ImportanceLarge-scale biobanks provide important opportunities for mental health research, but selection biases raise questions regarding the comparability of individuals with those in clinical research settings.ObjectiveTo compare the genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium (PGC) and to compare genetic liability and phenotypic features with participants recruited from clinical settings.Design, Setting, and ParticipantsThis cross-sectional study included participants from the population-based UK Biobank and schizophrenia samples recruited from clinical settings (CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected between January 1993 and July 2021. Data analysis was conducted between July 2021 and June 2023.Main Outcomes and MeasuresA genome-wide association study of UK Biobank schizophrenia case-control status was conducted, and the results were compared with those from the PGC via genetic correlations. To test for differences with the clinical samples, polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression, and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using pairwise logistic regressions. The proportions of individuals with copy number variants associated with schizophrenia were compared using Firth logistic regression.ResultsThe sample of 517 375 participants included 1438 UK Biobank participants with schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499 475 UK Biobank controls (271 884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to schizophrenia in UK Biobank was highly correlated with the latest genome-wide association study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained samples and significantly lower rates of schizophrenia-associated copy number variants than the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational attainment and employment rates than the clinically ascertained schizophrenia samples, lower rates of smoking, and a later age of onset of psychosis.Conclusions and RelevanceIndividuals with schizophrenia in the UK Biobank, and likely other volunteer-based biobanks, represent those less severely affected. Their inclusion in wider studies should enhance the representation of the full spectrum of illness severity.

中文翻译：

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英国生物库中精神分裂症的遗传和表型特征

重要性大规模生物样本库为心理健康研究提供了重要的机会，但选择偏差引发了关于个体与临床研究环境中个体的可比性的问题。目的比较英国生物样本库中精神分裂症个体与精神病学个体的精神疾病遗传倾向基因组学联盟 (PGC) 并将遗传倾向和表型特征与从临床环境中招募的参与者进行比较。设计、环境和参与者这项横断面研究包括来自基于人群的英国生物库的参与者和从临床环境中招募的精神分裂症样本（CLOZUK、卡迪夫COGS） 、卡迪夫 F 系列和卡迪夫受影响的同胞对）。数据收集于1993年1月至2021年7月之间。数据分析于2021年7月至2023年6月之间进行。主要结果和措施进行了英国生物银行精神分裂症病例对照状态的全基因组关联研究，并将结果与​​来自英国生物银行的研究结果进行了比较。通过遗传相关性进行 PGC。为了测试与临床样本的差异，使用 PRS-CS 计算了精神分裂症、双相情感障碍、抑郁症和智力的多基因风险评分 (PRS)。使用成对逻辑回归进行 PRS 和表型比较。使用 Firth 逻辑回归比较具有与精神分裂症相关的拷贝数变异的个体的比例。结果 517 375 名参与者的样本包括 1438 名患有精神分裂症的 UK Biobank 参与者（550 [38.2%] 女性；平均 [SD] 年龄，54.7 [8.3] 岁） ）、499 475 名英国生物银行对照（271 884 [54.4%] 女性；平均 [SD] 年龄，56.5 [8.1] 岁）和 4 个精神分裂症研究样本（4758 [28.9%] 女性；平均 [SD] 年龄，38.2 [ 21.0] 年）。英国生物银行的精神分裂症风险与 PGC 最新的全基因组关联研究高度相关（遗传相关性，0.98；SE，0.18），并显示出与其他精神疾病的预期相关模式。精神分裂症 PRS 解释了英国生物银行中精神分裂症病例状态责任差异的 6.8%。患有精神分裂症的 UK Biobank 参与者的精神分裂症 PRS 显着低于 3 个临床确定的样本，并且与 CLOZUK 样本相比，精神分裂症相关的拷贝数变异率也显着降低。患有精神分裂症的英国生物银行参与者比临床确定的精神分裂症样本具有更高的教育程度和就业率、更低的吸烟率以及较晚的精神病发病年龄。结论和相关性英国生物银行和可能的其他基于志愿者的生物银行中的精神分裂症个体，代表受影响较轻的群体。将它们纳入更广泛的研究中应该可以增强对疾病严重程度的全面描述。