A polygenic resilience score moderates the genetic risk for schizophrenia

Jonathan L Hess; Daniel S Tylee; Manuel Mattheisen; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); Anders D Børglum; Thomas D Als; Jakob Grove; Thomas Werge; Preben Bo Mortensen; Ole Mors; Merete Nordentoft; David M Hougaard; Jonas Byberg-Grauholm; Marie Bækvad-Hansen; Tiffany A Greenwood; Ming T Tsuang; David Curtis; Stacy Steinberg; Engilbert Sigurdsson; Hreinn Stefánsson; Kári Stefánsson; Howard J Edenberg; Peter Holmans; Stephen V Faraone; Stephen J Glatt

doi:10.1038/s41380-019-0463-8

A polygenic resilience score moderates the genetic risk for schizophrenia

Mol Psychiatry. 2021 Mar;26(3):800-815. doi: 10.1038/s41380-019-0463-8. Epub 2019 Sep 6.

Authors

Jonathan L Hess¹, Daniel S Tylee^{1

2}, Manuel Mattheisen^{3

4

5}; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); Anders D Børglum^{3

4

5}, Thomas D Als^{3

4

5}, Jakob Grove^{3

4

5

6}, Thomas Werge^{3

7

8}, Preben Bo Mortensen^{3

4

9

10}, Ole Mors^{3

11}, Merete Nordentoft^{3

12}, David M Hougaard^{3

13}, Jonas Byberg-Grauholm^{3

13}, Marie Bækvad-Hansen^{3

13}, Tiffany A Greenwood¹⁴, Ming T Tsuang¹⁴, David Curtis^{15

16}, Stacy Steinberg¹⁷, Engilbert Sigurdsson^{18

19}, Hreinn Stefánsson¹⁷, Kári Stefánsson^{17

19}, Howard J Edenberg²⁰, Peter Holmans²¹, Stephen V Faraone^{1

22}, Stephen J Glatt^{23

24

25}

Collaborators

Rolf Adolfsson, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Ole A Andreassen, Maria J Arranz, Silviu A Bacanu, Steven Bakker, Gavin Band, Ines Barroso, Martin Begemann, Céline Bellenguez, Richard A Belliveau Jr, Stephan Bender, Judit Bene, Sarah E Bergen, Elizabeth Bevilacqua, Tim B Bigdeli, Donald W Black, Hannah Blackburn, Jenefer M Blackwell, Douglas H R Blackwood, Elvira Bramon, Matthew A Brown, Richard Bruggeman, Nancy G Buccola, Randy L Buckner, Brendan Bulik-Sullivan, Suzannah J Bumpstead, Joseph D Buxbaum, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M Cantor, Vaughan J Carr, Noa Carrera, Juan P Casas, Stanley V Catts, Kimberley D Chambert, Ronald Y L Chan, Raymond C K Chan, Eric Y H Chen, Wei Cheng, Eric F C Cheung, Siow Ann Chong, Sven Cichon, C Robert Cloninger, David Cohen, Nadine Cohen, David A Collier, Paul Cormican, Aiden Corvin, Nick Craddock, Benedicto Crespo-Facorro, James J Crowley, Mark J Daly, Ariel Darvasi, Michael Davidson, Kenneth L Davis, Franziska Degenhardt, Jurgen Del Favero, Panos Deloukas, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Enrico Domenici, Peter Donnelly, Gary Donohoe, Elodie Drapeau, Serge Dronov, Jubao Duan, Frank Dudbridge, Audrey Duncanson, Naser Durmishi, Sarah Edkins, Hannelore Ehrenreich, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Tõnu Esko, Laurent Essioux, Ayman H Fanous, Kai-How Farh, Martilias S Farrell, Josef Frank, Lude Franke, Robert Freedman, Colin Freeman, Nelson B Freimer, Marion Friedl, Joseph I Friedman, Menachem Fromer, Pablo V Gejman, Giulio Genovese, Lyudmila Georgieva, Eleni Giannoulatou, Ina Giegling, Michael Gill, Matthew Gillman, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Emma Gray, Hugh Gurling, Rhian Gwilliam, Lieuwe de Haan, Jeremy Hall, Christian Hammer, Naomi Hammond, Marian L Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M Hartmann, Garrett Hellenthal, Frans A Henskens, Stefan Herms, Joel N Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V Hollegaard, Hailiang Huang, Christina M Hultman, Sarah E Hunt, Masashi Ikeda, Nakao Iwata, Conrad Iyegbe, Assen V Jablensky, Janusz Jankowski, Alagurevathi Jayakumar, Inge Joa, Erik G Jönsson, Antonio Julià, Anna K Kähler, René S Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C Keller, Kenneth S Kendler, James L Kennedy, Andrey Khrunin, Yunjung Kim, George Kirov, Janis Klovins, Jo Knight, James A Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Cordelia Langford, Claudine Laurent, Stephen Lawrie, S Hong Lee, Phil Lee, Jimmy Lee, Sophie E Legge, Todd Lencz, Bernard Lerer, Douglas F Levinson, Cathryn M Lewis, Tao Li, Qingqin S Li, Miaoxin Li, Kung-Yee Liang, Jennifer Liddle, Jeffrey Lieberman, Svetlana Limborska, Kuang Lin, Don H Linszen, Jianjun Liu, Jouko Lönnqvist, Carmel M Loughland, Jan Lubinski, Milan Macek, Patrik K E Magnusson, Brion S Maher, Wolfgang Maier, Anil K Malhotra, Jacques Mallet, Hugh S Markus, Sara Marsal, Ignacio Mata, Christopher G Mathew, Morten Mattingsdal, Owen T McCann, Robert W McCarley, Steven A McCarroll, Mark I McCarthy, Colm McDonald, Andrew M McIntosh, Andrew McQuillin, Sandra Meier, Carin J Meijer, Bela Melegh, Ingrid Melle, Raquelle I Mesholam-Gately, Andres Metspalu, Patricia T Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Jennifer L Moran, Derek W Morris, Bryan J Mowry, Bertram Müller-Myhsok, Kieran C Murphy, Robin M Murray, Inez Myin-Germeys, Benjamin M Neale, Mari Nelis, Igor Nenadic, Deborah A Nertney, Gerald Nestadt, Kristin K Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Markus M Nöthen, Eadbhard O'Callaghan, Michael C O'Donovan, Colm O'Dushlaine, F Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Roel A Ophoff, Jim Van Os, Michael J Owen, Colin N A Palmer, Aarno Palotie, Christos Pantelis, George N Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T Pato, Carlos N Pato, Tiina Paunio, Richard Pearson, Murray J Cairns, Lynn E DeLisi, Elliot S Gershon, Brian J Kelly, Max Lam, Nina Norgren, Sara A Paciga, Paul A Tooney, Jing Qin Wu, Milica Pejovic-Milovancevic, Diana O Perkins, Tune H Pers, Tracey L Petryshen, Olli Pietiläinen, Jonathan Pimm, Matti Pirinen, Robert Plomin, Andrew J Pocklington, Danielle Posthuma, Simon C Potter, John Powell, Alkes Price, Ann E Pulver, Shaun M Purcell, Digby Quested, Henrik B Rasmussen, Anna Rautanen, Radhi Ravindrarajah, Abraham Reichenberg, Mark A Reimers, Alexander L Richards, Michelle Ricketts, Marcella Rietschel, Brien P Riley, Stephan Ripke, Joshua L Roffman, Panos Roussos, Douglas M Ruderfer, Dan Rujescu, Veikko Salomaa, Alan R Sanders, Stephen J Sawcer, Ulrich Schall, Christian R Schubert, Thomas G Schulze, Sibylle G Schwab, Edward M Scolnick, Rodney J Scott, Larry J Seidman, Pak C Sham, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M Silverman, Kang Sim, Pamela Sklar, Petr Slominsky, Jordan W Smoller, Hon-Cheong So, Erik Söderman, Chris C A Spencer, David St Clair, Eli A Stahl, Elisabeth Stogmann, Amy Strange, Richard E Straub, Eric Strengman, Jana Strohmaier, T Scott Stroup, Zhan Su, Mythily Subramaniam, Patrick F Sullivan, Jaana Suvisaari, Dragan M Svrakic, Jin P Szatkiewicz, Avazeh Tashakkori-Ghanbaria, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Richard C Trembath, Juha Veijola, Peter M Visscher, Ananth C Viswanathan, Damjan Vukcevic, John Waddington, Matthew Waller, Dermot Walsh, Muriel Walshe, James T R Walters, Qiang Wang, Dai Wang, Bradley T Webb, Daniel R Weinberger, Matthias Weisbrod, Mark Weiser, Jens R Wendland, Paul Weston, Pamela Whittaker, Sara Widaa, Durk Wiersma, Dieter B Wildenauer, Stephanie Williams, Nigel M Williams, Stephanie H Witt, Aaron R Wolen, Emily H M Wong, Nicholas W Wood, Brandon K Wormley, Naomi R Wray, Hualin Simon Xi, Clement C Zai, Xuebin Zheng, Fritz Zimprich

Affiliations

¹ Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
² Department of Psychiatry, Yale New Haven Hospital, New Haven, CT, USA.
³ iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
⁴ iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
⁵ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
⁶ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
⁷ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
⁸ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁹ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁰ Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
¹¹ Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
¹² Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
¹³ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
¹⁴ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹⁵ University College London Genetics Institute, London, UK.
¹⁶ Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London, UK.
¹⁷ deCODE Genetics/Amgen, Reykjavik, Iceland.
¹⁸ Department of Psychiatry, National University Hospital, Reykjavik, Iceland.
¹⁹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
²⁰ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
²¹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
²² Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
²³ Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA. stephen.glatt@psychgenelab.com.
²⁴ Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA. stephen.glatt@psychgenelab.com.
²⁵ Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY, USA. stephen.glatt@psychgenelab.com.

Abstract

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Genomics
Humans
Multifactorial Inheritance / genetics
Polymorphism, Single Nucleotide / genetics
Risk Factors
Schizophrenia* / genetics

Abstract

Publication types

MeSH terms

Grants and funding