TY - JOUR
T1 - A polygenic resilience score moderates the genetic risk for schizophrenia
AU - The Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)
AU - Hess, Jonathan L.
AU - Tylee, Daniel S.
AU - Mattheisen, Manuel
AU - Adolfsson, Rolf
AU - Agartz, Ingrid
AU - Agerbo, Esben
AU - Albus, Margot
AU - Alexander, Madeline
AU - Amin, Farooq
AU - Andreassen, Ole A.
AU - Arranz, Maria J.
AU - Bacanu, Silviu A.
AU - Bakker, Steven
AU - Band, Gavin
AU - Barroso, Ines
AU - Begemann, Martin
AU - Bellenguez, Céline
AU - Belliveau, Richard A.
AU - Bender, Stephan
AU - Bene, Judit
AU - Bergen, Sarah E.
AU - Bevilacqua, Elizabeth
AU - Bigdeli, Tim B.
AU - Black, Donald W.
AU - Blackburn, Hannah
AU - Blackwell, Jenefer M.
AU - Blackwood, Douglas H.R.
AU - Bramon, Elvira
AU - Brown, Matthew A.
AU - Bruggeman, Richard
AU - Buccola, Nancy G.
AU - Buckner, Randy L.
AU - Bulik-Sullivan, Brendan
AU - Bumpstead, Suzannah J.
AU - Buxbaum, Joseph D.
AU - Byerley, William
AU - Cahn, Wiepke
AU - Cai, Guiqing
AU - Campion, Dominique
AU - Cantor, Rita M.
AU - Carr, Vaughan J.
AU - Carrera, Noa
AU - Casas, Juan P.
AU - Catts, Stanley V.
AU - Chambert, Kimberley D.
AU - Chan, Ronald Y.L.
AU - Chan, Raymond C.K.
AU - Chen, Eric Y.H.
AU - Davidson, Michael
AU - Weiser, Mark
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2021/3/1
Y1 - 2021/3/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85073941184&partnerID=8YFLogxK
U2 - 10.1038/s41380-019-0463-8
DO - 10.1038/s41380-019-0463-8
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C2 - 31492941
AN - SCOPUS:85073941184
SN - 1359-4184
VL - 26
SP - 800
EP - 815
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 3
ER -