Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy.
Epidemiol Psychiatr Sci. 2020 Nov 17;29:e182. doi: 10.1017/S2045796020000943.
Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum.
The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components).
Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions.
The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.
精神分裂症谱系障碍具有复杂的发病机制，其特征是环境和遗传易感性相互作用。本研究旨在使用整个精神分裂症易感性连续体的遗传（精神分裂症多基因风险评分（PRS-SCZ））和环境易感性（精神分裂症外显子组评分（ES-SCZ））的综合评分，来探讨基因-环境相互作用的作用。
该样本包括 1699 名患者、1753 名未受影响的兄弟姐妹和 1542 名健康对照参与者。对兄弟姐妹和健康对照参与者进行结构访谈性精神分裂症修订版（SIS-R）以分析总分、阳性和阴性精神分裂症评分。PRS-SCZ 是使用精神疾病基因组学联盟的结果进行训练的，ES-SCZ 是根据先前在当前数据集的报告中验证的方法计算的。回归模型用于测试 PRS-SCZ 和 ES-SCZ 的独立和联合作用（使用 10 个主成分进行年龄、性别和祖源调整）。
遗传和环境易感性均与病例对照状态相关。此外，PRS-SCZ 和 ES-SCZ 的二元模式之间存在累加交互作用的证据（超过控制分布的 75%），增加了精神分裂症谱系诊断的几率（交互的相对超额风险= 6.79 [95%置信区间（CI）3.32, 10.26]，p < 0.001）。使用连续 PRS-SCZ 和 ES-SCZ 的敏感性分析证实了基因-环境相互作用（交互的相对超额风险= 1.80 [95% CI 1.01, 3.32]，p = 0.004）。在兄弟姐妹和健康对照参与者中，PRS-SCZ 和 ES-SCZ 与 SIS-R 的所有维度均相关，并且在 PRS-SCZ 和 ES-SCZ 之间存在总（B = 0.006 [95% CI 0.003, 0.009]，p < 0.001）、阳性（B = 0.006 [95% CI，0.002，0.009]，p = 0.002）和阴性（B = 0.006，[95% CI 0.004, 0.009]，p < 0.001）精神分裂症维度之间存在交互作用。
外显子组负荷和精神分裂症遗传易感性在整个精神分裂症表达谱中的相互作用，为扩展的精神分裂症表型的病因连续性概念提供了进一步的经验支持。
