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.

中文翻译：

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多基因复原力评分可减轻精神分裂症的遗传风险：在精神病学基因组学联盟的 18,090 例病例和 28,114 例对照中进行复制。

确定可调节精神分裂症（SCZ）遗传风险的遗传因素可能有助于阐明为什么有些人尽管具有相对较高的遗传倾向，但仍未受到影响。此前，我们开发了一个框架来挖掘常见遗传变异的全基因组关联（GWAS）数据，这些变异可以保护未受影响的高风险个体免受 SCZ 的影响，从而得出 SCZ 的第一个“多基因弹性评分”（弹性对照 n = 3786；多基因风险评分匹配的 SCZ 病例 n = 18,619）。在这里，我们使用 Psychiatric Genomics 整理的 23 项独立病例对照研究新发布的 GWAS 数据进行了一项复制研究，以验证多基因复原力评分对 SCZ 风险的调节作用（OR = 1.09，p = 4.03 × 10-5）联盟 (PGC)（弹性对照 n = 2821；多基因风险评分匹配的 SCZ 病例 n = 5150）。此外，我们还试图优化我们的多基因弹性评分公式，以改进对 SCZ 和其他复杂疾病的弹性的后续建模。我们发现多基因弹性评分的显着复制，并发现基于已知风险 SNP 及其连锁位点的连锁不平衡对 SNP 进行严格修剪可以优化多基因弹性评分的性能。