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A polygenic resilience score moderates the genetic risk for schizophrenia

Authors :
Hess, Jonathan L
Tylee, Daniel S
Mors, Ole
Duan, Jubao
Dudbridge, Frank
Duncanson, Audrey
Durmishi, Naser
Edkins, Sarah
Ehrenreich, Hannelore
Eichhammer, Peter
Eriksson, Johan
Escott-Price, Valentina
Esko, Tõnu
Nordentoft, Merete
Essioux, Laurent
Fanous, Ayman H
Farh, Kai-How
Farrell, Martilias S
Frank, Josef
Franke, Lude
Freedman, Robert
Freeman, Colin
Freimer, Nelson B
Friedl, Marion
Hougaard, David M
Friedman, Joseph I
Fromer, Menachem
Gejman, Pablo V
Genovese, Giulio
Georgieva, Lyudmila
Giannoulatou, Eleni
Giegling, Ina
Gill, Michael
Gillman, Matthew
Giusti-Rodríguez, Paola
Byberg-Grauholm, Jonas
Godard, Stephanie
Goldstein, Jacqueline I
Golimbet, Vera
Gopal, Srihari
Gratten, Jacob
Gray, Emma
Gurling, Hugh
Gwilliam, Rhian
de Haan, Lieuwe
Hall, Jeremy
Bækvad-Hansen, Marie
Hammer, Christian
Hammond, Naomi
Hamshere, Marian L
Hansen, Mark
Hansen, Thomas
Haroutunian, Vahram
Hartmann, Annette M
Hellenthal, Garrett
Henskens, Frans A
Herms, Stefan
Greenwood, Tiffany A
Hirschhorn, Joel N
Hoffmann, Per
Hofman, Andrea
Hollegaard, Mads V
Huang, Hailiang
Hultman, Christina M
Hunt, Sarah E
Ikeda, Masashi
Iwata, Nakao
Iyegbe, Conrad
Tsuang, Ming T
Jablensky, Assen V
Jankowski, Janusz
Jayakumar, Alagurevathi
Joa, Inge
Jönsson, Erik G
Julià, Antonio
Kähler, Anna K
Kahn, René S
Kalaydjieva, Luba
Karachanak-Yankova, Sena
Curtis, David
Karjalainen, Juha
Kavanagh, David
Keller, Matthew C
Kendler, Kenneth S
Kennedy, James L
Khrunin, Andrey
Kim, Yunjung
Kirov, George
Klovins, Janis
Knight, Jo
Steinberg, Stacy
Knowles, James A
Konte, Bettina
Kucinskas, Vaidutis
Kucinskiene, Zita Ausrele
Kuzelova-Ptackova, Hana
Langford, Cordelia
Laurent, Claudine
Lawrie, Stephen
Lee, S Hong
Lee, Phil
Sigurdsson, Engilbert
Lee, Jimmy
Legge, Sophie E
Lencz, Todd
Lerer, Bernard
Levinson, Douglas F
Lewis, Cathryn M
Li, Tao
Li, Qingqin S
Li, Miaoxin
Liang, Kung-Yee
Mattheisen, Manuel
Stefánsson, Hreinn
Liddle, Jennifer
Lieberman, Jeffrey
Limborska, Svetlana
Lin, Kuang
Linszen, Don H
Liu, Jianjun
Lönnqvist, Jouko
Loughland, Carmel M
Lubinski, Jan
Macek, Milan
Stefánsson, Kári
Magnusson, Patrik K E
Maher, Brion S
Maier, Wolfgang
Malhotra, Anil K
Mallet, Jacques
Markus, Hugh S
Marsal, Sara
Mata, Ignacio
Mathew, Christopher G
Mattingsdal, Morten
Edenberg, Howard J
McCann, Owen T
McCarley, Robert W
McCarroll, Steven A
McCarthy, Mark I
McDonald, Colm
McIntosh, Andrew M
McQuillin, Andrew
Meier, Sandra
Meijer, Carin J
Melegh, Bela
Holmans, Peter
Melle, Ingrid
Mesholam-Gately, Raquelle I
Metspalu, Andres
Michie, Patricia T
Milani, Lili
Milanova, Vihra
Mokrab, Younes
Moran, Jennifer L
Morris, Derek W
Mowry, Bryan J
Faraone, Stephen V
Müller-Myhsok, Bertram
Murphy, Kieran C
Murray, Robin M
Myin-Germeys, Inez
Neale, Benjamin M
Nelis, Mari
Nenadic, Igor
Nertney, Deborah A
Nestadt, Gerald
Nicodemus, Kristin K
Glatt, Stephen J
Nikitina-Zake, Liene
Nisenbaum, Laura
Nordin, Annelie
Nöthen, Markus M
O'Callaghan, Eadbhard
O'Donovan, Michael C
O'Dushlaine, Colm
O'Neill, F Anthony
Oh, Sang-Yun
Olincy, Ann
Adolfsson, Rolf
Olsen, Line
Ophoff, Roel A
Van Os, Jim
Owen, Michael J
Palmer, Colin N A
Palotie, Aarno
Pantelis, Christos
Papadimitriou, George N
Papiol, Sergi
Parkhomenko, Elena
Agartz, Ingrid
Pato, Michele T
Pato, Carlos N
Paunio, Tiina
Pearson, Richard
Cairns, Murray J
DeLisi, Lynn E
Gershon, Elliot S
Kelly, Brian J
Lam, Max
Norgren, Nina
Agerbo, Esben
Paciga, Sara A
Tooney, Paul A
Wu, Jing Qin
Pejovic-Milovancevic, Milica
Perkins, Diana O
Pers, Tune H
Petryshen, Tracey L
Pietiläinen, Olli
Pimm, Jonathan
Pirinen, Matti
Albus, Margot
Plomin, Robert
Pocklington, Andrew J
Posthuma, Danielle
Potter, Simon C
Powell, John
Price, Alkes
Pulver, Ann E
Purcell, Shaun M
Quested, Digby
Rasmussen, Henrik B
Consortium, Schizophrenia Working Group of the Psychiatric Genomics
Alexander, Madeline
Rautanen, Anna
Ravindrarajah, Radhi
Reichenberg, Abraham
Reimers, Mark A
Richards, Alexander L
Ricketts, Michelle
Rietschel, Marcella
Riley, Brien P
Ripke, Stephan
Roffman, Joshua L
Amin, Farooq
Roussos, Panos
Ruderfer, Douglas M
Rujescu, Dan
Salomaa, Veikko
Sanders, Alan R
Sawcer, Stephen J
Schall, Ulrich
Schubert, Christian R
Schulze, Thomas G
Schwab, Sibylle G
Andreassen, Ole A
Scolnick, Edward M
Scott, Rodney J
Seidman, Larry J
Sham, Pak C
Shi, Jianxin
Silagadze, Teimuraz
Silverman, Jeremy M
Sim, Kang
Sklar, Pamela
Arranz, Maria J
Slominsky, Petr
Smoller, Jordan W
So, Hon-Cheong
Söderman, Erik
Spencer, Chris C A
Clair, David St
Stahl, Eli A
Stogmann, Elisabeth
Strange, Amy
Straub, Richard E
Bacanu, Silviu A
Strengman, Eric
Strohmaier, Jana
Stroup, T Scott
Su, Zhan
Subramaniam, Mythily
Sullivan, Patrick F
Suvisaari, Jaana
Svrakic, Dragan M
Szatkiewicz, Jin P
Tashakkori-Ghanbaria, Avazeh
Bakker, Steven
Thirumalai, Srinivas
Toncheva, Draga
Tosato, Sarah
Trembath, Richard C
Veijola, Juha
Visscher, Peter M
Viswanathan, Ananth C
Vukcevic, Damjan
Waddington, John
Waller, Matthew
Band, Gavin
Walsh, Dermot
Walshe, Muriel
Walters, James T R
Wang, Qiang
Wang, Dai
Webb, Bradley T
Weinberger, Daniel R
Weisbrod, Matthias
Weiser, Mark
Wendland, Jens R
Barroso, Ines
Weston, Paul
Whittaker, Pamela
Widaa, Sara
Wiersma, Durk
Wildenauer, Dieter B
Williams, Stephanie
Williams, Nigel M
Witt, Stephanie H
Wolen, Aaron R
Wong, Emily H M
Begemann, Martin
Wood, Nicholas W
Wormley, Brandon K
Wray, Naomi R
Xi, Hualin Simon
Zai, Clement C
Zheng, Xuebin
Zimprich, Fritz
Bellenguez, Céline
Research, Lundbeck Foundation Initiative for Integrative Psychiatric
Belliveau, Richard A
Bender, Stephan
Bene, Judit
Bergen, Sarah E
Bevilacqua, Elizabeth
Bigdeli, Tim B
Black, Donald W
Blackburn, Hannah
Blackwell, Jenefer M
Blackwood, Douglas H R
Børglum, Anders D
Bramon, Elvira
Brown, Matthew A
Bruggeman, Richard
Buccola, Nancy G
Buckner, Randy L
Bulik-Sullivan, Brendan
Bumpstead, Suzannah J
Buxbaum, Joseph D
Byerley, William
Cahn, Wiepke
Als, Thomas D
Cai, Guiqing
Campion, Dominique
Cantor, Rita M
Carr, Vaughan J
Carrera, Noa
Casas, Juan P
Catts, Stanley V
Chambert, Kimberley D
Chan, Ronald Y L
Chan, Raymond C K
Grove, Jakob
Chen, Eric Y H
Cheng, Wei
Cheung, Eric F C
Chong, Siow Ann
Cichon, Sven
Cloninger, C Robert
Cohen, David
Cohen, Nadine
Collier, David A
Cormican, Paul
Werge, Thomas
Corvin, Aiden
Craddock, Nick
Crespo-Facorro, Benedicto
Crowley, James J
Daly, Mark J
Darvasi, Ariel
Davidson, Michael
Davis, Kenneth L
Degenhardt, Franziska
Del Favero, Jurgen
Mortensen, Preben Bo
Deloukas, Panos
Demontis, Ditte
Dikeos, Dimitris
Dinan, Timothy
Djurovic, Srdjan
Domenici, Enrico
Donnelly, Peter
Donohoe, Gary
Drapeau, Elodie
Dronov, Serge
Læknadeild (HÍ)
Faculty of Medicine (UI)
Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Háskóli Íslands
University of Iceland
Adult Psychiatry
ANS - Complex Trait Genetics
ANS - Mood, Anxiety, Psychosis, Stress & Sleep
APH - Mental Health
Hess, Jonathan L
Tylee, Daniel S
Mattheisen, Manuel
Borglum, Anders D
Glatt, Stephen J
Lee, Sand Hong
Schizophrenia Working Group of thePsychiatric Genomics Consortium
Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)
Amsterdam Neuroscience - Complex Trait Genetics
Complex Trait Genetics
Myin-Germeys, Inez
Source :
Hess, J L, Tylee, D S, Mattheisen, M, Børglum, A D, Als, T D, Grove, J, Werge, T, Mortensen, P B, Mors, O, Nordentoft, M, Hougaard, D M, Byberg-Grauholm, J, Bækvad-Hansen, M, Greenwood, T A, Tsuang, M T, Curtis, D, Steinberg, S, Sigurdsson, E, Stefánsson, H, Stefánsson, K, Edenberg, H J, Holmans, P, Faraone, S V, Glatt, S J, Schizophrenia Working Group of the Psychiatric Genomics Consortium & Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 2021, ' A polygenic resilience score moderates the genetic risk for schizophrenia ', Molecular Psychiatry, vol. 26, no. 3, pp. 800-815 . https://doi.org/10.1038/s41380-019-0463-8, Schizophrenia Working Group of the Psychiatric Genomics Consortium 2019, ' A polygenic resilience score moderates the genetic risk for schizophrenia ', Molecular Psychiatry . https://doi.org/10.1038/s41380-019-0463-8, Molecular psychiatry 26, 800–815 (2021). doi:10.1038/s41380-019-0463-8, Molecular psychiatry, Molecular psychiatry, 26, 800-815. Nature Publishing Group, Hess, J L, Tylee, D S, Mattheisen, M, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Børglum, A D, Als, T D, Grove, J, Werge, T, Mortensen, P B, Mors, O, Nordentoft, M, Hougaard, D M, Byberg-Grauholm, J, Bækvad-Hansen, M, Greenwood, T A, Tsuang, M T, Curtis, D, Steinberg, S, Sigurdsson, E, Stefánsson, H, Stefánsson, K, Edenberg, H J, Holmans, P, Faraone, S V & Glatt, S J 2021, ' A polygenic resilience score moderates the genetic risk for schizophrenia ', Molecular Psychiatry, vol. 26, no. 3, pp. 800–815 . https://doi.org/10.1038/s41380-019-0463-8, Molecular psychiatry, vol 26, iss 3, Hess, J L, Tylee, D S, Mattheisen, M, The Schizophrenia Working Group of the Psychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Børglum, A D, Als, T D, Grove, J, Werge, T, Mortensen, P B, Mors, O, Nordentoft, M, Hougaard, D M, Byberg-grauholm, J, Bækvad-hansen, M, Greenwood, T A, Tsuang, M T, Curtis, D, Steinberg, S, Sigurdsson, E, Stefánsson, H, Stefánsson, K, Edenberg, H J, Holmans, P, Faraone, S V & Glatt, S J 2021, ' A polygenic resilience score moderates the genetic risk for schizophrenia ', Molecular Psychiatry, vol. 26, pp. 800–815 . https://doi.org/10.1038/s41380-019-0463-8, Molecular Psychiatry, 26(3), 800-815. Nature Publishing Group
Publication Year :
2021
Publisher :
Nature Publishing Group, 2021.

Abstract

Publisher's version (útgefin grein)<br />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.<br />SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).

Details

Language :
English
ISSN :
14765578 and 13594184
Volume :
26
Issue :
3
Database :
OpenAIRE
Journal :
Molecular Psychiatry
Accession number :
edsair.doi.dedup.....3471197df8fec836d8bcf93e6e4b37fd