Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Am J Med Genet B Neuropsychiatr Genet. 2020 Oct;183(7):403-411. doi: 10.1002/ajmg.b.32814. Epub 2020 Aug 19.
Schizophrenia has substantial variation in symptom severity, course of illness, and overall functioning. Earlier age of onset (AOO) is consistently associated with negative outcomes and yet the causes of this association are still unknown. We used a multiplex, extended pedigree design (total N = 771; 636 relatives from 43 multigenerational families with at least 2 relatives diagnosed with schizophrenia and 135 matched controls) to examine among the schizophrenia relatives (N = 103) the relationship between AOO and negative and positive symptom severity, cognition, and community functioning. Most importantly, we assessed whether there are shared genetic effects between AOO and negative symptoms, positive symptoms, cognition, and community functioning. As expected, earlier AOO was significantly correlated with increased severity of negative and positive symptoms and poorer cognition and community functioning among schizophrenia patients. Notably, the genetic correlation between AOO of schizophrenia and negative symptoms was significant (R = -1.00, p = .007). Although the genetic correlations between AOO and positive symptoms, cognition, and community functioning were estimated at maximum and in the predicted direction, they were not statistically significant. AOO of schizophrenia itself was modestly heritable, although not significant and negative symptoms, positive symptoms, and cognition were all strongly and significantly heritable. In sum, we replicated prior findings indicating that earlier AOO is associated with increased symptom severity and extended the literature by detecting shared genetic effects between AOO and negative symptoms, suggestive of pleiotropy.
精神分裂症在症状严重程度、病程和整体功能方面存在很大差异。发病年龄较早（AOO）与不良结局始终相关，但导致这种关联的原因仍不清楚。我们使用了一种多重、扩展的家系设计（总 N = 771；来自 43 个多代家族的 636 名亲属，其中至少有 2 名亲属被诊断为精神分裂症，135 名匹配对照），在精神分裂症亲属（N = 103）中检查 AOO 与阴性和阳性症状严重程度、认知和社区功能之间的关系。最重要的是，我们评估了 AOO 与阴性症状、阳性症状、认知和社区功能之间是否存在共同的遗传效应。正如预期的那样，AOO 较早与精神分裂症患者的阴性和阳性症状严重程度增加以及认知和社区功能下降显著相关。值得注意的是，精神分裂症 AOO 与阴性症状之间的遗传相关性显著（R = -1.00，p =.007）。虽然 AOO 与阳性症状、认知和社区功能之间的遗传相关性估计达到最大值且方向与预测一致，但它们在统计学上并不显著。精神分裂症 AOO 本身具有中等程度的遗传性，但不显著，阴性症状、阳性症状和认知都具有很强且显著的遗传性。总之，我们复制了先前的发现，即 AOO 较早与症状严重程度增加有关，并通过检测 AOO 与阴性症状之间的共同遗传效应扩展了文献，提示存在多效性。
