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Previously, we developed a framework to mine genome\u2010wide association (GWAS) data for common genetic variants that protect high\u2010risk unaffected individuals from SCZ, leading to derivation of the first\u2010ever \u201cpolygenic resilience score\u201d for SCZ (resilient controls <jats:italic>n<\/jats:italic>\u2009=\u20093786; polygenic risk score\u2010matched SCZ cases <jats:italic>n<\/jats:italic>\u2009=\u200918,619). Here, we performed a replication study to verify the moderating effect of our polygenic resilience score on SCZ risk (OR\u2009=\u20091.09, <jats:italic>p<\/jats:italic>\u2009=\u20094.03\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>) using newly released GWAS data from 23 independent case\u2013control studies collated by the Psychiatric Genomics Consortium (PGC) (resilient controls <jats:italic>n<\/jats:italic>\u2009=\u20092821; polygenic risk score\u2010matched SCZ cases <jats:italic>n<\/jats:italic>\u2009=\u20095150). Additionally, we sought to optimize our polygenic resilience\u2010scoring 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.<\/jats:p>","DOI":"10.1002\/ajmg.b.32957","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T08:45:34Z","timestamp":1691484334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium"],"prefix":"10.1002","volume":"195","author":[{"given":"Jonathan L.","family":"Hess","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University  Syracuse New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Mattheisen","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry and Community Health and Epidemiology Dalhousie University  Halifax Nova Scotia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Schizophrenia Working Group of the Psychiatric Genomics Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany A.","family":"Greenwood","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming T.","family":"Tsuang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard J.","family":"Edenberg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Holmans","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences School of Medicine, Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen V.","family":"Faraone","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University  Syracuse New York USA"},{"name":"Department of Neuroscience and Physiology SUNY Upstate Medical University  Syracuse New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0360-7567","authenticated-orcid":false,"given":"Stephen J.","family":"Glatt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University  Syracuse New York USA"},{"name":"Department of Neuroscience and Physiology SUNY Upstate Medical University  Syracuse New York 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