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A polygenic resilience score moderates the genetic risk for schizophrenia

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DOI

  • Jonathan L Hess, Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
  • ,
  • Daniel S Tylee, Department of Psychiatry, Yale New Haven Hospital, New Haven, CT, USA.
  • ,
  • 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, Københavns Universitet, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
  • ,
  • Preben Bo Mortensen
  • Ole Mors
  • Merete Nordentoft, Københavns Universitet, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
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  • David M Hougaard, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
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  • Jonas Byberg-Grauholm, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
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  • Marie Bækvad-Hansen, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
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  • Tiffany A Greenwood, University of California San Diego
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  • Ming T Tsuang, University of California San Diego
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  • David Curtis, Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London, UK., University College London
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  • Stacy Steinberg, DeCODE Genetics/Amgen
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  • Engilbert Sigurdsson, National University Hospital Reykjavik, University of Iceland, Reykjavik
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  • Hreinn Stefánsson, DeCODE Genetics/Amgen
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  • Kári Stefánsson, DeCODE Genetics/Amgen, University of Iceland, Reykjavik
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  • Howard J Edenberg, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
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  • Peter Holmans, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
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  • Stephen V Faraone, Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
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  • Stephen J Glatt, Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY, USA. stephen.glatt@psychgenelab.com.

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.

OriginalsprogEngelsk
TidsskriftMolecular Psychiatry
Vol/bind26
Nummer3
Sider (fra-til)800–815
Antal sider16
ISSN1359-4184
DOI
StatusUdgivet - mar. 2021

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