ImportanceSchizophrenia and bipolar disorder are highly heritable psychiatric disorders with strong genetic and phenotypic overlap. Twin and molecular methods can be leveraged to predict the shared genetic liability to these disorders.ObjectiveTo investigate whether twin concordance for psychosis depends on the level of polygenic risk score (PRS) for psychosis and zygosity and compare PRS from cases and controls from several large samples and estimate the twin heritability of psychosis.Design, Setting, and ParticipantsIn this case-control study, psychosis PRS were generated from a genome-wide association study (GWAS) combining schizophrenia and bipolar disorder into a single psychosis phenotype and compared between cases and controls from the Schizophrenia and Bipolar Twin Study in Sweden (STAR) project. Further tests were conducted to ascertain if twin concordance for psychosis depended on the mean PRS for psychosis. Structural equation modeling was used to estimate heritability. This study constituted an analysis of existing clinical and population datasets with genotype and/or twin data. Included were twins from the STAR cohort and from the Swedish Twin Registry. Data were collected during the 2006 to 2013 period and analyzed from March 2023 to June 2024.ExposuresPRS for psychosis based on the most recent GWAS of combined schizophrenia/bipolar disorder.Main Outcomes and MeasuresPsychosis case status was assessed by clinical interviews and/or Swedish National Register data.ResultsThe final cohort comprised 87 pairs of twins with 1 or both affected and 59 unaffected pairs from the STAR project (for a total of 292 twins) as well as 443 pairs with 1 or both affected and 20 913 unaffected pairs from the Swedish Twin Registry. Among the 292 twins (mean [SD] birth year, 1960 [10.8] years; 158 female [54.1%]; 134 male [45.9%]), 134 were monozygotic twins, and 158 were dyzygotic twins. PRS for psychosis was higher in cases than in controls and associated with twin concordance for psychosis (1-SD increase in PRS, odds ratio [OR], 2.12; 95% CI, 1.23-3.87 on case status in monozygotic twins and OR, 2.74; 95% CI, 1.56-5.30 in dizygotic twins). The association between PRS for psychosis and concordance was not modified by zygosity. The twin heritability was estimated at 0.73 (95% CI, 0.30-1.00), which overlapped with the estimate in the full Swedish Twin Registry (0.69; 95% CI, 0.43-0.85).Conclusions and RelevanceIn this case-control study, using the natural experiment of twins, results suggest that twins with greater inherited liability for psychosis were more likely to have an affected co-twin. Results from twin and molecular designs largely aligned. Even as illness vulnerability is not solely genetic, PRS carried predictive power for psychosis even in a modest sample size.

中文翻译：

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精神分裂症和双相情感障碍的多基因风险评分和双胞胎一致性


重要性精神分裂症和双相情感障碍是高度遗传的精神疾病，具有很强的遗传和表型重叠。可以利用双胞胎和分子方法来预测这些疾病的共同遗传责任。目的调查精神病的双胞胎一致性是否取决于精神病和接合性的多基因风险评分（PRS）水平，并比较来自多个大样本的病例和对照的 PRS设计、设置和参与者在这项病例对照研究中，精神病 PRS 是根据全基因组关联研究 (GWAS) 生成的，该研究将精神分裂症和双相情感障碍合并为单一精神病表型，并在病例和对照之间进行比较来自瑞典精神分裂症和双相情感障碍研究 (STAR) 项目。进行了进一步的测试以确定双胞胎精神病的一致性是否取决于精神病的平均 PRS。结构方程模型用于估计遗传力。这项研究对现有的临床和人群数据集以及基因型和/或双胞胎数据进行了分析。其中包括来自 STAR 队列和瑞典双胞胎登记处的双胞胎。数据收集于 2006 年至 2013 年期间，并于 2023 年 3 月至 2024 年 6 月进行分析。精神病暴露 PRS 基于合并精神分裂症/双相情感障碍的最新 GWAS。主要结果和措施精神病病例状态通过临床访谈和/或瑞典国家评估进行评估登记数据。结果最终队列包括来自 STAR 项目的 87 对双胞胎，其中 1 对或全部受影响，59 对未受影响（总共 292 对双胞胎），以及来自瑞典的 443 对双胞胎，其中 1 对或全部受影响，20 913 对未受影响。双注册表。 在292对双胞胎中（平均[SD]出生年份，1960[10.8]年；158名女性[54.1%]；134名男性[45.9%]），134名是同卵双胞胎，158名是异卵双胞胎。病例中精神病的 PRS 高于对照组，并且与精神病的双胞胎一致性相关（PRS 的 1-SD 增加，比值比 [OR]，2.12；同卵双胞胎病例状态的 95% CI，1.23-3.87，OR，2.74 ；异卵双胞胎中 95% CI，1.56-5.30）。 PRS 与精神病和一致性之间的关联并未因接合性而改变。双胞胎遗传力估计为 0.73（95% CI，0.30-1.00），与完整瑞典双胞胎登记处的估计值（0.69；95% CI，0.43-0.85）重叠。结论和相关性在这项病例对照研究中，使用对双胞胎进行的自然实验，结果表明，患有精神病的遗传倾向较高的双胞胎更有可能有一个受影响的同卵双胞胎。双胞胎和分子设计的结果基本一致。尽管疾病脆弱性不仅仅与遗传有关，但 PRS 即使在样本量不大的情况下也具有对精神病的预测能力。