lindgren, John D. Isaacs, Jack Satsangi, Liz Forty, John M. C. Connell, Neelam Hassanali, Hazel E. Drummond, Matthew A. Brown, John A. Todd, Joanna M. M. Howson, Jennifer G. Sambrook, Graham A. Hitman, Michael N. Weedon, Christopher Yau, Abiodun Onipinla, Kathy Stirrups, Chris Tyler-Smith, Darshna Dudakia, G. Mark Lathrop, Katherine Gordon-Smith, Nazneen Rahman, Christopher J. Groves, William G. Newman, Kirstie Parnell, Stephen G. Ball, Tomas W Fitzgerald, Paul Gilbert, Kevin Lewis, Charlie W. Lees, Polly Gibbs, Rachel M. Freathy, Aarno Palotie, Katarzyna Blaszczyk, Matthew E. Hurles, Jonathan Stephens, Lynne J. Hocking, Nicholas A. Watkins, Christopher G. Mathew, Helen Schuilenburg, David Pernet, Eleni Giannoulatou, Kimmo Palin, Nigel W. Rayner, Donald F. Conrad, Susan M. Ring, John R. Thompson, Debbie J. Smyth, Wendy L. McArdle, B. Paul Wordsworth, David M. Evans, Dunecan Massey, Naomi Hammond, Diana Eccles, Panos Deloukas, Sian Caesar, Chris P. Barnes, Sophia Steer, Anthony Attwood, Chris Wallace, Richard Redon, Paul Burton, Anne Barton, Marcus Pembrey, Michael John Owen, Jane Worthington, Mary E. Travers, Jeremy D. Sanderson, Meeta Maisuria-Armer, Elaine K. Green, Michael A. Quail, Oliver J. Brand, Anne Farmer, Matthew J. Simmonds, Neil Robertson, Nicholas John Craddock, Zhan Su, Jan Aerts, Martin Farrall, Hazel Arbury, Damjan Vukcevic, Paul Emery, Omer Gokumen, A Hall, Wendy Thomson, Jeffrey C. Barrett, Margaret Warren-Perry, Rhian Gwilliam, Sarah E. Hunt, Samuel Robson, Paul Martin, Audrey Duncanson, Anthony Renwick, John Webster, Lisa Jones, Mark I. McCarthy, Nilesh J. Samani, Matthew Hardy, Miles Parkes, John Burton, Jayne A. Franklyn, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Statistics [Oxford], University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], The Wellcome Trust Case Control Consortium, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], and Medical Research Council (MRC)

Subjects
endocrine system diseases, [SDV]Life Sciences [q-bio], Genome-wide association study, Pilot Projects, CCL3L1, SUSCEPTIBILITY, Arthritis, Rheumatoid, Diabetes mellitus genetics, 0302 clinical medicine, Crohn Disease, Gene Frequency, DUPLICATIONS, SCHIZOPHRENIA, Disease, Copy-number variation, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Multidisciplinary, PSORIASIS, HERITABILITY, LARGE-SCALE, Nucleic Acid Hybridization, Science & Technology - Other Topics, Wellcome Trust Case Control Consortium, Quality Control, DNA Copy Number Variations, General Science & Technology, Single-nucleotide polymorphism, COPY-NUMBER VARIATION, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, MD Multidisciplinary, mental disorders, Genetic predisposition, Diabetes Mellitus, SNP, Humans, Genetic Predisposition to Disease, Allele frequency, POLYMORPHISMS, 030304 developmental biology, Genetic association, Science & Technology, MULTIDISCIPLINARY SCIENCES, DELETION, C431 Medical Genetics, Case-Control Studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Published
2016
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19. Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case–control sample

Author

Detelina Grozeva, Peter Holmans, Jennifer L. Moran, Shaun Purcell, Elaine K. Green, Pamela Sklar, Michael Conlon O'Donovan, Nicholas John Craddock, Ian Jones, Lisa Jones, Katherine Gordon-Smith, Liz Forty, Christine Fraser, George Kirov, M. J. Owen, E. Russell, and Marian L. Hamshere

Subjects
Genetics, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Linkage disequilibrium, SNP, Single-nucleotide polymorphism, Genome-wide association study, ANK3, Biology, Molecular Biology, Genotyping Techniques, Genotyping, SNP genotyping
Abstract

We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value

Published
2012
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20. Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms

Author

Dessa Sadovnick, Elliot S. Gershon, Derek W. Morris, Jessica Ross, George Kirov, John R. Kelsoe, Alan W Maclean, William Byerley, William M. McMahon, Reid Robinson, Tatiana Foroud, John I. Nurnberger, Muhammad Ayub, Peter P. Zandi, Douglas Blackwood, James B. Potash, Michael Gill, Judith A. Badner, Howard J. Edenberg, Lisa Jones, Ronald A. Remick, Marian L. Hamshere, Chunyu Liu, Francis J. McMahon, Detelina Grozeva, Gholson J. Lyon, Paul E. Keck, Virginia L. Willour, Ricardo Segurado, Ian Jones, Daniel L. Koller, Nicholas John Craddock, and Elaine K. Green

Subjects
Bipolar Disorder, Genotype, 2q12, Genetic Linkage, Bipolar disorder, Single Nucleotide Polymorphisms, Single-nucleotide polymorphism, Pedigree chart, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 9q21, Single-nucleotide polymorphisms, White People, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Centimorgan, Whole genome linkage, Genetic linkage, Humans, Genetic Predisposition to Disease, Molecular Biology, Genotyping, 030304 developmental biology, Genetics, Linkage (software), Depressive Disorder, Major, 0303 health sciences, 030305 genetics & heredity, Pedigree, 6q21, 3. Good health, Psychiatry and Mental health, Psychotic Disorders, Microsatellite, Genome-wide linkage analysis, Genome-Wide Association Study
Abstract

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the similar to 1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing. Molecular Psychiatry (2012) 17, 818-826; doi:10.1038/mp.2011.89; published online 19 July 2011

Published
2011
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21. Polygenic dissection of the bipolar phenotype

Author

Michael Conlon O'Donovan, I. N. Ferrier, Pamela Sklar, Detelina Grozeva, Peter Holmans, Peter McGuffin, A. H. Young, Hugh Gurling, N Bass, Andrew McQuillin, George Kirov, Ian Jones, D. St Clair, Michael John Owen, Valentina Moskvina, Anne Farmer, Marian L. Hamshere, Shaun Purcell, Lisa Jones, Elaine K. Green, and Nicholas John Craddock

Subjects
Multifactorial Inheritance, Psychosis, medicine.medical_specialty, Bipolar Disorder, Adolescent, Genotype, Genetic Linkage, Research Diagnostic Criteria, Genome-wide association study, Polymorphism, Single Nucleotide, Genetic determinism, 03 medical and health sciences, 0302 clinical medicine, International Classification of Diseases, mental disorders, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Bipolar disorder, Psychiatry, Alleles, medicine.disease, United Kingdom, 030227 psychiatry, Diagnostic and Statistical Manual of Mental Disorders, Psychiatry and Mental health, Logistic Models, Phenotype, Psychotic Disorders, Schizophrenia, Case-Control Studies, Papers, sense organs, Psychology, Clinical psychology, Psychopathology
Abstract

BackgroundRecent data provide strong support for a substantial common polygenic contribution (i.e. many alleles each of small effect) to genetic susceptibility for schizophrenia and overlapping susceptibility for bipolar disorder.AimsTo test hypotheses about the relationship between schizophrenia and psychotic types of bipolar disorder.MethodUsing a polygenic score analysis to test whether schizophrenia polygenic risk alleles, en masse, significantly discriminate between individuals with bipolar disorder with and without psychotic features. The primary sample included 1829 participants with bipolar disorder and the replication sample comprised 506 people with bipolar disorder.ResultsThe subset of participants with Research Diagnostic Criteria schizoaffective bipolar disorder (n = 277) were significantly discriminated from the remaining participants with bipolar disorder (n = 1552) in both the primary (P = 0.00059) and the replication data-sets (P = 0.0070). In contrast, those with psychotic bipolar disorder as a whole were not significantly different from those with non-psychotic bipolar disorder in either data-set.ConclusionsGenetic susceptibility influences at least two major domains of psychopathological variation in the schizophrenia–bipolar disorder clinical spectrum: one that relates to expression of a ‘bipolar disorder-like’ phenotype and one that is associated with expression of ‘schizophrenia-like’ psychotic symptoms.

Published
2011
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22. Identification of high risk DISC1 protein structural variants in patients with bipolar spectrum disorder

Author

Steve S. Sommer, Jeff Longmate, Wenjia Song, Wen Yan Li, Jin Yan, Elaine K. Green, Ian Jones, Nicholas John Craddock, Katie Noltner, Jinong Feng, and Detelina Valentinova Grozeva

Subjects
Adult, Male, Linkage disequilibrium, Bipolar Disorder, Nerve Tissue Proteins, Risk Assessment, Linkage Disequilibrium, Translocation, Genetic, Cohort Studies, DISC1, DISC2, medicine, Humans, Genetic Predisposition to Disease, Spectrum disorder, Bipolar disorder, Genetics, biology, General Neuroscience, Haplotype, Genetic Variation, Odds ratio, medicine.disease, Scotland, Schizophrenia, Case-Control Studies, biology.protein, Female, Psychology
Abstract

In a large Scottish pedigree, a balanced translocation t (1;11)(q42.1;q14.3) disrupting the DISC1 and DISC2 genes segregates with major mental illness, including schizophrenia and depression. A frame-shift carboxyl-terminal deletion was reported in DISC1 in an American family with schizophrenia, but subsequently found in two controls. Herein, we test one hypothesis utilizing a large scale case-control mutation analysis: uncommon DISC1 variants are associated with high risk for bipolar spectrum disorder. We have analyzed the regions of likely functional significance in the DISC1 gene in 504 patients with bipolar spectrum disorder and 576 ethnically similar controls. Five patients were heterozygous for ultra-rare protein structural variants not found in the 576 controls (p=0.02, one-sided Fisher's exact test) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. In our sample, ultra-rare (private) protein structural variants in DISC1 are associated with an estimated attributable risk of about 0.5% in bipolar spectrum disorder. These data are consistent with: (i) the high frequency of depression in the large Scottish family with a translocation disrupting DISC1; (ii) linkage disequilibrium analysis demonstrating haplotypes associated with relatively small increases in risk for bipolar disorder (

Published
2010
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23. Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept

Author

Allan H. Young, David A. Collier, Christine Fraser, Michael Conlon O'Donovan, I. N. Ferrier, Peter McGuffin, E. Russell, Katherine Gordon-Smith, Ian Jones, Marian L. Hamshere, Lisa Jones, George Kirov, D. St Clair, Damjan Vukcevic, Sian Caesar, Valentina Moskvina, Anne Farmer, Detelina Grozeva, Peter Holmans, Gerome Breen, Elaine K. Green, Ivan Nikolov, Nicholas John Craddock, and M. J. Owen

Subjects
Adult, Male, Bipolar Disorder, Bipolar I disorder, Adolescent, Genotype, Research Diagnostic Criteria, Genome-wide association study, Schizoaffective disorder, Polymorphism, Single Nucleotide, Genetic determinism, Young Adult, 03 medical and health sciences, Bipolar II disorder, 0302 clinical medicine, mental disorders, medicine, Humans, 030212 general & internal medicine, Bipolar disorder, Aged, Genetic association, Aged, 80 and over, Psychiatric Status Rating Scales, Serotonin Plasma Membrane Transport Proteins, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Case-Control Studies, Papers, Female, Psychology, Genome-Wide Association Study, Clinical psychology
Abstract

BackgroundPsychiatric phenotypes are currently defined according to sets of descriptive criteria. Although many of these phenotypes are heritable, it would be useful to know whether any of the various diagnostic categories in current use identify cases that are particularly helpful for biological–genetic research.AimsTo use genome-wide genetic association data to explore the relative genetic utility of seven different descriptive operational diagnostic categories relevant to bipolar illness within a large UK case–control bipolar disorder sample.MethodWe analysed our previously published Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder genome-wide association data-set, comprising 1868 individuals with bipolar disorder and 2938 controls genotyped for 276 122 single nucleotide polymorphisms (SNPs) that met stringent criteria for genotype quality. For each SNP we performed a test of association (bipolar disorder group v. control group) and used the number of associated independent SNPs statistically significant atPResultsThe RDC schizoaffective disorder, bipolar type (v. controls) stood out from the other diagnostic subsets as having a significant excess of independent association signals (PP= 2.42 × 10–7). Biological systems implicated included gamma amniobutyric acid (GABA)Areceptors. Genes having at least one associated polymorphism atP–4includedB3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2andCDH12.ConclusionsOur findings show that individuals with broadly defined bipolar schizoaffective features have either a particularly strong genetic contribution or that, as a group, are genetically more homogeneous than the other phenotypes tested. The results point to the importance of using diagnostic approaches that recognise this group of individuals. Our approach can be applied to similar data-sets for other psychiatric and non-psychiatric phenotypes.

Published
2009
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24. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia

Author

Anne Farmer, Elaine K. Green, Nicholas John Craddock, M. J. Owen, Christine Fraser, Ian Jones, Michael Conlon O'Donovan, Marian L. Hamshere, Peter McGuffin, George Kirov, Valentina Moskvina, Liz Forty, Detelina Grozeva, Peter Holmans, E. Russell, Ivan Nikolov, Sian Caesar, Lisa Jones, and Katherine Gordon-Smith

Subjects
Nosology, Adult, Male, medicine.medical_specialty, Calcium Channels, L-Type, Genotype, nosology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Recurrence, Risk Factors, medicine, Humans, genetics, Bipolar disorder, ANK3, unipolar depression, Psychiatry, Molecular Biology, Alleles, 030304 developmental biology, Genetic association, bipolar disorder, 0303 health sciences, Depressive Disorder, Major, Odds ratio, Middle Aged, medicine.disease, Mental illness, United Kingdom, 3. Good health, schizophrenia, Psychiatry and Mental health, Mood, Phenotype, classification, Schizophrenia, Original Article, Female, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10(-7)) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ∼1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data.

Published
2009

25. Genome-wide association study identifies eight loci associated with blood pressure

Author

Peter Holmans, Udo Seedorf, Beverley M. Shields, Peter McGruffin, Arne Pfeufer, Steve Eyre, Nathalie J. Prescott, Michael Boehnke, Valentina Moskovina, Abiodun Onipinla, Leena Peltonen, Nadira Yuldasheva, Peter M. Nilsson, Valeria Romanazzi, Vincent Mooser, Göran Berglund, Alistair S. Hall, Dominic P. Kwiatkowski, Barry Widmer, Benjamin F. Voight, Stefania Bandinelli, Mark M. Iles, Sven Bergmann, Thomas Meitinger, James P. Boorman, Simonetta Guarrera, Nazneen Rahman, Murielle Bochud, Graham A. Hitman, Emma Keniry, Nelson B. Freimer, Richard Dobson, Francis S. Collins, Gerjan Navis, Jennifer L. Pointon, Richard N. Bergman, Ruth J. F. Loos, Roberto Lorbeer, Carolina A. Braga Marcano, Christian Gieger, Florian Ernst, Xin Yuan, Catherine Potter, Hazel E. Drummond, Allan H. Young, George Kirov, John F. Peden, Helen Stevens, David Clayton, Mattijs E. Numans, Katherine Gordon-Smith, Anne Farmer, Alastair Forbes, M. Khalid Mohiuddin, John A. Todd, Christopher G. Mathew, David A. Collier, Mark I. McCarthy, Francesca Bredin, Clive M. Onnie, Dan Davidson, Markus Perola, Pamela Whittaker, Yvonne T. van der Schouw, Rathi Ravindrarajan, I. C.A. Spencer, Teresa Ferreira, Nilesh J. Samani, Serge Hercberg, Gonçalo R. Abecasis, Christopher J. Groves, Nicholas John Craddock, Angela Döring, Edward G. Lakatta, Muminatou Jallow, Wendy L. McArdle, David Bentley, Susana Eyheramendy, Uwe Völker, Christopher Newton-Cheh, Jaspal S. Kooner, Hugh Watkins, Gavin Lucas, H. T. Leung, Marjo Ritta Jarvelin, Johanna Kuusisto, Wiek H. van Gilst, Wendy Thomson, Lou R. Cardon, Harold Snieder, Marju Orho-Melander, Patricia B. Munroe, Toshiko Tanaka, Jeffrey C. Barrett, Azhar Maqbool, Henry Völzke, John M. C. Connell, Elaine R. Nimmo, John R. B. Perry, Michael R. Stratton, Ralph McGinnis, Pekka Jousilahti, Michiel L. Bots, Ian Jones, Elizabeth Meech, Matthew A. Brown, Johannie Gungadoo, Jian'an Luan, Jilur Ghori, Richard J. Dixon, N. Charlotte Onland-Moret, Fulvio Ricceri, Anthony J. Balmforth, Catherine E. Todhunter, Inês Barroso, Sheila Bingham, Timo T. Valle, Fredrik O. Vannberg, Diana Zelenika, Stephen Sawcer, Anneli Pouta, David M. Evans, Cuno S. P. M. Uiterwaal, Pilar Galan, Georg Homuth, Hannah Donovan, David J. Conway, Paul Elliott, Alessandra Allione, Paul E. de Jong, Miles Parkes, Amy Chaney, John C. Chambers, Toby Johnson, Isaac Subirana, Vesela Gateva, Cathryn M. Lewis, Christopher J. O'Donnell, Hana Lango, David Schlessinger, Mark J. Caulfield, Thorsten Reffelmann, Jamie Barbour, Karen L. Mohlke, Sarah E. Hunt, Thilo Winzer, Frances M K Williams, Christopher Mathew, I. Wallace, Anuj Goel, Jaakko Tuomilehto, Louise V. Wain, Gabriel Crawford, Samantha L. Hider, Detelinea Grozeva, Elaine K. Green, Paul D. Gilbert, Peter S. Braund, Jaume Marrugat, Rainer Rettig, Pim van der Harst, Yik Ying Teo, Andrew P. Morris, Guiseppe Matullo, Serena Sanna, Cristen J. Willer, Suzannah Bumpstead, Niall C. Taylor, Jacques S. Beckmann, Pierre Meneton, Elin Org, Luigi Ferrucci, Doug Easton, Sheila Seal, Joanne M. Heward, Anne U. Jackson, Eleftheria Zeggini, Rachel M. Freathy, Maris Laan, Paul Wordsworth, Sarah Nutland, Kerstin Koch, Sian Ceasar, Anders Hamsten, Judith M. Hussey, Tariq Ahmad, Derek P. Jewell, Paul Scheet, Charlie W. Lees, C Farrar, Christopher Prowse, Markku Laakso, David St Clair, Kate Downes, Diederick E. Grobbee, Paul Burton, Simon C. Potter, Ian N. Bruce, Tim D. Spector, Anne Barton, H.-Erich Wichmann, Matthew J. Simmonds, David Hadley, Cecilia M. Lindgren, Gérard Waeber, Nigel W. Rayner, Melanie J. Newport, Manjinder S. Sandhu, Audrey Duncanson, Guangju Zhai, Simon Heath, Susan M. Ring, Alessandra Di Gregorio, Richard Williamson, Nicholas J. Wareham, Zhan Su, Olle Melander, John R. Thompson, Alexander Teumer, Sheila A. Fisher, Lachlan J. M. Coin, Leif Groop, Giovanni Tognoni, Amanda Elkin, Alan J. Silman, Jack Satsangi, Jane Worthington, Martin Farrall, John Webster, Niall Cardin, Neil Walker, Anna F. Dominiczak, Jeremy D. Sanderson, Damjan Vukcevic, Bryan Howie, Silvia Polidoro, Stephen G. Ball, Mark Tremelling, Stephen Newhouse, Stephen M. Schwartz, Lori L. Bonnycastle, Chris Wallace, Kijoung Song, Mario A. Morken, I. Nicol Ferrier, Beverley Barke, Paolo Vineis, Manuela Uda, Deborah P M Symmons, Emily J. Lyons, Mingzhan Xue, Timothy M. Frayling, Stephen C.L. Cough, David Withers, Adrian V. S. Hill, Suzanne Stevens, Jennifer Jolley, Marcus Dörr, Kirk A. Rockett, David B. Dunger, Mark Walker, Jayne A. Franklyn, Lisa Jones, David S. Siscovick, Ann-Christine Syvänen, Laura J. Scott, Morris J. Brown, Barbera Cant, Michael Inouye, Feng Zhang, Carlotta Sacerdote, Katherine S. Elliott, Jonathan Marchini, Peter Donnely, Michael John Owen, An Goris, Marcus Prembey, Andrew T. Hattersley, Gerome Breen, Marian L. Hamshere, Thomas Illig, Samer S. Najjar, Nicole Soranzo, Kay-Tee Khaw, Graham R. Walters, Willem H. Ouwehand, David P. Strachan, Martin D. Tobin, Alastair Compston, John C. Mansfield, David Altshuler, Salvatore Panico, Sekar Kathiresan, Dawn M. Waterworth, Michael N. Weedon, D. Timothy Bishop, Claire Bryan, Alexandra S. Knight, Kate L. Lee, Paul F. O'Reilly, Massimo Mangino, Michael Conlon O'Donovan, Jing Hua Zhao, Konstantinos A. Papadakis, Jennifer H. Barrett, Joanne Pereira-Gale, N J Timpson, Stephan B. Felix, Panos Deloukas, Nicholas A. Watkins, Anna-Liisa Hartikainen, Peter Vollenweider, Richard Jones, Anne Hinks, Fraser Cummings, Noha Lim, Linda A. Bradbury, Rhian G. William, Nita G. Forouhi, Roberto Eluosa, Ingeleif B. Hallgrimsdottir, Giorgio Sirugo, Robert Luben, Veikko Salomaa, Robert Clarke, Sally John, Ursula Everson, Emma King, Ivan Nikolov, Heather M. Stringham, Antony P. Attwood, Angelo Scuteri, Wellcome Trust Case Control Consortium, Burton, PR., Clayton, DG., Cardon, LR., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, DP., McCarthy, MI., Ouwehand, WH., Samani, NJ., Todd, JA., Donnelly, P., Barrett, JC., Davison, D., Easton, D., Evans, D., Leung, HT., Marchini, JL., Morris, AP., Spencer, IC., Tobin, MD., Attwood, AP., Boorman, JP., Cant, B., Everson, U., Hussey, JM., Jolley, JD., Knight, AS., Koch, K., Meech, E., Nutland, S., Prowse, CV., Stevens, HE., Taylor, NC., Walters, GR., Walker, NM., Watkins, NA., Winzer, T., Jones, RW., McArdle, WL., Ring, SM., Strachan, DP., Pembrey, M., Breen, G., St Clair, D., Caesar, S., Gordon-Smith, K., Jones, L., Fraser, C., Green, EK., Grozeva, D., Hamshere, ML., Holmans, PA., Jones, IR., Kirov, G., Moskvina, V., Nikolov, I., O'Donovan, MC., Owen, MJ., Collier, DA., Elkin, A., Farmer, A., Williamson, R., McGuffin, P., Young, AH., Ferrier, IN., Ball, SG., Balmforth, AJ., Barrett, JH., Bishop, DT., Iles, MM., Maqbool, A., Yuldasheva, N., Hall, AS., Braund, PS., Dixon, RJ., Mangino, M., Stevens, S., Thompson, JR., Bredin, F., Tremelling, M., Parkes, M., Drummond, H., Lees, CW., Nimmo, ER., Satsangi, J., Fisher, SA., Forbes, A., Lewis, CM., Onnie, CM., Prescott, NJ., Sanderson, J., Mathew, CG., Barbour, J., Mohiuddin, MK., Todhunter, CE., Mansfield, JC., Ahmad, T., Cummings, FR., Jewell, DP., Webster, J., Brown, MJ., Lathrop, GM., Connell, J., Dominiczak, A., Braga Marcano, CA., Burke, B., Dobson, R., Gungadoo, J., Lee, KL., Munroe, PB., Newhouse, SJ., Onipinla, A., Wallace, I., Xue, M., Caulfield, M., Farrall, M., Barton, A., Bruce, IN., Donovan, H., Eyre, S., Gilbert, PD., Hider, SL., Hinks, AM., John, SL., Potter, C., Silman, AJ., Symmons, DP., Thomson, W., Worthington, J., Dunger, DB., Widmer, B., Frayling, TM., Freathy, RM., Lango, H., Perry, JR., Shields, BM., Weedon, MN., Hattersley, AT., Hitman, GA., Walker, M., Elliott, KS., Groves, CJ., Lindgren, CM., Rayner, NW., Timpson, NJ., Zeggini, E., Newport, M., Sirugo, G., Lyons, E., Vannberg, F., Hill, AV., Bradbury, LA., Farrar, C., Pointon, JJ., Wordsworth, P., Brown, MA., Franklyn, JA., Heward, JM., Simmonds, MJ., Gough, SC., Seal, S., Stratton, MR., Rahman, N., Ban, M., Goris, A., Sawcer, SJ., Compston, A., Conway, D., Jallow, M., Rockett, KA., Bryan, C., Bumpstead, SJ., Chaney, A., Downes, K., Ghori, J., Gwilliam, R., Hunt, SE., Inouye, M., Keniry, A., King, E., McGinnis, R., Potter, S., Ravindrarajah, R., Whittaker, P., Withers, D., Cardin, NJ., Ferreira, T., Pereira-Gale, J., Hallgrimsdóttir, IB., Howie, BN., Su, Z., Teo, YY., Vukcevic, D., Bentley, D., Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Medical Research Council (MRC)

Subjects
Hemodynamics, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, 0302 clinical medicine, Diastole, 11 Medical and Health Sciences, POPULATION, Genetics, Genetics & Heredity, RISK, 0303 health sciences, education.field_of_study, Econometric and Statistical Methods: General, CELL-DIFFERENTIATION, biology, Intracellular Signaling Peptides and Proteins, Chromosome Mapping, Steroid 17-alpha-Hydroxylase, COMMON VARIANTS, 3. Good health, DNA-Binding Proteins, Europe, Cardiovascular Diseases, PUBLIC-HEALTH, BARTTERS-SYNDROME, Blood Pressure/genetics, Cardiovascular Diseases/genetics, Cardiovascular Diseases/physiopathology, Cytochrome P-450 CYP1A2/genetics, DNA-Binding Proteins/genetics, Diastole/genetics, European Continental Ancestry Group/genetics, Fibroblast Growth Factor 5/genetics, Genetic Variation, Genome-Wide Association Study, Humans, India, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, Open Reading Frames/genetics, Phospholipase C delta/genetics, Polymorphism, Single Nucleotide, Proteins/genetics, Steroid 17-alpha-Hydroxylase/genetics, Systole/genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, hypertension, Fibroblast Growth Factor 5, Systole, Population, European Continental Ancestry Group, METHYLENETETRAHYDROFOLATE REDUCTASE GENE, Single-nucleotide polymorphism, LOW-RENIN HYPERTENSION, White People, Article, 03 medical and health sciences, Open Reading Frames, Fibroblast growth factor-5, Cytochrome P-450 CYP1A2, Geneeskunde(GENK), education, Methylenetetrahydrofolate Reductase (NADPH2), Adaptor Proteins, Signal Transducing, 030304 developmental biology, Genetic association, genome-wide association, Science & Technology, MUTATIONS, Proteins, 06 Biological Sciences, POLYMORPHISM, Blood pressure, Methylenetetrahydrofolate reductase, biology.protein, biology.gene, Phospholipase C delta, Developmental Biology
Abstract

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Published
2009
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26. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author

Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. Barnes, Adebayo Anjorin, O'Dushlaine, C, Rossin, L, Lee, Ph, Duncan, L, Parikshak, Nn, Newhouse, S, Ripke, S, Neale, Bm, Purcell, Sm, Posthuma, D, Nurnberger, Ji, Lee, Sh, Faraone, Sv, Perlis, Rh, Mowry, Bj, Thapar, A, Goddard, Me, Witte, J, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, Oa, Anjorin, A, Anney, R, Anttila, V, Arking, De, Asherson, P, Azevedo, Mh, Backlund, L, Badner, Ja, Bailey, Aj, Banaschewski, T, Barchas, Jd, Barnes, Mr, Barrett, Tb, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, Se, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, Eb, Black, Dw, Blackwood, Dh, Bloss, C, Boehnke, M, Boomsma, Di, Breuer, R, Bruggeman, R, Cormican, P, Buccola, Ng, Buitelaar, Jk, Bunney, We, Buxbaum, Jd, Byerley, Wf, Byrne, Em, Caesar, S, Cahn, W, Cantor, Rm, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, Cichon, S, Mattheisen, M, Cloninger, Cr, Collier, Da, Cook, Eh, Coon, H, Cormand, B, Corvin, A, Coryell, Wh, Craig, Dw, Craig, Iw, Crosbie, J, Cuccaro, Ml, Curtis, D, Czamara, D, Datta, S, Dawson, G, Day, R, De Geus, Ej, Degenhardt, F, Djurovic, S, Donohoe, Gj, Doyle, Ae, Duan, J, Dudbridge, F, Duketis, E, Ebstein, Rp, Edenberg, Hj, Elia, J, Ennis, S, Etain, B, Fanous, A, Farmer, Ae, Ferrier, In, Flickinger, M, Fombonne, E, Foroud, T, Frank, J, Franke, B, Fraser, C, Freedman, R, Freimer, Nb, Freitag, Cm, Friedl, M, Frisén, L, Gallagher, L, Gejman, Pv, Georgieva, L, Gershon, E, Giegling, I, Gill, M, Gordon, Sd, Gordon-Smith, K, Green, Ek, Greenwood, Ta, Grice, De, Gross, M, Grozeva, D, Guan, W, Gurling, H, De Haan, L, Haines, Jl, Hakonarson, H, Hallmayer, J, Hamilton, Sp, Hamshere, Ml, Hansen, Tf, Hartmann, Am, Hautzinger, M, Heath, Ac, Henders, Ak, Herms, S, Hickie, Ib, Hipolito, M, Hoefels, S, Holsboer, F, Hoogendijk, Wj, Hottenga, Jj, Hultman, Cm, Hus, V, Ingason, A, Ising, M, Jamain, S, Jones, Eg, Jones, I, Jones, L, Tzeng, Jy, Kähler, Ak, Kahn, R, Kandaswamy, R, Keller, Mc, Kennedy, Jl, Kenny, E, Kent, L, Kim, Y, Kirov, Gk, Klauck, Sm, Klei, L, Knowles, Ja, Kohli, Ma, Koller, Dl, Konte, B, Korszun, A, Krabbendam, L, Krasucki, R, Kuntsi, J, Kwan, P, Landén, M, Längström, N, Lathrop, M, Lawrence, J, Lawson, Wb, Leboyer, M, Ledbetter, Dh, Lencz, T, Lesch, Kp, Levinson, Df, Lewis, Cm, Li, J, Lichtenstein, P, Lieberman, Ja, Lin, Dy, Linszen, Dh, Liu, C, Lohoff, Fw, Loo, Sk, Lord, C, Lowe, Jk, Lucae, S, Macintyre, Dj, Madden, Pa, Maestrini, E, Magnusson, Pk, Mahon, Pb, Maier, W, Malhotra, Ak, Mane, Sm, Martin, Cl, Martin, Ng, Matthews, K, Mattingsdal, M, Mccarroll, Sa, Mcghee, Ka, Mcgough, Jj, Mcgrath, Pj, Mcguffin, P, Mcinnis, Mg, Mcintosh, A, Mckinney, R, Mclean, Aw, Mcmahon, Fj, Mcmahon, Wm, Mcquillin, A, Medeiros, H, Medland, Se, Meier, S, Melle, I, Meyer, J, Middeldorp, Cm, Middleton, L, Milanova, V, Miranda, A, Monaco, A, Montgomery, Gw, Moran, Jl, Moreno-De-Luca, D, Morken, G, Morris, Dw, Morrow, Em, Moskvina, V, Muglia, P, Mühleisen, Tw, Muir, Wj, Müller-Myhsok, B, Murtha, M, Myers, Rm, Myin-Germeys, I, Neale, Mc, Nelson, Sf, Nievergelt, Cm, Nikolov, I, Nimgaonkar, V, Nolen, Wa, Nöthen, Mm, Nwulia, Ea, Nyholt, Dr, Oades, Rd, Olincy, A, Oliveira, G, Olsen, L, Ophoff, Ra, Osby, U, Owen, Mj, Palotie, A, Parr, Jr, Paterson, Ad, Pato, Cn, Pato, Mt, Penninx, Bw, Pergadia, Ml, Pericak-Vance, Ma, Pickard, B, Pimm, J, Piven, J, Potash, Jb, Poustka, F, Propping, P, Puri, V, Quested, Dj, Quinn, Em, Ramos-Quiroga, Ja, Rasmussen, Hb, Raychaudhuri, S, Rehnström, K, Reif, A, Ribasés, M, Rice, Jp, Rietschel, M, Roeder, K, Roeyers, H, Rothenberger, A, Rouleau, G, Ruderfer, D, Rujescu, D, Sanders, Ar, Sanders, Sj, Santangelo, Sl, Sergeant, Ja, Schachar, R, Schalling, M, Schatzberg, Af, Scheftner, Wa, Schellenberg, Gd, Scherer, Sw, Schork, Nj, Schulze, Tg, Schumacher, J, Schwarz, M, Scolnick, E, Scott, Lj, Shi, J, Shilling, Pd, Shyn, Si, Silverman, Jm, Slager, Sl, Smalley, Sl, Smit, Jh, Smith, En, Sonuga-Barke, Ej, St Clair, D, State, M, Steffens, M, Steinhausen, Hc, Strauss, J, Strohmaier, J, Stroup, T, Sutcliffe, J, Szatmari, P, Szelinger, S, Thirumalai, S, Thompson, Rc, Todorov, Aa, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, Jc, Van Grootheest, G, Van Os, J, Vicente, A, Vieland, Vj, Vincent, Jb, Visscher, Pm, Walsh, Ca, Wassink, Th, Watson, Sj, Weissman, Mm, Werge, T, Wienker, Tf, Wijsman, Em, Willemsen, G, Williams, N, Willsey, Aj, Witt, Sh, Xu, W, Young, Ah, Yu, Tw, Zammit, S, Zandi, Pp, Zhang, P, Zitman, Fg, Zöllner, S, Devlin, B, Kelsoe, Jr, Sklar, P, Daly, Mj, O'Donovan, Mc, Craddock, N, Kendler, K, Weiss, La, Wray, Nr, Zhao, Z, Geschwind, Dh, Sullivan, Pf, Smoller, Jw, Holmans, Pa, Breen, G., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez

Subjects
Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint

Published
2015
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27. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Author

Robert Maier, Gerhard Moser, Guo-Bo Chen, Stephan Ripke, William Coryell, James B. Potash, William A. Scheftner, Jianxin Shi, Myrna M. Weissman, Christina M. Hultman, Mikael Landén, Douglas F. Levinson, Kenneth S. Kendler, Jordan W. Smoller, Naomi R. Wray, S. Hong Lee, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A. Andreassen, Adebayo Anjorin, Richard Anney, Dan E. Arking, Philip Asherson, Maria H. Azevedo, Lena Backlund, Judith A. Badner, Anthony J. Bailey, Tobias Banaschewski, Jack D. Barchas, Michael R. Barnes, Thomas B. Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E. Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B. Binder, Donald W. Black, Douglas H.R. Blackwood, Cinnamon S. Bloss, Michael Boehnke, Dorret I. Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Nancy G. Buccola, Jan K. Buitelaar, William E. Bunney, Joseph D. Buxbaum, William F. Byerley, Sian Caesar, Wiepke Cahn, Rita M. Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C. Robert Cloninger, David A. Collier, Edwin H. Cook, Hilary Coon, Bru Cormand, Paul Cormican, Aiden Corvin, William H. Coryell, Nicholas Craddock, David W. Craig, Ian W. Craig, Jennifer Crosbie, Michael L. Cuccaro, David Curtis, Darina Czamara, Mark J. Daly, Susmita Datta, Geraldine Dawson, Richard Day, Eco J. De Geus, Franziska Degenhardt, Bernie Devlin, Srdjan Djurovic, Gary J. Donohoe, Alysa E. Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P. Ebstein, Howard J. Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Stephen V. Faraone, Anne E. Farmer, I. Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B. Freimer, Christine M. Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V. Gejman, Lyudmila Georgieva, Elliot S. Gershon, Daniel H. Geschwind, Ina Giegling, Michael Gill, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Tiffany A. Greenwood, Dorothy E. Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe De Haan, Jonathan L. Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P. Hamilton, Marian L. Hamshere, Thomas F. Hansen, Annette M. Hartmann, Martin Hautzinger, Andrew C. Heath, Anjali K. Henders, Stefan Herms, Ian B. Hickie, Maria Hipolito, Susanne Hoefels, Peter A. Holmans, Florian Holsboer, Witte J. Hoogendijk, Jouke-Jan Hottenga, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Ian Jones, Lisa Jones, Anna K. Kähler, René S. Kahn, Radhika Kandaswamy, Matthew C. Keller, John R. Kelsoe, James L. Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K. Kirov, Sabine M. Klauck, Lambertus Klei, James A. Knowles, Martin A. Kohli, Daniel L. Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B. Lawson, Marion Leboyer, David H. Ledbetter, Phil H. Lee, Todd Lencz, Klaus-Peter Lesch, Cathryn M. Lewis, Jun Li, Paul Lichtenstein, Jeffrey A. Lieberman, Dan-Yu Lin, Don H. Linszen, Chunyu Liu, Falk W. Lohoff, Sandra K. Loo, Catherine Lord, Jennifer K. Lowe, Susanne Lucae, Donald J. MacIntyre, Pamela A.F. Madden, Elena Maestrini, Patrik K.E. Magnusson, Pamela B. Mahon, Wolfgang Maier, Anil K. Malhotra, Shrikant M. Mane, Christa L. Martin, Nicholas G. Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A. McCarroll, Kevin A. McGhee, James J. McGough, Patrick J. McGrath, Peter McGuffin, Melvin G. McInnis, Andrew McIntosh, Rebecca McKinney, Alan W. McLean, Francis J. McMahon, William M. McMahon, Andrew McQuillin, Helena Medeiros, Sarah E. Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M. Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P. Monaco, Grant W. Montgomery, Jennifer L. Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W. Morris, Eric M. Morrow, Valentina Moskvina, Bryan J. Mowry, Pierandrea Muglia, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael Murtha, Richard M. Myers, Inez Myin-Germeys, Benjamin M. Neale, Stan F. Nelson, Caroline M. Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A. Nolen, Markus M. Nöthen, John I. Nurnberger, Evaristus A. Nwulia, Dale R. Nyholt, Michael C. O’Donovan, Colm O’Dushlaine, Robert D. Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A. Ophoff, Urban Osby, Michael J. Owen, Aarno Palotie, Jeremy R. Parr, Andrew D. Paterson, Carlos N. Pato, Michele T. Pato, Brenda W. Penninx, Michele L. Pergadia, Margaret A. Pericak-Vance, Roy H. Perlis, Benjamin S. Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, Fritz Poustka, Peter Propping, Shaun M. Purcell, Vinay Puri, Digby J. Quested, Emma M. Quinn, Josep Antoni Ramos-Quiroga, Henrik B. Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P. Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R. Sanders, Stephan J. Sanders, Susan L. Santangelo, Russell Schachar, Martin Schalling, Alan F. Schatzberg, Gerard D. Schellenberg, Stephen W. Scherer, Nicholas J. Schork, Thomas G. Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J. Scott, Joseph A. Sergeant, Paul D. Shilling, Stanley I. Shyn, Jeremy M. Silverman, Pamela Sklar, Susan L. Slager, Susan L. Smalley, Johannes H. Smit, Erin N. Smith, Edmund J.S. Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S. Strauss, Jana Strohmaier, T. Scott Stroup, Patrick F. Sullivan, James Sutcliffe, Peter Szatmari, Szabocls Szelinger, Anita Thapar, Srinivasa Thirumalai, Robert C. Thompson, Alexandre A. Todorov, Federica Tozzi, Jens Treutlein, Jung-Ying Tzeng, Manfred Uhr, Edwin J.C.G. van den Oord, Gerard Van Grootheest, Jim Van Os, Astrid M. Vicente, Veronica J. Vieland, John B. Vincent, Peter M. Visscher, Christopher A. Walsh, Thomas H. Wassink, Stanley J. Watson, Lauren A. Weiss, Thomas Werge, Thomas F. Wienker, Durk Wiersma, Ellen M. Wijsman, Gonneke Willemsen, Nigel Williams, A. Jeremy Willsey, Stephanie H. Witt, Wei Xu, Allan H. Young, Timothy W. Yu, Stanley Zammit, Peter P. Zandi, Peng Zhang, Frans G. Zitman, Sebastian Zöllner, University of Zurich, Lee, S Hong, Epidemiology and Data Science, Psychiatry, EMGO - Mental health, NCA - Neurobiology of mental health, Human genetics, NCA - Brain mechanisms in health and disease, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Maier, Robert, Moser, Gerhard, Chen, Guo-Bo, Ripke, Stephan, Coryell, William, Potash, James B, Scheftner, William A, Shi, Jianxin, Weissman, Myrna M, Hultman, Christina M, Landen, Mikael, Levinson, Douglas F, Kendler, Kenneth S, Smoller, Jordan, Wray, Naomi R, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Oades, Robert D. (Beitragende*r), Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Maier R., Moser G., Chen G.-B., Ripke S., Coryell W., Potash J.B., Scheftner W.A., Shi J., Weissman M.M., Hultman C.M., Landen M., Levinson D.F., Kendler K.S., Smoller J.W., Wray N.R., Lee S.H., Absher D., Agartz I., Akil H., Amin F., Andreassen O.A., Anjorin A., Anney R., Arking D.E., Asherson P., Azevedo M.H., Backlund L., Badner J.A., Bailey A.J., Banaschewski T., Barchas J.D., Barnes M.R., Barrett T.B., Bass N., Battaglia A., Bauer M., Bayes M., Bellivier F., Bergen S.E., Berrettini W., Betancur C., Bettecken T., Biederman J., Binder E.B., Black D.W., Blackwood D.H.R., Bloss C.S., Boehnke M., Boomsma D.I., Breen G., Breuer R., Bruggeman R., Buccola N.G., Buitelaar J.K., Bunney W.E., Buxbaum J.D., Byerley W.F., Caesar S., Cahn W., Cantor R.M., Casas M., Chakravarti A., Chambert K., Choudhury K., Cichon S., Robert Cloninger C., Collier D.A., Cook E.H., Coon H., Cormand B., Cormican P., Corvin A., Coryell W.H., Craddock N., Craig D.W., Craig I.W., Crosbie J., Cuccaro M.L., Curtis D., Czamara D., Daly M.J., Datta S., Dawson G., Day R., De Geus E.J., Degenhardt F., Devlin B., Djurovic S., Donohoe G.J., Doyle A.E., Duan J., Dudbridge F., Duketis E., Ebstein R.P., Edenberg H.J., Elia J., Ennis S., Etain B., Fanous A., Faraone S.V., Farmer A.E., Nicol Ferrier I., Flickinger M., Fombonne E., Foroud T., Frank J., Franke B., Fraser C., Freedman R., Freimer N.B., Freitag C.M., Friedl M., Frisen L., Gallagher L., Gejman P.V., Georgieva L., Gershon E.S., Geschwind D.H., Giegling I., Gill M., Gordon S.D., Gordon-Smith K., Green E.K., Greenwood T.A., Grice D.E., Gross M., Grozeva D., Guan W., Gurling H., De Haan L., Haines J.L., Hakonarson H., Hallmayer J., Hamilton S.P., Hamshere M.L., Hansen T.F., Hartmann A.M., Hautzinger M., Heath A.C., Henders A.K., Herms S., Hickie I.B., Hipolito M., Hoefels S., Holmans P.A., Holsboer F., Hoogendijk W.J., Hottenga J.-J., Hus V., Ingason A., Ising M., Jamain S., Jones I., Jones L., Kahler A.K., Kahn R.S., Kandaswamy R., Keller M.C., Kelsoe J.R., Kennedy J.L., Kenny E., Kent L., Kim Y., Kirov G.K., Klauck S.M., Klei L., Knowles J.A., Kohli M.A., Koller D.L., Konte B., Korszun A., Krabbendam L., Krasucki R., Kuntsi J., Kwan P., Langstrom N., Lathrop M., Lawrence J., Lawson W.B., Leboyer M., Ledbetter D.H., Lee P.H., Lencz T., Lesch K.-P., Lewis C.M., Li J., Lichtenstein P., Lieberman J.A., Lin D.-Y., Linszen D.H., Liu C., Lohoff F.W., Loo S.K., Lord C., Lowe J.K., Lucae S., MacIntyre D.J., Madden P.A.F., Maestrini E., Magnusson P.K.E., Mahon P.B., Maier W., Malhotra A.K., Mane S.M., Martin C.L., Martin N.G., Mattheisen M., Matthews K., Mattingsdal M., McCarroll S.A., McGhee K.A., McGough J.J., McGrath P.J., McGuffin P., McInnis M.G., McIntosh A., McKinney R., McLean A.W., McMahon F.J., McMahon W.M., McQuillin A., Medeiros H., Medland S.E., Meier S., Melle I., Meng F., Meyer J., Middeldorp C.M., Middleton L., Milanova V., Miranda A., Monaco A.P., Montgomery G.W., Moran J.L., Moreno-De-Luca D., Morken G., Morris D.W., Morrow E.M., Moskvina V., Mowry B.J., Muglia P., Muhleisen T.W., Muller-Myhsok B., Murtha M., Myers R.M., Myin-Germeys I., Neale B.M., Nelson S.F., Nievergelt C.M., Nikolov I., Nimgaonkar V., Nolen W.A., Nothen M.M., Nurnberger J.I., Nwulia E.A., Nyholt D.R., O'Donovan M.C., O'Dushlaine C., Oades R.D., Olincy A., Oliveira G., Olsen L., Ophoff R.A., Osby U., Owen M.J., Palotie A., Parr J.R., Paterson A.D., Pato C.N., Pato M.T., Penninx B.W., Pergadia M.L., Pericak-Vance M.A., Perlis R.H., Pickard B.S., Pimm J., Piven J., Posthuma D., Poustka F., Propping P., Purcell S.M., Puri V., Quested D.J., Quinn E.M., Ramos-Quiroga J.A., Rasmussen H.B., Raychaudhuri S., Rehnstrom K., Reif A., Ribases M., Rice J.P., Rietschel M., Roeder K., Roeyers H., Rossin L., Rothenberger A., Rouleau G., Ruderfer D., Rujescu D., Sanders A.R., Sanders S.J., Santangelo S.L., Schachar R., Schalling M., Schatzberg A.F., Schellenberg G.D., Scherer S.W., Schork N.J., Schulze T.G., Schumacher J., Schwarz M., Scolnick E., Scott L.J., Sergeant J.A., Shilling P.D., Shyn S.I., Silverman J.M., Sklar P., Slager S.L., Smalley S.L., Smit J.H., Smith E.N., Sonuga-Barke E.J.S., St Clair D., State M., Steffens M., Steinhausen H.-C., Strauss J.S., Strohmaier J., Scott Stroup T., Sullivan P.F., Sutcliffe J., Szatmari P., Szelinger S., Thapar A., Thirumalai S., Thompson R.C., Todorov A.A., Tozzi F., Treutlein J., Tzeng J.-Y., Uhr M., van den Oord E.J.C.G., Van Grootheest G., Van Os J., Vicente A.M., Vieland V.J., Vincent J.B., Visscher P.M., Walsh C.A., Wassink T.H., Watson S.J., Weiss L.A., Werge T., Wienker T.F., Wiersma D., Wijsman E.M., Willemsen G., Williams N., Jeremy Willsey A., Witt S.H., Xu W., Young A.H., Yu T.W., Zammit S., Zandi P.P., Zhang P., Zitman F.G., and Zollner S.

Subjects
Netherlands Twin Register (NTR), Multifactorial Inheritance, Multivariate analysis, Bipolar Disorder, genome annotation, Medizin, R Medicine (General), Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, 2.5 Research design and methodologies (aetiology), GWAS, Genetics(clinical), Aetiology, Multivariate Analysi, Genetics (clinical), Genetics & Heredity, bipolar disorder, 0303 health sciences, education.field_of_study, Depression, Mental Disorders, Single Nucleotide, 3rd-DAS, Biological Sciences, 10058 Department of Child and Adolescent Psychiatry, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Mental Health, Schizophrenia, Mental Disorder, Linear Model, Major depressive disorder, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Risk assessment, Human, medicine.medical_specialty, 2716 Genetics (clinical), Genetics, Medical, Population, SNP, 610 Medicine & health, QH426 Genetics, Best linear unbiased prediction, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, 1311 Genetics, Medical, Report, medicine, Genetics, Humans, Bipolar disorder, Genetic Testing, Polymorphism, education, Psychiatry, QH426, 030304 developmental biology, Depressive Disorder, Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Prevention, Human Genome, Major, medicine.disease, genetic risk prediction, R1, Brain Disorders, schizophrenia, Sample size determination, Perturbações do Desenvolvimento Infantil e Saúde Mental, Multivariate Analysis, Linear Models, business, depressive disorders, 030217 neurology & neurosurgery
Abstract

Cross-Disorder Working Group of the Psychiatric Genomics Consortium - Vicente A.M. Acessível em: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25640677/ Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk

Published
2015
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28. Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: Evidence, limitations, and implications

Author

Elaine K. Green and Nicholas John Craddock

Subjects
Candidate gene, Bipolar Disorder, Locus (genetics), Treatment of bipolar disorder, Mice, Neurotrophic factors, Risk Factors, medicine, Animals, Humans, Genetic Predisposition to Disease, Bipolar disorder, CAMP response element binding, Genetic association, Brain-derived neurotrophic factor, Mice, Knockout, Polymorphism, Genetic, Brain-Derived Neurotrophic Factor, Chromosomes, Human, Pair 11, Chromosome Mapping, Genetic Variation, medicine.disease, Psychiatry and Mental health, nervous system, Pshychiatric Mental Health, Psychology, Neuroscience
Abstract

Brain-derived neurotrophic factor (BDNF) plays an important role in promoting and modifying growth, development, and survival of neuronal populations, and, in the mature nervous system, is involved in activity-dependent neuronal plasticity. Based on several lines of evidence, BDNF has been hypothesized to play an important role in the pathogenesis of mood disorder and the therapeutic action of at least some effective treatments. The gene encoding BDNF lies on the short arm of chromosome 11 in a region where some linkage studies of bipolar disorder have reported evidence for a susceptibility gene. BDNF can, thus, be considered as an attractive candidate gene for involvement in the pathogenesis of bipolar disorder, and two recent family-based association studies have provided evidence that one or more sequence variants within or near the BDNF gene show an association with disease susceptibility. These findings are of great interest and may open up a new chapter in the understanding of the causation and treatment of bipolar disorder. However, it is still early in the genetic investigation of BDNF in bipolar disorder, and it is important that these findings are replicated in large independent samples and that functional studies can confirm and characterize the pathogenic relevance of this genetic variation.

Published
2004
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29. DISC1 exon 11 rare variants found more commonly in schizoaffective spectrum cases than controls

Author

Rachel Raybould, Michael John Owen, Nicholas John Craddock, Lisa Jones, Ian Jones, Katherine Gordon-Smith, Michael Conlon O'Donovan, A. H. Young, E. Russell, I. N. Ferrier, Elaine K. Green, Rebecca Sims, George Kirov, D. St Clair, Liz Forty, and Detelina Grozeva

Subjects
Linkage (software), Proband, Genetics, Bipolar Disorder, Genetic Linkage, Mutation, Missense, Chromosome, Nerve Tissue Proteins, Schizoaffective disorder, Single-nucleotide polymorphism, Exons, Biology, medicine.disease, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, Psychiatry and Mental health, DISC1, Exon, Psychotic Disorders, Case-Control Studies, medicine, biology.protein, Humans, Genetic Predisposition to Disease, Genetics (clinical)
Abstract

We previously performed a linkage study using families identified through probands meeting criteria for DSM-IV schizoaffective disorder, bipolar type (SABP) and observed a genome-wide significant signal (LOD = 3.54) at chromosome 1q42 close to DISC1. An initial sequencing study of DISC1 using 14 unrelated DSM-IV SABP samples from the linkage study identified 2 non-synonymous coding SNPs in exon 11 in 2 separate individuals. Here we provide evidence of additional rare coding SNPs within exon 11. In sequencing exon 11 in 506 cases and 1,211 controls for variants that occurred only once, 4 additional rare variants were found in cases (P-value = 0.008, Fisher's exact trend test).

Published
2011
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30. Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder

Author

Katherine Gordon-Smith, Michael Conlon O'Donovan, Valentina Moskvina, Jouke-Jan Hottenga, Hugh Gurling, Peter Heutink, I. N. Ferrier, Nicholas John Craddock, Michael John Owen, August B. Smit, Danyu Lin, Jan Smit, Edward M. Scolnick, E.J.C. de Geus, Danielle Posthuma, George Kirov, Shaun Purcell, Ian Jones, Detelina Grozeva, Peter Holmans, Patrick F. Sullivan, R. van Dyck, Anne Farmer, Youfang Liu, Gonneke Willemsen, B.W.J.H. Penninx, Willem A. Nolen, Elaine K. Green, Dorret I. Boomsma, Lisa Jones, Marian L. Hamshere, D. H. R. Blackwood, Witte J.G. Hoogendijk, Roy H. Perlis, Peter McGuffin, Manuel A. R. Ferreira, Pamela Sklar, D. St Clair, Jordan W. Smoller, Matthijs Verhage, Allan H. Young, T. Zandbelt, Sian Caesar, Christine Fraser, Biological Psychology, Functional Genomics, Molecular and Cellular Neurobiology, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Systems Biology of the Synapse, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Human genetics, Psychiatry, NCA - Systems Biology of the Synapse, NCA - Anxiety & Depression, NCA - Attention & Cognition, EMGO - Mental health, Faculteit Medische Wetenschappen/UMCG, and Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE)

Subjects
Netherlands Twin Register (NTR), medicine.medical_specialty, Bipolar Disorder, Calcium Channels, L-Type, Population, Genome-wide association study, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, Reference Values, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, education, Psychiatry, Molecular Biology, POPULATION, Depressive Disorder, Major, education.field_of_study, medicine.disease, Psychiatry and Mental health, Case-Control Studies, Reference values, Meta-analysis, Meta analisis, Major depressive disorder, sense organs, Psychology, Genome-Wide Association Study
Abstract

Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder

Published
2010
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31. Detailed mapping of a congenital heart disease gene in chromosome 3p25

Author

Jonathan J Waters, Elaine K. Green, Chris Maliszewska, Farida Latif, Eamonn R. Maher, and Matthew D Priestley

Subjects
Heart Defects, Congenital, Genetics, Heart disease, Molecular pathology, Chromosome Mapping, Karyotype, Telecanthus, Locus (genetics), Original Articles, Biology, medicine.disease, Genetic determinism, Gene mapping, Genetic marker, Karyotyping, medicine, Humans, Genetic Predisposition to Disease, Chromosomes, Human, Pair 3, Genetics (clinical)
Abstract

Distal deletion of chromosome 3p25-pter (3p− syndrome) produces a distinct clinical syndrome characterised by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia. Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD), occurs in about a third of patients. In total, approximately 25 cases of 3p− syndrome have been reported world wide. We previously analysed five cases and showed that (1) the 3p25-pter deletions were variable and (2) the presence of CHD correlated with the proximal extent of the deletion, mapping a CHD gene centromeric to D3S18. To define the molecular pathology of the 3p− syndrome further, we have now proceeded to analyse the deletion region in a total of 10 patients (five with CHD), using a combination of FISH analysis and polymorphic markers, for up to 21 loci from 3p25-p26. These additional investigations further supported the location of an AVSD locus within 3p25 and refined its localisation. Thus, the critical region was reduced to an interval between D3S1263 and D3S3594. Candidate 3p25 CHD genes, such as PMCA2 (ATP2B2), fibulin 2, TIMP4, and Sec13R, were shown to map outside the target interval. Additionally, the critical region for the phenotypic features of the 3p− phenotype was mapped to D3S1317 to D3S17 (19-21 cM). These findings will accelerate the identification of the 3p25 CHD susceptibility locus and facilitate investigations of the role of this locus in non-syndromic AVSDs, which are a common form of familial and isolated CHD. Keywords: congenital heart disease; chromosome 3p25

Published
2000
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32. Clonal Diversity of Ig and T-cell Receptor Gene Rearrangements in Childhood B-Precursor Acute Lymphoblastic Leukaemia

Author

Carmel McConville, J. E. Powell, Elaine K. Green, Jillian R. Mann, V Weston, Philip Darbyshire, T. Stankovic, and Alex M. Taylor

Subjects
Genome instability, Cancer Research, Genes, Immunoglobulin, Stem Cells, Genetic Variation, Hematology, Disease, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Biology, Gene Rearrangement, T-Lymphocyte, Burkitt Lymphoma, Clone Cells, Haematopoiesis, Immune system, Oncology, Monoclonal, Immunology, Humans, Immunoglobulin heavy chain, Allele, Gene Rearrangement, B-Lymphocyte, Gene, Forecasting
Abstract

The majority of paediatric B precursor acute lymphoblastic leukaemias in children are derived from a single transformed haematopoietic cell with complete or partial VDJ recombination within the immunoglobulin heavy chain gene. A high frequency of patients also show rearrangements within TCRdelta and TCRgamma loci and in up to 40% of children there is an excess of immune system gene rearrangements compared with the number of identified alleles of immune system genes, suggesting the presence of multiple leukaemic subclones -clonal diversity. It has been observed by us and other investigators that in individual patients the pattern of immune system gene rearrangements often changes between presentation and relapse. In order to explore the possibility that clonal diversity plays a biological role during disease progression we optimised methods for subclone detection and analysed the prognostic significance of clonal diversity among 75 children with B precursor-ALL. Our results suggest that clonal diversity plays a role in disease progression as patients with oligoclonal disease showed a significantly shorter disease free survival than patients with monoclonal disease. This trend was of particular importance in the 'standard risk' group of ALL where aggressive disease could not be recognised by other means. In addition, generation of independent subclones from an early, non-rearranged tumour progenitor appears to be a common feature among leukaemias with aggressive clinical behaviour. We speculate on the type of genetic factors which may participate both in the generation of subclones and also in wider genomic instability and which are likely to be required for the aggressive clinical phenotype in children with ALL.

Published
2000
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33. Genomic organization and chromosomal localization of the humanCUL2 gene and the role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1) mutation and loss in renal-cell carcinoma development

Author

Francesco Gianelli, Katie Hewson, Eamonn R. Maher, Peter M. Green, Elaine K. Green, Astrid Brinke, Sally Walsh, Charis Eng, and Steven C. Clifford

Subjects
Genetics, Cancer Research, Mutation, endocrine system diseases, Tumor suppressor gene, Point mutation, Biology, urologic and male genital diseases, medicine.disease_cause, female genital diseases and pregnancy complications, Loss of heterozygosity, Germline mutation, Von Hippel–Lindau tumor suppressor, DNA methylation, medicine, biology.protein, Carcinogenesis, neoplasms
Abstract

Germline mutations in the von Hippel-Lindau (VHL) disease tumor suppressor gene (TSG) convey a high risk of clear-cell renal-cell carcinoma (CC-RCC) and most sporadic CC-RCCs demonstrate somatic inactivation of the VHL TSG. However, the existence of further CC-RCC gatekeeper genes is implied by CC-RCC kindreds not linked to the VHL gene and the absence of somatic VHL inactivation in approximately 30% of sporadic CC-RCC. Genes that encode proteins which interact with the VHL gene product (VHL) provide candidate gatekeeper RCC genes. VHL forms a multimeric complex with two subunits (B and C) of the SIII (elongin) transcriptional elongation complex and CUL2, a member of the cullin family. Most pathogenic VHL mutations inhibit formation of the VHL/elonginB+C/CUL2 complex. A further VHL-binding protein of unknown function, VBP1, fails to bind to truncated forms of VHL. We have investigated the possible roles of CUL2 and VBP1 in renal tumorigenesis by analyzing sporadic RCC of known VHL mutation or hypermethylation status, including CC-RCC without VHL inactivation (n = 40); CC-RCC with VHL inactivation (n = 35); and non-CC-RCC (n = 14). No VBP1 mutations were identified in 89 sporadic RCCs, suggesting that VBP1 is not an RCC gatekeeper gene. To investigate CUL2, we mapped the CUL2 gene to chromosome band 10p11.1-p11.2, a region reported to show loss of heterozygosity (LOH) in several human cancers (including non-CC-RCC); determined the genomic organization; and performed mutation analysis of the 21 exons identified. Using novel intragenic polymorphisms, we detected LOH in 6/25 informative RCCs; however, no pathogenic CUL2 mutations were identified in the 89 RCCs analyzed. These findings suggest that unless CUL2 is inactivated by epigenetic events, it is not a major RCC TSG. However, CUL2 remains a candidate TSG for other tumor types demonstrating 10p LOH. Genes Chromosomes Cancer 26:20-28, 1999.

Published
1999
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34. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author

Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), 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), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University (VCU), University of Dundee School of Medicine, University of Dundee, Department of Biostatistics and Center for Statistical Genetics, University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Howard University College of Medicine, University of Colorado [Denver], Center for Neurobehavioral Genetics, Department of Genomics, Department of Molecular Medicine, Department of Neurology, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Medical Research Council-Cardiff University, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genetics, Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Clinical and Developmental Psychology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Functional Genomics, Neuronal Plasticity / Mouse Behaviour, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medical Epidemiology and Biostatistics (MEB), Autism and Communicative Disorders Centre, Center for Human Genetic Research, Center for neuroscience-University of California [Davis] (UC Davis), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Emory University [Atlanta, GA]-Atlanta Veterans Affairs Medical Center, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Medicine, University of St Andrews [Scotland], Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology

Subjects
Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Published
2013
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35. The consistent association between Epstein-Barr virus and Hodgkin's disease in children in Kenya

Author

Elaine K. Green, A Nyongo, Jillian R. Mann, NA Othieno-Abinya, M. Weinreb, M. S. Riyat, F. Niggli, Philip J. R. Day, and F. Raafat

Subjects
biology, business.industry, Immunology, Cell Biology, Hematology, medicine.disease_cause, biology.organism_classification, medicine.disease, Biochemistry, Epstein–Barr virus, Virology, Herpesviridae, Virus, Lymphoma, Antigen, Nodular sclerosis, hemic and lymphatic diseases, biology.protein, Medicine, Gammaherpesvirinae, Antibody, business
Abstract

Recent studies have suggested that Epstein-Barr virus (EBV) may play a role in the etiology of Hodgkin's disease (HD). In a previous study, we used a latent membrane protein 1 (LMP1)-specific antibodies to examine archival material from 74 British children with HD and found 50% of cases to be positive. It is known that there are geographic and ethnic variations in the incidence of HD. We have investigated LMP1 status in formalin-fixed, paraffin wax-embedded lymph nodes with HD involvement from 53 children and 48 adults from Kenya using immunohistochemical staining. We also developed sensitive and specific in vitro gene amplification protocols for examining the EBV strain type in such material using several combinations of primers derived from the EBNA 2 and EBNA 3 coding regions. LMP1 positivity was present in 100% of the pediatric cases (two lymphocyte-predominant, 25 nodular sclerosis, 16 mixed cellularity, 5 lymphocyte depletion, and 5 unclassified) and in 66% of the adult cases (two of three lymphocyte-predominant, 26 of 39 nodular, sclerosis, two of two mixed cellularity, and two of four lymphocyte depletion). Tests to type the EBV strain were undertaken in 25 EBV-positive pediatric cases. A combination of type-specific polymerase chain reactions for EBNA 2 and EBNA 3C genes indicated that seven patients had type 1, eight had type 2, and 10 had dual infections with both types. Five cases with dual infections were further investigated using a sensitive in situ hybridization for the EBV- encoded, small nuclear nonpolyadenylated RNAs (EBERs). EBER transcripts were detected in Reed-Sternberg and Hodgkin cells and in occasional infiltrating lymphocytes. These observations indicate that in Kenya EBV is consistently associated with pediatric cases of HD, and that biopsies from a number of such cases appear to carry both type 1 and type 2 viral sequences.

Published
1996
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36. Association at SYNE1 in both bipolar disorder and recurrent major depression

Author

Michael Conlon O'Donovan, Ian Jones, Katherine Gordon-Smith, Detelina Grozeva, Pamela Sklar, Liz Forty, Marian L. Hamshere, Shaun Purcell, Anne Farmer, Peter McGuffin, Lisa Jones, Jennifer L. Moran, E. Russell, M. J. Owen, Nicholas John Craddock, and Elaine K. Green

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Bipolar Disorder, Genotype, Locus (genetics), Genome-wide association study, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, Gene Frequency, Recurrence, Internal medicine, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Bipolar disorder, Allele, Molecular Biology, Genetic association, Genetics, Depressive Disorder, Major, Nuclear Proteins, Odds ratio, Middle Aged, medicine.disease, Recurrent major depression, Psychiatry and Mental health, Cytoskeletal Proteins, Mood disorders, Female, Psychology, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10−7, odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10−8, OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.

Published
2012

37. Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders

Author

Detelina Grozeva, Dirk Goossens, Daniel Souery, Karl-Fredrik Norrback, Nicholas John Craddock, Chris Bervoets, Maarten J. A. Van Den Bossche, Bernard Sabbe, Stephan De Bruyne, Sonia De Zutter, Julien Mendlewicz, An-Sofie Lenaerts, Annelie Nordin, Peter De Rijk, Elaine K. Green, Rolf Adolfsson, Mojca Strazisar, Jurgen Del-Favero, Clinical sciences, Neuroprotection & Neuromodulation, and Faculty of Sciences and Bioengineering Sciences

Subjects
Adult, Male, medicine.medical_specialty, Calcium Channels, L-Type, Genome-wide association study, Schizoaffective disorder, Cellular and Molecular Neuroscience, Exon, Belgium, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Bipolar disorder, Age of Onset, Psychiatry, Base Pairing, Genetics (clinical), Genetics, bipolar disorder, Sweden, Chromosomes, Human, Pair 12, Voltage-dependent calcium channel, business.industry, Breakpoint, Middle Aged, medicine.disease, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, Female, Human medicine, business, Gene Deletion
Abstract

The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7?kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 1726 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular. (C) 2012 Wiley Periodicals, Inc.

Published
2012

38. Are interleukin-1 gene polymorphisms risk factors or disease modifiers in AD?

Author

Judith Harris, Helen Lemmon, Marie-Christine Chartier-Harlin, Jean-Charles Lambert, Takeshi Iwatsubo, C. Lendon, Elaine K. Green, D M Mann, and D. St Clair

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Genotype, medicine.medical_treatment, Disease, Cohort Studies, Degenerative disease, Gene Frequency, Alzheimer Disease, Risk Factors, Polymorphism (computer science), medicine, Humans, Age of Onset, Risk factor, Aged, Aged, 80 and over, Analysis of Variance, Chi-Square Distribution, Polymorphism, Genetic, business.industry, Interleukin, Middle Aged, medicine.disease, Cytokine, Immunology, Female, Neurology (clinical), Alzheimer's disease, business, Interleukin-1, Cohort study
Abstract

Polymorphisms in the interleukin-1 genes, IL-1A and IL-1B, have been associated with AD, but not in all studies. The authors genotyped the IL-1A(-889) and IL-1B(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with AD, and a further 100 with brain Abeta load. No evidence was found of risk for AD with these variants, nor of an effect on age at onset. However, an impact of IL-1B(-511) on Abeta(40) load (p < 0.05) was detected.

Published
2002
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39. Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries

Author

Giancarlo Russo, Michael Conlon O'Donovan, Nicholas John Craddock, Valentina Moskvina, Sarah Dwyer, Marian L. Hamshere, Michael John Owen, Detelina Grozeva, Rhodri L. Smith, Peter Holmans, Elaine K. Green, and Hywel Williams

Subjects
Ankyrins, Psychosis, Bipolar Disorder, Ubiquitin-Protein Ligases, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Transfection, Polymorphism, Single Nucleotide, Major Histocompatibility Complex, Mice, Transcription Factor 4, Genetics, medicine, Autophagy, Animals, Humans, Genetic Predisposition to Disease, ANK3, Neurogranin, Ataxin-3, Molecular Biology, Genetics (clinical), Genetic association, Protein Stability, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Association Studies Articles, Ubiquitination, Nuclear Proteins, General Medicine, Machado-Joseph Disease, medicine.disease, Repressor Proteins, DNA-Binding Proteins, HEK293 Cells, Phenotype, Genetic epidemiology, Genetic Loci, Schizophrenia, Mutant Proteins, Peptides, Genome-Wide Association Study, Transcription Factors
Abstract

Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10−5). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects.

Published
2010

40. An examination of single nucleotide polymorphism selection prioritization strategies for tests of gene-gene interaction

Author

Bertram Müller-Myhsok, Nicholas John Craddock, Valentina Moskvina, Elaine K. Green, Michael Conlon O'Donovan, Michael John Owen, Peter Holmans, and Tony Kam-Thong

Subjects
Genetics, Ankyrins, Linkage disequilibrium, Bipolar Disorder, Single-nucleotide polymorphism, Genome-wide association study, Epistasis, Genetic, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Gene interaction, Multiple comparisons problem, SNP, Humans, Calcium Channels, Biological Psychiatry, Genetic association, SNP array, Genome-Wide Association Study
Abstract

Background Given that genome-wide association studies (GWAS) of psychiatric disorders have identified only a small number of convincingly associated variants (single nucleotide polymorphism [SNP]), there is interest in seeking additional evidence for associated variants with tests of gene–gene interaction. Comprehensive pair-wise single SNP–SNP interaction analysis is computationally intensive, and the penalty for multiple testing is severe, given the number of interactions possible. Aiming to minimize these statistical and computational burdens, we have explored approaches to prioritize SNPs for interaction analyses. Methods Primary interaction analyses were performed with the Wellcome Trust Case-Control Consortium bipolar disorder GWAS (1868 cases, 2938 control subjects). Replication analyses were performed with the Genetic Association Information Network bipolar disorder dataset (1001 cases, 1033 control subjects). The SNPs were prioritized for interaction analysis that showed evidence for association that surpassed a number of nominally significant thresholds, are within genome-wide significant genes, or are within genes that are functionally related. Results For no set of prioritized SNPs did we obtain evidence to support the hypothesis that the selection strategy identified pairs of variants that were enriched for true (statistical) interactions. Conclusions The SNPs prioritized according to a number of criteria do not have a raised prior probability for significant interaction that is detectable in samples of this size. We argue that the use of significance levels reflecting only the number of tests performed, as is now widely accepted for single SNP analysis, does not offer an appropriate degree of protection against the potential for GWAS studies to generate an enormous number of false positive interactions.

Published
2010

41. Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder

Author

Elaine K. Green, Christine Fraser, Detelina Grozeva, Peter Holmans, Allan H. Young, E. Russell, David St Clair, Peter McGuffin, Nicholas John Craddock, Michael John Owen, Katherine Gordon-Smith, Ian Jones, Michael Conlon O'Donovan, Liz Forty, Sian Caesar, Marian L. Hamshere, Anne Farmer, Valentina Moskvina, Lisa Jones, and Nicol Ferrier

Subjects
medicine.medical_specialty, Bipolar Disorder, GABRA5, GABRA4, Research Diagnostic Criteria, Schizoaffective disorder, Genetic determinism, Cellular and Molecular Neuroscience, GABA receptor, Gene Frequency, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Genetics (clinical), Polymorphism, Genetic, biology, GABAA receptor, business.industry, medicine.disease, Receptors, GABA-A, Psychiatry and Mental health, Endocrinology, Case-Control Studies, biology.protein, Schizophrenia, business
Abstract

We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).

Published
2010

42. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia

Author

Detelina, Grozeva, George, Kirov, Dobril, Ivanov, Ian R, Jones, Lisa, Jones, Elaine K, Green, David M, St Clair, Allan H, Young, Nicol, Ferrier, Anne E, Farmer, Peter, McGuffin, Peter A, Holmans, Michael J, Owen, Michael C, O'Donovan, Nick, Craddock, and Jane, Worthington

Subjects
Bipolar Disorder, DNA Copy Number Variations, Genotype, Risk Factors, Schizophrenia, Humans, Genetic Predisposition to Disease, Article, Genome-Wide Association Study, Oligonucleotide Array Sequence Analysis
Abstract

Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date.To determine whether large (100,000 base pairs) and rare (found in1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia.A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray.The Wellcome Trust Case Control Consortium.There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents.Overall load of CNVs and presence of rare CNVs.The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder.Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.

Published
2010

43. A systematic association mapping on chromosome 6q in bipolar affective disorder--evidence for the melanin-concentrating-hormone-receptor-2 gene as a risk factor for bipolar affective disorder

Author

Felix F. Brockschmidt, Marcella Rietschel, Tim Becker, Elaine K. Green, Markus M. Nöthen, Rami Abou Jamra, Alexander Georgi, Mazda Adli, Johannes Schumacher, Nicholas John Craddock, Jana Strohmeier, Thomas G. Schulze, Margrieta A. Alblas, Peter Propping, Jens R. Wendland, Sven Cichon, and Detelina Grozeva

Subjects
Oncology, Adult, Affective Disorders, Psychotic, Male, medicine.medical_specialty, Bipolar Disorder, Genotype, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Chromosomes, White People, Cellular and Molecular Neuroscience, Risk Factors, Internal medicine, medicine, Humans, Bipolar disorder, Allele, Risk factor, Association mapping, Genetics (clinical), Genetics, Haplotype, Odds ratio, Middle Aged, medicine.disease, Psychiatry and Mental health, Haplotypes, Case-Control Studies, Chromosomal region, Female
Abstract

Strong evidence of linkage between chromosomal region 6q16-q22 and bipolar affective disorder (BPAD) has previously been reported. We conducted a systematic association mapping of the 6q-linkage interval using 617 SNP markers in a BPAD case–control sample of German descent (cases = 330, controls = 325). In this screening step, 46 SNPs showed nominally significant BPAD-association (P-values between 0.0007 and 0.0484). Although none of the 46 SNPs survived correction for multiple testing, they were genotyped in a second and ethnically matched BPAD sample (cases = 328, controls = 397). At the melanin-concentrating-hormone-receptor-2 (MCHR2) gene, we found nominal association in both the initial and second BPAD samples (combined P = 0.008). This finding was followed up by the genotyping of 17 additional MCHR2-SNPs in the combined sample in order to define our findings more precisely. We found that the MCHR2-locus can be divided into three different haplotype-blocks, and observed that the MCHR2-association was most pronounced in BPAD male patients with psychotic symptoms. In two neighboring blocks, putative risk-haplotypes were found to be 7% more frequent in patients (block II: 23.3% vs. 16.2%, P = 0.005, block III: 39.2% vs. 32.0%, P = 0.024), whereas the putative protective haplotypes were found to be 5–8% less frequent in patients (block II: 11.6% vs. 16.4%, P = 0.041, block III: 30.0% vs. 38.8%, P = 0.007). The corresponding odds ratios (single-marker analysis) ranged between 1.25 and 1.46. Our findings may indicate that MCHR2 is a putative risk factor for BPAD. These findings should be interpreted with caution and replicated in independent BPAD samples.

Published
2009

44. Affective temperaments across the bipolar-unipolar spectrum: examination of the TEMPS-A in 927 patients and controls

Author

Nicholas John Craddock, Daniel J. Smith, Ian Jones, Liz Forty, Elaine K. Green, Christine Fraser, Katherine Gordon-Smith, Detelina Grozeva, Arianna Di Florio, Lisa Jones, Sian Caesar, and Marian L. Hamshere

Subjects
Adult, Cross-Cultural Comparison, Male, medicine.medical_specialty, Bipolar Disorder, Personality Inventory, Psychometrics, media_common.quotation_subject, Individuality, Sex Factors, Recurrence, Reference Values, mental disorders, medicine, Personality, Humans, Bipolar disorder, Association (psychology), Psychiatry, Temperament, Depression (differential diagnoses), media_common, Multinomial logistic regression, Depressive Disorder, Major, Confounding, Age Factors, Reproducibility of Results, Middle Aged, medicine.disease, United States, Psychiatry and Mental health, Clinical Psychology, Affect, Cross-Sectional Studies, Italy, Endophenotype, Female, France, Dysthymic Disorder, Psychology, Clinical psychology
Abstract

Objective There is currently a great deal of interest in the use of affective temperaments as possible intermediate phenotypes for bipolar disorder. However, much of the literature in this area is conflicting. Our aims were to test the hypothesis of a gradient in affective temperament scores, as measured by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A), from bipolar disorder type I (BP-I), through bipolar disorder type II (BP-II), recurrent major depressive disorder (MDD-R), and a control group (CG) in the largest sample to date of 927 subjects. Methods Non parametric tests were used to compare TEMPS-A scores between diagnostic groups and multinomial logistic regression was used to test the association between TEMPS-A scores and diagnosis while controlling for current mood state, age and gender. Results Although the BP-II group scored higher than the BP-I and MDD-R groups on several TEMPS-A subscales, these differences were not significant when confounding variables were controlled for. The dysthymic subscale differentiated between affected and controls and the anxious subscale differentiated the MDD-R group from controls. Limitations The cross-sectional design did not allow us to evaluate potential longitudinal changes of temperament scores, which were assessed only with a self-report questionnaire. Conclusion We failed to find evidence of a gradient in affective temperament scores. Both unipolar and bipolar patients reported high dysthymic scores relative to controls, perhaps supporting a unitary view of depression across the bipolar–unipolar spectrum. Taking account of potential confounders will be important in future studies which seek to use affective temperaments as intermediate phenotypes in genetic research.

Published
2009

45. P2RX7: A bipolar and unipolar disorder candidate susceptibility gene?

Author

Liz Forty, Elaine K. Green, Stuart MacGregor, Gareth Elvidge, Nicholas John Craddock, Detelina Grozeva, Rachel Raybould, Ian W. Craig, Michael John Owen, Ian Jones, Anne Farmer, M O'Donovan, George Kirov, Peter McGuffin, and Lisa Jones

Subjects
Bipolar I disorder, Bipolar Disorder, Genotype, Single-nucleotide polymorphism, Locus (genetics), behavioral disciplines and activities, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, Genetic linkage, mental disorders, Medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Genetics (clinical), Genetics, Depressive Disorder, Chromosomes, Human, Pair 12, Polymorphism, Genetic, business.industry, Receptors, Purinergic P2, medicine.disease, United Kingdom, Psychiatry and Mental health, Mood, Mood disorders, Amino Acid Substitution, Case-Control Studies, Chromosomal region, Receptors, Purinergic P2X7, business
Abstract

The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Darier's disease that show linkage across this region. The gene P2RX7 is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The non-synonymous SNP rs2230912 (resulting in amino-acid polymorphism Q460R) showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK case-control sample (bipolar I disorder N = 687, unipolar recurrent major depression N = 1,036, controls N = 1,204). Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7 was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12-linked bipolar-Darier families showed no evidence of rare variants at P2RX7 that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders.

Published
2009

46. Detection of human apolipoprotein E3, E2, and E4 genotypes by an allele-specific oligonucleotide-primed polymerase chain reaction assay: development and validation

Author

P. J. R. Day, A. F. Jones, F. Charleson, M. R. Walker, S. C. Bain, A. H. Barnett, and Elaine K. Green

Subjects
Oligonucleotide, Biochemistry (medical), Clinical Biochemistry, Multiple displacement amplification, Biology, Molecular biology, law.invention, genomic DNA, Plasmid, law, Allele-specific oligonucleotide, Primer (molecular biology), Genotyping, Polymerase chain reaction
Abstract

A polymerase chain reaction (PCR) assay has been developed and validated by using allele-specific oligonucleotide (ASO) primers to specifically amplify E3, E2, and E4 polymorphic sequences of the human apolipoprotein E (apo E) genes. Degenerate ASOs containing one or two additional 3' mismatches provided greater specificity than did ASOs containing a single mid-sequence or 3' allele-specific mismatch with plasmid pEB4 or genomic DNA as template. Optimal specificity and efficiency of amplification did not correlate with primer annealing conditions, whether determined theoretically or via oligo-melting experiments. Pre-cycling denaturation times and high cycling denaturation temperatures were also required for optimal amplification, presumably because of the high G:C content (75-85%) of apo E gene sequences. Conditions permissive for amplification and discrimination with plasmid DNA did not transpose favorably to amplification from human genomic DNA from peripheral blood leukocytes; the latter required nested primer reactions. These data may be valuable in predicting PCR assay conditions for other G:C-rich sequences containing polymorphic sequence differences. The assay described is both more accurate and rapid (24 h) than previously described methods for phenotyping or genotyping human apo E from blood specimens.

Published
1991
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47. Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder

Author

Peter Holmans, Jaspreet Singh Pahwa, Michael Conlon O'Donovan, Michael John Owen, N. Craddock, Manuel A. R. Ferreira, Elaine K. Green, Pamela Sklar, and Shaun Purcell

Subjects
Linkage disequilibrium, Bipolar Disorder, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Biological pathway, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Databases, Genetic, Genetics, medicine, Humans, Genetics(clinical), Genetic Predisposition to Disease, Bipolar disorder, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Computational Biology, medicine.disease, Multiple comparisons problem, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We present a method for testing overrepresentation of biological pathways, indexed by gene-ontology terms, in lists of significant SNPs from genome-wide association studies. This method corrects for linkage disequilibrium between SNPs, variable gene size, and multiple testing of nonindependent pathways. The method was applied to the Wellcome Trust Case-Control Consortium Crohn disease (CD) data set. At a general level, the biological basis of CD is relatively well known for a complex genetic trait, and it thus acted as a test of the method. The method, known as ALIGATOR (Association LIst Go AnnoTatOR), successfully detected biological pathways implicated in CD. The method was also applied to a meta-analysis of bipolar disorder, and it implicated the modulation of transcription and cellular activity, including that which occurs via hormonal action, as an important player in pathogenesis.

Published
2008

48. Gene-wide analyses of genome-wide association datasets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk

Author

Michael Conlon O'Donovan, Valentina Moskvina, Ivan Nikolov, Michael John Owen, Elaine K. Green, Nicholas John Craddock, Jaspreet Singh Pahwa, and Peter Holmans

Subjects
medicine.medical_specialty, Bipolar Disorder, Genetic Linkage, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Genome, Polymorphism, Single Nucleotide, Genetic determinism, Article, Cellular and Molecular Neuroscience, Genetic linkage, Molecular genetics, Databases, Genetic, medicine, Humans, Genetic Predisposition to Disease, International HapMap Project, Molecular Biology, Genetics, Genomic Library, Models, Genetic, Genome, Human, Psychiatry and Mental health, Schizophrenia, Genome-Wide Association Study
Abstract

Genome-wide association (GWAS) analyses have identified susceptibility loci for many diseases, but most risk for any complex disorder remains unattributed. There is therefore scope for complementary approaches to these data sets. Gene-wide approaches potentially offer additional insights. They might identify association to genes through multiple signals. Also, by providing support for genes rather than single nucleotide polymorphisms (SNPs), they offer an additional opportunity to compare the results across data sets. We have undertaken gene-wide analysis of two GWAS data sets: schizophrenia and bipolar disorder. We performed two forms of analysis, one based on the smallest P-value per gene, the other on a truncated product of P method. For each data set and at a range of statistical thresholds, we observed significantly more SNPs within genes (P(min) for excess0.001) showing evidence for association than expected whereas this was not true for extragenic SNPs (P(min) for excess0.1). At a range of thresholds of significance, we also observed substantially more associated genes than expected (P(min) for excess in schizophrenia=1.8 x 10(-8), in bipolar=2.4 x 10(-6)). Moreover, an excess of genes showed evidence for association across disorders. Among those genes surpassing thresholds highly enriched for true association, we observed evidence for association to genes reported in other GWAS data sets (CACNA1C) or to closely related family members of those genes including CSF2RB, CACNA1B and DGKI. Our analyses show that association signals are enriched in and around genes, large numbers of genes contribute to both disorders and gene-wide analyses offer useful complementary approaches to more standard methods.

Published
2008

49. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder

Author

Marian L. Hamshere, Derek W. Morris, Douglas M. Ruderfer, Matthew Defelice, Ian Jones, Donald J. MacIntyre, Ana C. Parente Pereira, Kevin A. McGhee, Michael Conlon O'Donovan, Detelina Grozeva, Peter Holmans, Hugh Gurling, Vishwajit L. Nimgaonkar, David St Clair, Valentina Moskvina, Brendan Blumenstiel, Alan W Maclean, Andrew McQuillin, Peter McGuffin, Jennifer Stone, Elaine K. Green, Margaret Van Beck, Michael E. Thase, Adebayo Anjorin, Michael John Owen, George Kirov, Mark J. Daly, Jacob Lawrence, David A. Collier, Jennifer Franklin, Yan A Meng, Pamela Sklar, Shaun Purcell, Michelle Robinson, Manuel A. R. Ferreira, Nicholas John Craddock, Anne Farmer, Radhika Kandaswamy, Walter J. Muir, Sian Caesar, Stacey Gabriel, Allan H. Young, Aiden Corvin, Christine Fraser, Douglas Blackwood, Jinbo Fan, Katherine Gordon-Smith, I. Nicol Ferrier, Michael Gill, David Curtis, Kristin G. Ardlie, Gary S. Sachs, Edward M. Scolnick, Gerome Breen, Kimberly Chambert, Nicholas Bass, Ivan Nikolov, Roy H. Perlis, Richard Williamson, Jordan W. Smoller, Amanda Elkin, and Lisa Jones

Subjects
Ankyrins, Bipolar Disorder, Calcium Channels, L-Type, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Pathogenesis, Polymorphism (computer science), medicine, Genetics, Ankyrin, Humans, Genetic Predisposition to Disease, Bipolar disorder, ANK3, Gene, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), chemistry.chemical_classification, Psychiatry, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 10, Calcium channel, medicine.disease, Logistic Models, chemistry, Genome-Wide Association Study
Abstract

PUBLISHED, To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 10-9) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 10-8, rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Published
2008
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50. P4–101: The influence of polymorphisms in interleukin –1 gene on amyloid and non–amyloid vascular pathologies in Alzheimer's disease

Author

Jean-Charles Lambert, Kevin Morgan, David G. Mann, Jing Shi, L. Araria-Goumidi, Yongyan Wang, Elaine K. Green, Corinne Lendon, and Jinzhou Tian

Subjects
Amyloid, Epidemiology, business.industry, Health Policy, Interleukin 1 Gene, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Immunology, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2006
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