Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.
Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
Transl Psychiatry. 2022 Jul 25;12(1):296. doi: 10.1038/s41398-022-02055-0.
Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
多基因风险评分（PRSs）可以提高迟发性阿尔茨海默病（LOAD）的风险预测能力，超出载脂蛋白 E（APOE）的预测能力，但尚未利用这些评分来识别遗传抗性因素。在这里，我们试图在（1）具有高 LOAD PRS 的无患病个体和（2）具有高 LOAD PRS 的无 APOE-ε4 携带者的无患病个体中识别出具有抗性的常见遗传变异。我们使用全基因组关联研究（GWAS）将 LOAD 最高遗传风险的“有弹性”的无患病个体与具有可比风险的 LOAD 病例进行对比。从 GWAS 结果中，我们构建了多基因弹性评分，以聚合促进 LOAD 弹性的风险正交常见变体的累加贡献。在八项独立研究中对弹性评分进行了复制。我们成功复制了两个降低 LOAD 遗传风险外显率的多基因弹性评分。我们还表明，多基因弹性评分与无患病个体中的多基因风险评分呈正相关，这可能有助于阻止疾病的发生。我们的研究结果与假设一致，即风险无关的常见变体组合通过调节遗传疾病风险来介导对 LOAD 的抗性。
