A polygenic resilience score moderates the genetic risk for schizophrenia

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Francis O'Neill

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Number of pages16
JournalMolecular Psychiatry
Early online date06 Sep 2019
DOIs
Publication statusEarly online date - 06 Sep 2019

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Schizophrenia
Disease Resistance
Penetrance
Genomics
Psychiatry
Alleles
Psychology

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Schizophrenia Working Group of the Psychiatric Genomics Consortium ; O'Neill, Francis. / A polygenic resilience score moderates the genetic risk for schizophrenia. In: Molecular Psychiatry. 2019.
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A polygenic resilience score moderates the genetic risk for schizophrenia. / Schizophrenia Working Group of the Psychiatric Genomics Consortium ; O'Neill, Francis.

In: Molecular Psychiatry, 06.09.2019.

Research output: Contribution to journalArticle

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AU - Stefánsson, Hreinn

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