A polygenic resilience score moderates the genetic risk for schizophrenia

Hess, Jonathan L.; Sigurdsson, Engilbert; Stefansson, Hreinn; Stefansson, Kari

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dc.contributor	Háskóli Íslands
dc.contributor	University of Iceland
dc.contributor.author	Hess, Jonathan L.
dc.contributor.author	Sigurdsson, Engilbert
dc.contributor.author	orcid.org/0000-0002-9331-6666 Stefansson, Hreinn
dc.contributor.author	orcid.org/0000-0003-1676-864X Stefansson, Kari
dc.date.accessioned	2020-06-22T12:53:37Z
dc.date.available	2020-06-22T12:53:37Z
dc.date.issued	2019-09-06
dc.identifier.citation	Hess, J.L., Tylee, D.S., Mattheisen, M. et al. A polygenic resilience score moderates the genetic risk for schizophrenia. Molecular Psychiatry (2019). https://doi.org/10.1038/s41380-019-0463-8
dc.identifier.issn	1359-4184
dc.identifier.issn	1476-5578 (eISSN)
dc.identifier.uri	https://hdl.handle.net/20.500.11815/1898
dc.description	Publisher's version (útgefin grein)
dc.description.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.
dc.description.sponsorship	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).
dc.language.iso	en
dc.publisher	Springer Science and Business Media LLC
dc.relation	info:eu-repo/grantAgreement/EC/H2020/667302
dc.relation	info:eu-repo/grantAgreement/EC/FP7/602805
dc.relation.ispartofseries	Molecular Psychiatry;2019
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Mendelian disease
dc.subject	Schizophrenia
dc.subject	Genetics
dc.subject	Geðklofi
dc.subject	Erfðarannsóknir
dc.title	A polygenic resilience score moderates the genetic risk for schizophrenia
dc.type	info:eu-repo/semantics/article
dcterms.license	Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.description.version	Peer Reviewed
dc.identifier.journal	Molecular Psychiatry
dc.identifier.doi	10.1038/s41380-019-0463-8
dc.relation.url	https://www.nature.com/articles/s41380-019-0463-8
dc.contributor.department	Læknadeild (HÍ)
dc.contributor.department	Faculty of Medicine (UI)
dc.contributor.school	Heilbrigðisvísindasvið (HÍ)
dc.contributor.school	School of Health Sciences (UI)