Journal
MOLECULAR PSYCHIATRY
Volume 26, Issue 3, Pages 800-815Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-019-0463-8
Keywords
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Funding
- Medical Research Council [G0901310, G19/2, MR/L010305/1] Funding Source: Medline
- NIAAA NIH HHS [U10 AA008401] Funding Source: Medline
- NIA NIH HHS [R01 AG064955, R01 AG050595, R01 AG022381, R01 AG054002] Funding Source: Medline
- NIMH NIH HHS [R01 MH085548, U01 MH109532, R01 MH085521, R01 MH123451, R01 MH104964, R01 MH106611, U01 MH109536, R01 MH101519] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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This study proposed a theoretical framework based on genetic variations that promote resilience to highly heritable polygenic disorders, such as schizophrenia. By establishing a procedure to identify unaffected individuals with relatively high polygenic risk for the disease and generating the first known polygenic resilience score, this work laid a foundation for finding resilience variants for any complex, heritable disorder.
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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