Experimental and Clinical Pharmacopsychology, Clinic for Affective Disorders and General Psychiatry, University Hospital of Psychiatry Zurich, 8032 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6271-6. doi: 10.1073/pnas.1118051109. Epub 2012 Mar 26.
Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥ 4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.
几种转录因子 4（TCF4）的多态性已被证明会增加精神分裂症的风险，尤其是 TCF4 rs9960767。这种多态性与感觉运动门控受损有关，感觉运动门控通过前脉冲抑制来衡量，这是精神分裂症的一个既定的内表型。因此，我们研究了 TCF4 多态性是否也会影响精神分裂症的另一个拟议的内表型，即听觉诱发电位 P50 抑制评估的感觉门控。尽管感觉运动门控和感觉门控并不完全相同，但最近的数据表明它们具有共同的遗传基础。在德国六所学术机构的一项多中心研究中，我们应用听觉 P50 抑制范式对 1821 名（1023 名从不吸烟者，798 名吸烟者）随机从普通人群中选择的受试者进行了研究。样本被 21 个 TCF4 多态性进行了基因分型。鉴于吸烟在精神分裂症中非常普遍并影响感觉门控，我们还评估了吸烟行为、可替宁血浆浓度、呼出的一氧化碳和 Fagerström 测试（FTND）。TCF4 多态性 rs9960767、rs10401120rs、rs17597926 和 17512836 的精神分裂症风险等位基因携带者的 P50 抑制显著降低（P <0.0002-0.00005）。这些基因效应受到吸烟行为的调节，这表明 TCF4 基因型和吸烟状态之间存在显著的相互作用；重度吸烟者（FTND 评分≥4）比轻度吸烟者和从不吸烟者对 P50 抑制的基因效应更强。我们的发现表明，感觉门控受到 TCF4 基因型与吸烟的相互作用的调节，并且这两个因素可能在精神分裂症早期信息处理缺陷中发挥作用。因此，考虑到吸烟行为可能有助于寻找精神分裂症的遗传风险因素。
