OBJECTIVE Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia. METHODS The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites. RESULTS PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. CONCLUSIONS The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.

中文翻译：

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四个医疗保健系统 106,160 名患者的精神分裂症多基因风险评分的外显率和多效性。


目的 精神分裂症高风险个体可能受益于早期干预，但很少有经过验证的风险预测因子。基因分析是一种风险分层方法，已在研究队列中得到广泛验证。作者试图测试这种方法在临床环境中的实用性，并评估精神分裂症高遗传风险的更广泛的健康后果。方法 作者使用来自四个医疗保健系统的 106,160 名患者的电子健康记录来评估精神分裂症遗传风险的外显率和多效性。精神分裂症的多基因风险评分 (PRS) 是根据汇总统计数据计算得出的，并在全表组关联研究中测试了与 1,359 种疾病类别（包括精神分裂症和精神病）的关联。通过跨站点荟萃分析将效果结合起来。结果 PRS 与精神分裂症密切相关（PRS 每标准差增加的比值比为 1.55；95% CI=1.4、1.7），且处于 PRS 分布最高风险十分位数的患者患精神分裂症的几率比其他患者高 4.6 倍与最低十分之一的人 (95% CI=2.9, 7.3)。 PRS 还与其他表型呈正相关，包括焦虑、情绪、物质使用、神经系统和人格障碍，以及自杀行为、记忆丧失和泌尿系统综合症；它们与肥胖呈负相关。结论 该研究表明，精神分裂症遗传风险的可用测量方法与医疗机构中的精神分裂症密切相关，并且对相关精神疾病以及其他医学综合征具有多效性影响。 结果初步表明了未来 PRS 测试在医疗保健系统中的应用可能出现的机会和限制。