A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts
Guiyan Ni(The University of Queensland), Jian Zeng(The University of Queensland), Joana Revez(The University of Queensland), Ying Wang(The University of Queensland), Zhili Zheng(The University of Queensland), Tian Ge(Massachusetts General Hospital), Restuadi Restuadi(The University of Queensland), Jacqueline Kiewa(The University of Queensland), Dale R. Nyholt(Queensland University of Technology), Jonathan R. I. Coleman(King's College London), Jordan W. Smoller(Broad Institute), Stephan Ripke(The University of Queensland), Benjamin M. Neale(The University of Queensland), Aiden Corvin(The University of Queensland), James Walters, Kai-How Farh, Peter Holmans, Phil Lee, Brendan Bulik‐Sullivan, David Collier(The University of Queensland), Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu‐Alin Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C. K. Chan, Ronald Y.L. Chen, Eric Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del‐Favero, Ditte Demontis, Dimitris Dikeos, Timothy G. Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan G. Eriksson, Valentina Escott‐Price, Laurent Essioux(The University of Queensland), Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti‐Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, В. Е. Голимбет, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Folkmann Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva(The University of Queensland), Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Jānis Kloviņš, James A. Knowles, Bettina Konte, Vaidutis Kučinskas, Zita Aušrelė Kučinskienė, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, Sang Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung‐Yee Liang, Jeffrey Lieberman(The University of Queensland), Limborskaia Sa(The University of Queensland), Carmel M. Loughland, Jan Lubiński, Jouko Lönnqvist, Milan Maçek, Patrik K. E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Béla Melegh, Ingrid Melle, Raquelle I. Mesholam‐Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin Murray, Inez Myin‐Germeys(King's College London), Bertram Müller‐Myhsok, Mari Nelis, Igor Nenadić, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Ņikitina-Zaķe, 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(The University of Queensland), George N. Papadimitriou(The University of Queensland), Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejović-Milovančević, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew Pocklington, John Powell, Alkes L. Price, Ann E. Pulver(King's College London), Shaun Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, P. A. Slominsky, Jordan W. Smoller(Massachusetts General Hospital), Hon‐Cheong So, Chris C. A. Spencer, Eli A. Stahl, Hreinn Stefánsson(Broad Institute), Stacy Steinberg, Elisabeth Stögmann, Richard E. Straub(The University of Queensland), Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Švrakić, Jin Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Драга Тончева, Sarah Tosato, Juha Veijola, John L. Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer(The University of Queensland), Nigel Williams(The University of Queensland), Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray(The University of Queensland), Kari Stefansson, Peter M. Visscher(The University of Queensland), Rolf Adolfsson, Ole A. Andreassen(The University of Queensland), Douglas Blackwood, Elvira Bramon(The University of Queensland), Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon(King's College London), Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra(Broad Institute), Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran(The University of Queensland), Preben Bo Mortensen, Bryan Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Daniëlle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland(Broad Institute), Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael O‘Donovan, Naomi R. Wray(The University of Queensland), Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui(The University of Queensland), Mark J. Adams, Esben Agerbo, Tracy Air, Till F. M. Andlauer, Silviu‐Alin Bacanu, Marie Bækvad‐Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg‐Grauholm, Na Cai, Enrique Castelao, Jane Christensen, Toni‐Kim Clarke, Jonathan R. I. Coleman(King's College London), Lucía Colodro‐Conde(The University of Queensland), Baptiste Couvy‐Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies(King's College London), Ian J. Deary, Franziska Degenhardt, Eske M. Derks, Neşe Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott‐Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas Folkmann Hansen, Stefan Herms, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke‐Jan Hottenga, David M. Hougaard, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa Jones, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft(The University of Queensland), Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert Maier, Wolfgang Maier(The University of Queensland), Jonathan Marchini, Hamdi Mbarek, Patrick J. McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta(King's College London), Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi(The University of Queensland), Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt(Queensland University of Technology), Paul F. O’Reilly, Högni Óskarsson, Michael J. Owen(The University of Queensland), Jodie N. Painter, Carsten Bøcker Pedersen(Queensland University of Technology), Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Daniëlle Posthuma, Jorge Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Robert A. Schoevers, Eva C. Schulte, Ling Shen, Jianxin Shi, Stanley I. Shyn, Engilbert Sigurdsson, Grant Sinnamon, Johannes H. Smit, Daniel J. Smıth, Hreinn Stefánsson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley K. 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(The University of Queensland), Yunpeng Wang(The University of Queensland), Bradley T. Webb, Shantel Weinsheimer, Jürgen Wellmann, Gonneke Willemsen(The University of Queensland), Stephanie H. Witt(The University of Queensland), Yang Wu, Hualin Simon Xi, Jian Yang(The University of Queensland), Futao Zhang, Volker Arolt, Bernhard T. Baune(The University of Queensland), Klaus Berger, Dorret I. Boomsma(The University of Queensland), Sven Cichon, Udo Dannlowski, Eco 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. E. Magnusson, Nicholas G. Martin, Andrew M. McIntosh(The University of Queensland), Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller‐Myhsok, Merete Nordentoft, Markus M. Nöthen, Michael O‘Donovan(King's College London), Sara A. Paciga, Nancy L. Pedersen, Jian Yang(The University of Queensland), Peter M. Visscher(The University of Queensland), Naomi R. Wray(The University of Queensland)
Cited by 205Open Access
Abstract
BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors. METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared. RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively. CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.
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