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。可以利用孪生和分子方法来预测这些疾病的共同遗传易感性。目的探讨精神病的双胞胎一致性是否取决于精神病和合子的多基因风险评分 （PRS） 水平，比较病例和几个大样本的对照 PRS，估计精神病的双胞胎遗传性。设计、设置和参与者在这项病例对照研究中，精神病 PRS 是由一项全基因组关联研究 （GWAS） 产生的，该研究将精神分裂症和双相情感障碍结合成单一的精神病表型，并在瑞典精神分裂症和双相情感障碍研究 （STAR） 项目的病例和对照之间进行比较。进行了进一步的测试以确定精神病的双胞胎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。本研究对具有基因型和/或双胞胎数据的现有临床和人群数据集进行了分析。包括来自 STAR 队列和瑞典双胞胎登记处的双胞胎。数据是在 2006 年至 2013 年期间收集的，并在 2023 年 3 月至 2024 年 6 月期间进行了分析。主要结局和措施通过临床访谈和/或瑞典国家登记数据评估精神病病例状态。结果最终队列包括 87 对双胞胎，其中 1 对或同时受到影响，来自 STAR 项目的 59 对未受影响的双胞胎（总共 292 对双胞胎），以及 443 对患有 1 对或同时受影响的双胞胎和 20 913 对未受影响的双胞胎来自瑞典双胞胎登记处。 在 292 例双胞胎 （平均 [SD] 出生年份，1960 年 [10.8] 岁;158 例女性 [54.1%];134 例男性 [45.9%]）中，134 例是同卵双胞胎，158 例是匀卵双胞胎。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 增加 1-SD，比值比 [OR]，2.12;95% CI，1.23-3.87 在同卵双胞胎中，OR，2.74;95% CI，1.56-5.30）。精神病的 PRS 与一致性之间的关联未被合子改变。双胞胎遗传力估计为 0.73 （95% CI，0.30-1.00），这与完整的瑞典双胞胎登记处 （0.69;95% CI，0.43-0.85） 中的估计值重叠。结论和相关性在这项病例对照研究中，使用双胞胎的自然实验，结果表明，精神病遗传倾向更大的双胞胎更有可能患上受影响的双胞胎。双胞胎和分子设计的结果基本一致。尽管疾病易感性不仅仅是遗传性的，即使在适度的样本量中，PRS 也具有对精神病的预测能力。