A polygenic resilience score moderates the genetic risk for schizophrenia

Hess, Jonathan L and Tylee, Daniel S and Mattheisen, Manuel and Børglum, Anders D and Als, Thomas D and Grove, Jakob and Werge, Thomas and Mortensen, Preben Bo and Mors, Ole and Nordentoft, Merete and Hougaard, David M and Byberg-Grauholm, Jonas and Bækvad-Hansen, Marie and Greenwood, Tiffany A and Tsuang, Ming T and Curtis, David and Steinberg, Stacy and Sigurdsson, Engilbert and Stefánsson, Hreinn and Stefánsson, Kári and Edenberg, Howard J and Holmans, Peter and Faraone, Stephen V and Glatt, Stephen J and Knight, Jo (2019) A polygenic resilience score moderates the genetic risk for schizophrenia. Molecular Psychiatry, 2019. ISSN 1359-4184

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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.

Item Type:
Journal Article
Journal or Publication Title:
Molecular Psychiatry
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2738
Subjects:
ID Code:
137409
Deposited By:
Deposited On:
07 Oct 2019 10:00
Refereed?:
Yes
Published?:
Published
Last Modified:
23 Mar 2020 00:52