A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium

Hess, Jonathan L., Mattheisen, Manuel, Greenwood, Tiffany A., Tsuang, Ming T., Edenberg, Howard J., Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Faraone, Stephen V. and Glatt, Stephen J. 2024. A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 195 (2) , e32957. 10.1002/ajmg.b.32957

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Abstract

Identifying heritable factors that moderate the genetic risk for schizophrenia (SCZ) could help clarify why some individuals remain unaffected despite having relatively high genetic liability. Previously, we developed a framework to mine genome-wide association (GWAS) data for common genetic variants that protect high-risk unaffected individuals from SCZ, leading to derivation of the first-ever “polygenic resilience score” for SCZ (resilient controls n = 3786; polygenic risk score-matched SCZ cases n = 18,619). Here, we performed a replication study to verify the moderating effect of our polygenic resilience score on SCZ risk (OR = 1.09, p = 4.03 × 10−5) using newly released GWAS data from 23 independent case–control studies collated by the Psychiatric Genomics Consortium (PGC) (resilient controls n = 2821; polygenic risk score-matched SCZ cases n = 5150). Additionally, we sought to optimize our polygenic resilience-scoring formula to improve subsequent modeling of resilience to SCZ and other complex disorders. We found significant replication of the polygenic resilience score, and found that strict pruning of SNPs based on linkage disequilibrium to known risk SNPs and their linked loci optimizes the performance of the polygenic resilience score.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Wiley
ISSN:	1552-4841
Date of First Compliant Deposit:	25 October 2023
Date of Acceptance:	25 July 2023
Last Modified:	08 Nov 2024 19:45
URI:	https://orca.cardiff.ac.uk/id/eprint/163489

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