Sieradzka Dominika, Power Robert A, Freeman Daniel, Cardno Alastair G, McGuire Philip, Plomin Robert, Meaburn Emma L, Dudbridge Frank, Ronald Angelica
Centre for Brain and Cognitive Development, Birkbeck, University of London, London, United Kingdom.
King's College London, Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London, United Kingdom.
PLoS One. 2014 Apr 9;9(4):e94398. doi: 10.1371/journal.pone.0094398. eCollection 2014.
Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value = 2.57×10⁻⁴) and rs9960767 (p-value = 6.23×10⁻⁴). Replication in an independent sample of 16-year-olds (N = 3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed.
精神病被假设为一种连续分布的定量表型，而精神分裂症和双相情感障碍等疾病则代表了其极端表现。有证据表明，常见的基因变异在精神分裂症和双相情感障碍的易感性中起着重要作用。在此，我们检验了这样一个假设，即这些常见变异也会影响普通人群中青少年以维度方式测量的精神病体验。我们的目的是检验精神分裂症和双相情感障碍的多基因风险评分（PRS）以及先前被确定为精神分裂症风险变异的特定单核苷酸多态性（SNP）是否与青少年维度特异性精神病体验相关。通过特定精神病体验问卷（SPEQ）测量的自我报告的偏执、幻觉、认知紊乱、夸大、快感缺失以及父母评定的阴性症状，在一个由2152名16岁青少年组成的社区样本中进行了评估。多基因风险评分是使用来自精神病基因组学联盟对精神分裂症和双相情感障碍的GWAS第一阶段大型分析的优势比对数估计值来计算的。多基因风险分析未发现精神分裂症和双相情感障碍PRS与SPEQ测量值之间存在显著关联。对先前与精神分裂症相关的28个个体SNP的分析发现，TCF4中的两个SNP与SPEQ偏执维度存在显著关联，即rs17512836（p值 = 2.57×10⁻⁴）和rs9960767（p值 = 6.23×10⁻⁴）。在一个使用类精神病症状问卷（PLIKS - Q）评估的16岁独立样本（N = 3427）中进行重复验证，PLIKS - Q是多种阳性精神病体验的综合测量指标，但未得出显著结果。未来使用来自更大样本的PRS以及更大规模青少年验证样本的研究，将提高进一步检验这些假设的预测能力。文中还讨论了在基因水平上，将精神分裂症等成人临床诊断结构与青少年精神病体验联系起来所面临的挑战。
