A polygenic resilience score moderates the genetic risk for schizophrenia

被引：32

作者：

Hess, Jonathan L. ^{[1
]}

Tylee, Daniel S. ^{[1
,2
]}

Mattheisen, Manuel ^{[3
,4
,5
]}

Borglum, Anders D. ^{[3
,4
,5
]}

Als, Thomas D. ^{[3
,4
,5
]}

Grove, Jakob ^{[3
,4
,5
,6
]}

Werge, Thomas ^{[3
,7
,8
]}

Mortensen, Preben Bo ^{[3
,4
,9
,10
]}

Mors, Ole ^{[3
,11
]}

Nordentoft, Merete ^{[3
,12
]}

Hougaard, David M. ^{[3
,13
]}

Byberg-Grauholm, Jonas ^{[3
,13
]}

Baekvad-Hansen, Marie ^{[3
,13
]}

Greenwood, Tiffany A. ^{[14
]}

Tsuang, Ming T. ^{[14
]}

Curtis, David ^{[15
,16
]}

Steinberg, Stacy ^{[17
]}

Sigurdsson, Engilbert ^{[18
,19
]}

Stefansson, Hreinn ^{[17
]}

Stefansson, Kari ^{[17
,19
]}

Edenberg, Howard J. ^{[20
]}

Holmans, Peter ^{[21
]}

Faraone, Stephen, V ^{[1
,22
]}

Glatt, Stephen J. ^{[1
,22
,23
]}

机构：

[1] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Psychiat Genet Epidemiol & Neurobiol Lab PsychGEN, Syracuse, NY 13210 USA

[2] Yale New Haven Med Ctr, Dept Psychiat, 20 York St, New Haven, CT 06504 USA

[3] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Copenhagen, Denmark

[4] Aarhus Univ, Ctr Integrat Sequencing, iSEQ, Aarhus, Denmark

[5] Aarhus Univ, Dept Biomed Human Genet, Aarhus, Denmark

[6] Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark

[7] Mental Hlth Serv Copenhagen, Inst Biol Psychiat, MHC Sct Hans, Roskilde, Denmark

[8] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark

[9] Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark

[10] Aarhus Univ, Ctr Integrated Register Based Res, Aarhus, Denmark

[11] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark

[12] Univ Copenhagen, Mental Hlth Ctr Copenhagen, Mental Hlth Serv Capital Reg Denmark, Copenhagen, Denmark

[13] Statens Serum Inst, Ctr Neonatal Screening, Dept Congenital Disorders, Copenhagen, Denmark

[14] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[15] UCL, Genet Inst, London, England

[16] Barts & London Queen Marys Sch Med & Dent, Ctr Psychiat, London, England

[17] deCODE Genet Amgen, Reykjavik, Iceland

[18] Natl Univ Hosp Reykjavik, Dept Psychiat, Reykjavik, Iceland

[19] Univ Iceland, Fac Med, Reykjavik, Iceland

[20] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[21] Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, Med Res Council Ctr Neuropsychiat Genet & Genom, Cardiff, Wales

[22] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA

[23] SUNY Upstate Med Univ, Dept Publ Hlth & Prevent Med, Syracuse, NY 13210 USA

来源：

MOLECULAR PSYCHIATRY | 2021年 / 26卷 / 03期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1038/s41380-019-0463-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：800 / 815

页数：16

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