A polygenic resilience score moderates the genetic risk for schizophrenia

Jonathan L. Hess; Daniel S. Tylee; Manuel Mattheisen; 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

Jonathan L. Hess, Daniel S. Tylee, Manuel Mattheisen, 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 StefánssonHoward J. Edenberg, Peter Holmans, Stephen V. Faraone, Stephen J. Glatt

Department of Clinical Medicine

6 Citations (Scopus)

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.

Original language	English
Journal	Molecular Psychiatry
Number of pages	16
ISSN	1359-4184
DOIs	https://doi.org/10.1038/s41380-019-0463-8
Publication status	Published - 1 Mar 2021

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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., ... Glatt, S. J. (2021). A polygenic resilience score moderates the genetic risk for schizophrenia. Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0463-8

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 2021, 'A polygenic resilience score moderates the genetic risk for schizophrenia', Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0463-8

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title = "A polygenic resilience score moderates the genetic risk for schizophrenia",

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.",

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AU - Tylee, Daniel S.

AU - Mattheisen, Manuel

AU - Børglum, Anders D.

AU - Als, Thomas D.

AU - Grove, Jakob

AU - Werge, Thomas

AU - Mortensen, Preben Bo

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Byberg-grauholm, Jonas

AU - Bækvad-hansen, Marie

AU - Greenwood, Tiffany A.

AU - Tsuang, Ming T.

AU - Curtis, David

AU - Steinberg, Stacy

AU - Sigurdsson, Engilbert

AU - Stefánsson, Hreinn

AU - Stefánsson, Kári

AU - Edenberg, Howard J.

AU - Holmans, Peter

AU - Faraone, Stephen V.

AU - Glatt, Stephen J.

PY - 2021/3/1

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N2 - 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.

AB - 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.

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JF - Molecular Psychiatry

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A polygenic resilience score moderates the genetic risk for schizophrenia

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