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

Simone de Jong; Mateus Jose Abdalla Diniz; Andiara Saloma; Ary Gadelha; Marcos L Santoro; Vanessa K Ota; Cristiano Noto; Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium; Charles Curtis; Stephen J Newhouse; Hamel Patel; Lynsey S Hall; Paul F O Reilly; Sintia I Belangero; Rodrigo A Bressan; Gerome Breen

doi:10.1038/s42003-018-0155-y

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

Commun Biol. 2018 Oct 8:1:163. doi: 10.1038/s42003-018-0155-y. eCollection 2018.

Authors

Simone de Jong^{1

2}, Mateus Jose Abdalla Diniz^{3

4}, Andiara Saloma^{3

4}, Ary Gadelha³, Marcos L Santoro⁵, Vanessa K Ota^{3

5}, Cristiano Noto³; Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium; Charles Curtis^{1

2}, Stephen J Newhouse^{2

6

7}, Hamel Patel^{2

6}, Lynsey S Hall⁸, Paul F O Reilly¹, Sintia I Belangero^{3

5}, Rodrigo A Bressan³, Gerome Breen^{9

10}

Collaborators

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

Affiliations

¹ MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
² National Institute of Health Research Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
³ Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, 04021-001, Brazil.
⁴ Pax Instituto de Psiquiatria, BR153, km 505, Villa Sul V, Aparecida de Goiânia, 74911-516, Brazil.
⁵ Department of Morphology and Genetics, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, 04021-001, Brazil.
⁶ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
⁷ Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, NW1 2DA, UK.
⁸ Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF10 3AT, UK.
⁹ MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, SE5 8AF, UK. gerome.breen@gmail.com.
¹⁰ National Institute of Health Research Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK. gerome.breen@gmail.com.

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.

Abstract

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