TY - JOUR
T1 - A polygenic resilience score moderates the genetic risk for schizophrenia
AU - Hess, Jonathan L.
AU - Tylee, Daniel S.
AU - Mattheisen, Manuel
AU - The Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)
A2 - Adolfsson, Rolf
A2 - Agartz, Ingrid
A2 - Agerbo, Esben
A2 - Albus, Margot
A2 - Alexander, Madeline
A2 - Amin, Farooq
A2 - Andreassen, Ole A.
A2 - Arranz, Maria J.
A2 - Bacanu, Silviu A.
A2 - Bakker, Steven
A2 - Band, Gavin
A2 - Barroso, Ines
A2 - Begemann, Martin
A2 - Bellenguez, Céline
A2 - Belliveau, Richard A.
A2 - Bender, Stephan
A2 - Bene, Judit
A2 - Bergen, Sarah E.
A2 - Bevilacqua, Elizabeth
A2 - Bigdeli, Tim B.
A2 - Black, Donald W.
A2 - Blackburn, Hannah
A2 - Blackwell, Jenefer M.
A2 - Blackwood, Douglas H.R.
A2 - Bramon, Elvira
A2 - Brown, Matthew A.
A2 - Bruggeman, Richard
A2 - Buccola, Nancy G.
A2 - Buckner, Randy L.
A2 - Bulik-Sullivan, Brendan
A2 - Bumpstead, Suzannah J.
A2 - Buxbaum, Joseph D.
A2 - Byerley, William
A2 - Cahn, Wiepke
A2 - Cai, Guiqing
A2 - Campion, Dominique
A2 - Cantor, Rita M.
A2 - Carr, Vaughan J.
A2 - Carrera, Noa
A2 - Casas, Juan P.
A2 - Catts, Stanley V.
A2 - Chambert, Kimberley D.
A2 - Chan, Ronald Y.L.
A2 - Chan, Raymond C.K.
A2 - Chen, Eric Y.H.
A2 - Cheng, Wei
A2 - Nikitina-Zake, Liene
A2 - Klovins, Janis
N1 - Funding Information:
Acknowledgements SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).
Publisher Copyright:
© 2019, The Author(s).
PY - 2021
Y1 - 2021
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
M3 - Article
C2 - 31492941
AN - SCOPUS:85073941184
SN - 1359-4184
VL - 26
SP - 800
EP - 815
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 3
ER -
