A polygenic resilience score moderates the genetic risk for schizophrenia

Hess JL, Tylee DS, Mattheisen M, Børglum AD, Als TD, Grove J, Werge T, Mortensen PB, Mors O, Nordentoft M, Hougaard DM, Byberg-Grauholm J, Bækvad-Hansen M, Greenwood TA, Tsuang MT, Curtis D, Steinberg S, Sigurdsson E, Stefánsson H, Stefánsson K, Edenberg HJ, Holmans P, Faraone SV, Glatt SJ, Adolfsson R, Agartz I, Agerbo E, Albus M, Alexander M, Amin F, Andreassen OA, Arranz MJ, Bacanu SA, Bakker S, Band G, Barroso I, Begemann M, Bellenguez C, Belliveau RA, Bender S, Bene J, Bergen SE, Bevilacqua E, Bigdeli TB, Black DW, Blackburn H, Blackwell JM, Blackwood DH, Bramon E, Brown MA, Bruggeman R, Buccola NG, Buckner RL, Bulik-Sullivan B, Bumpstead SJ, Buxbaum JD, Byerley W, Cahn W, Cai G, Campion D, Cantor RM, Carr VJ, Carrera N, Casas JP, Catts SV, Chambert KD, Chan RY, Chan RC, Chen EY, Cheng W, Cheung EF, Chong SA, Cichon S, Cloninger CR, Cohen D, Cohen N, Collier DA, Cormican P, Corvin A, Craddock N, Crespo-Facorro B, Crowley JJ, Daly MJ, Darvasi A, Davidson M, Davis KL, Degenhardt F, Del Favero J, Deloukas P, Demontis D, Dikeos D, Dinan T, Djurovic S, Domenici E, Donnelly P, Donohoe G, Drapeau E, Dronov S, Duan J, Dudbridge F, Duncanson A, Durmishi N, Edkins S, Ehrenreich H, Eichhammer P, Eriksson J, Escott-Price V, Esko T, Essioux L, Fanous AH, Farh KH, Farrell MS, Frank J, Franke L, Freedman R, Freeman C, Freimer NB, Friedl M, Friedman JI, Fromer M, Gejman PV, Genovese G, Georgieva L, Giannoulatou E, Giegling I, Gill M, Gillman M, Giusti-Rodríguez P, Godard S, Goldstein JI, Golimbet V, Gopal S, Gratten J, Gray E, Gurling H, Gwilliam R, de Haan L, Hall J, Hammer C, Hammond N, Hamshere ML, Hansen M, Hansen T, Haroutunian V, Hartmann AM, Hellenthal G, Henskens FA, Herms S, Hirschhorn JN, Hoffmann P, Hofman A, Hollegaard MV, Huang H, Hultman CM, Hunt SE, Ikeda M, Iwata N, Iyegbe C, Jablensky AV, Jankowski J, Jayakumar A, Joa I, Jönsson EG, Julià A, Kähler AK, Kahn RS, Kalaydjieva L, Karachanak-Yankova S, Karjalainen J, Kavanagh D, Keller MC, Kendler KS, Kennedy JL, Khrunin A, Kim Y, Kirov G, Klovins J, Knight J, Knowles JA, Konte B, Kucinskas V, Kucinskiene ZA, Kuzelova-Ptackova H, Langford C, Laurent C, Lawrie S, Lee SH, Lee P, Lee Chee Keong J, Legge SE, Lencz T, Lerer B, Levinson DF, Lewis CM, Li T, Li QS, Li M, Liang KY, Liddle J, Lieberman J, Limborska S, Lin K, Linszen DH, Liu J, Lönnqvist J, Loughland CM, Lubinski J, Macek M, Magnusson PK, Maher BS, Maier W, Malhotra AK, Mallet J, Markus HS, Marsal S, Mata I, Mathew CG, Mattingsdal M, McCann OT, McCarley RW, McCarroll SA, McCarthy MI, McDonald C, McIntosh AM, McQuillin A, Meier S, Meijer CJ, Melegh B, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mokrab Y, Moran JL, Morris DW, Mowry BJ, Müller-Myhsok B, Murphy KC, Murray RM, Myin-Germeys I, Neale BM, Nelis M, Nenadic I, Nertney DA, Nestadt G, Nicodemus KK, Nikitina-Zake L, Nisenbaum L, Nordin A, Nöthen MM, O'callaghan E, O'Donovan MC, O'Dushlaine C, O'neill FA, Oh SY, Olincy A, Olsen L, Ophoff RA, Van Os J, Owen MJ, Palmer CN, Palotie A, Pantelis C, Papadimitriou GN, Papiol S, Parkhomenko E, Pato MT, Pato CN, Paunio T, Pearson R, Cairns MJ, Delisi LE, Gershon ES, Kelly BJ, Lam M, Norgren N, Paciga SA, Tooney PA, Wu JQ, Pejovic-Milovancevic M, Perkins DO, Pers TH, Petryshen TL, Pietiläinen O, Pimm J, Pirinen M, Plomin R, Pocklington AJ, Posthuma D, Potter SC, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Rasmussen HB, Rautanen A, Ravindrarajah R, Reichenberg A, Reimers MA, Richards AL, Ricketts M, Rietschel M, Riley BP, Ripke S, Roffman JL, Roussos P, Ruderfer DM, Rujescu D, Salomaa V, Sanders AR, Sawcer SJ, Schall U, Schubert CR, Schulze TG, Schwab S, Scolnick EM, Scott RJ, Seidman LJ, Sham PC, Shi J, Silagadze T, Silverman JM, Sim K, Sklar P, Slominsky P, Smoller JW, So HC, Söderman E, Spencer CC, Clair DS, Stahl EA, Stogmann E, Strange A, Straub RE, Strengman E, Strohmaier J, Stroup TS, Su Z, Subramaniam M, Sullivan PF, Suvisaari J, Svrakic DM, Szatkiewicz JP, Tashakkori-Ghanbaria A, Thirumalai S, Toncheva D, Tosato S, Trembath RC, Veijola J, Visscher PM, Viswanathan AC, Vukcevic D, Waddington J, Waller M, Walsh D, Walshe M, Walters JT, Wang Q, Wang D, Webb BT, Weinberger DR, Weisbrod M, Weiser M, Wendland JR, Weston P, Whittaker P, Widaa S, Wiersma D, Wildenauer DB, Williams S, Williams NM, Witt SH, Wolen AR, Wong EH, Wood NW, Wormley BK, Wray NR, Xi HS, Zai CC, Zheng X, Zimprich F (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 26

Pages Range: 800-815

Journal Issue: 3

DOI: 10.1038/s41380-019-0463-8

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.

Authors with CRIS profile

Involved external institutions

Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Hadassah Medical Center / מרכז רפואי הדסה‎‎ Israel (IL) deCODE genetics Iceland (IS) Virginia Commonwealth University (VCU) United States (USA) (US) Massachusetts General Hospital United States (USA) (US) National Institute for Health and Welfare (THL) Finland (FI) University of Cambridge United Kingdom (GB) Stanford University United States (USA) (US) Institute of Mental Health Singapore (SG) Institute of Molecular Genetics, Russian Academy of Sciences Russian Federation (RU) Universität Basel Switzerland (CH) Karolinska Institute Sweden (SE) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) Illumina Inc United States (USA) (US) Keck School of Medicine of USC United States (USA) (US) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) State University of New York Upstate Medical University (SUNY) United States (USA) (US) kbo-Isar-Amper-Klinikum gemeinnützige GmbH Germany (DE) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) University of Pécs / Pécsi Tudományegyetem Hungary (HU) University of Edinburgh United Kingdom (GB) Icahn School of Medicine at Mount Sinai United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) Castle Peak Hospital China (CN) University of Antwerp / Universiteit Antwerpen Belgium (BE) University of Aberdeen United Kingdom (GB) Oulun Yliopisto / University of Oulo Finland (FI) University College London (UCL) United Kingdom (GB) Wellcome Centre for Human Genetics United Kingdom (GB) Wellcome Trust Sanger Institute - Genome Research Limited United Kingdom (GB) Emory University United States (USA) (US) Louisiana State University Health Sciences Center United States (USA) (US) Harvard University United States (USA) (US) Janssen Global Services, LLC United States (USA) (US) University of Newcastle (UoN) Australia (AU) Technical University of Denmark / Danmarks Tekniske Universitet (DTU) Denmark (DK) Churchill Hospital United Kingdom (GB) Tbilisi State Medical University Georgia (GE) Berkshire Healthcare NHS Foundation Trust United Kingdom (GB) Health Research Board Ireland (IE) University of Belgrade / Универзитет у Београду Serbia (RS) King’s College London United Kingdom (GB) University of Oxford United Kingdom (GB) Queen Elizabeth II Medical Centre (QEIIMC) Australia (AU) Centre for Addiction and Mental Health (CAMH) Canada (CA) Trinity College Dublin Ireland (IE) NorthShore University HealthSystem United States (USA) (US) Institute of Biological Psychiatry Denmark (DK) University of Amsterdam Netherlands (NL) VA Boston Healthcare System United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) University of Verona / Università degli Studi di Verona Italy (IT) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) University of California Los Angeles (UCLA) United States (USA) (US) Zucker Hillside Hospital United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Eli Lilly and Company United States (USA) (US) Johns Hopkins Hospital United States (USA) (US) University of California, Berkeley (UC Berkeley) United States (USA) (US) Georg-August-Universität Göttingen Germany (DE) Lieber Institute for Brain Development United States (USA) (US) Royal College of Surgeons in Ireland (RCSI) Ireland (IE) The Jane and Terry Semel Institute for Neuroscience and Human Behavior United States (USA) (US) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Johns Hopkins University (JHU) United States (USA) (US) University of Dundee United Kingdom (GB) Pfizer, Inc. United States (USA) (US) University of Oslo Norway (NO) University of Iowa United States (USA) (US) The University of Hong Kong (HKU) / 香港大學 Hong Kong (HK) Federal State Budget Scientific Institution Research Center of Neurology Russian Federation (RU) Genome Institute of Singapore Singapore (SG) Stavanger University Hospital Norway (NO) University of Galway (NUIG) / Ollscoil na Gaillimhe Ireland (IE) Queen's University United Kingdom (GB) Max-Planck-Institut für Experimentelle Medizin Germany (DE) Cardiff University United Kingdom (GB) University of Queensland Australia (AU) Landspítali / National University Hospital of Iceland Iceland (IS) Schizophrenia Research Institute Australia (AU) Martin-Luther-Universität Halle-Wittenberg (MLU) Germany (DE) University of Tartu Estonia (EE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Vilnius University / Vilniaus universitetas Lithuania (LT) University College Cork (UCC) Ireland (IE) Universität Regensburg Germany (DE) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) University of Western Australia (UWA) Australia (AU) Lancaster University United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Indiana University – Purdue University Indianapolis United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) PHI University Psychiatric Clinic / ЈЗУ Универзитетска клиника за психијатрија Republic of North Macedonia (MK) University of North Carolina at Chapel Hill United States (USA) (US) Medical University Sofia / Медицински университет Bulgaria (BG) Hebrew University of Jerusalem Israel (IL) University of Colorado at Boulder United States (USA) (US) NIHR Oxford Biomedical Research Centre United Kingdom (GB) Sorbonne Université France (FR) Maastricht University Netherlands (NL) Helsingin yliopisto / University of Helsinki Finland (FI) University of Chicago United States (USA) (US) Aarhus University Denmark (DK) London School of Hygiene and Tropical Medicine United Kingdom (GB) Wellcome Trust (WT) United Kingdom (GB) Folkhälsan Research Center Finland (FI) Fujita Health University Japan (JP) Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) West China Medical Center of Sichuan University / 四川大学华西医学中心 China (CN) Guy's Hospital United Kingdom (GB) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) Technische Universität Dresden Germany (DE) Chinese Academy of Sciences (CAS) / 中国科学院 China (CN) University of Colorado Anschutz Medical Campus United States (USA) (US) Umeå University Sweden (SE) Universitätsklinikum Jena Germany (DE) Washington University in St. Louis United States (USA) (US) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ Israel (IL) Beth Israel Deaconess Medical Center (BIDMC) United States (USA) (US) F. Hoffmann-La Roche Ltd Switzerland (CH) Veterans Health Administration (VHA) United States (USA) (US) Marqués de Valdecilla University Hospital / Hospital Universitario de Marqués de Valdecilla (HUMV) Spain (ES) Statens Serum Institut Denmark (DK) Peninsula College of Medicine and Dentistry (PCMD) United Kingdom (GB) Latvian Biomedical Research and Study centre (BMC) / Latvijas Biomedicīnas pētījumu un studiju centrs Latvia (LV) The University of Melbourne Australia (AU) Medizinische Universität Wien Austria (AT) St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB)

How to cite

APA:

Hess, J.L., Tylee, D.S., Mattheisen, M., Børglum, A.D., Als, T.D., Grove, J.,... Zimprich, F. (2021). A polygenic resilience score moderates the genetic risk for schizophrenia. Molecular Psychiatry, 26(3), 800-815. https://doi.org/10.1038/s41380-019-0463-8

MLA:

Hess, Jonathan L., et al. "A polygenic resilience score moderates the genetic risk for schizophrenia." Molecular Psychiatry 26.3 (2021): 800-815.

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