Experimental and Clinical Pharmacopsychology, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.
Schizophr Res. 2018 Aug;198:52-59. doi: 10.1016/j.schres.2017.12.011. Epub 2017 Dec 26.
Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5∗10). These results imply that PPI might be modulated by four genotypes - COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 - indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is - like the disease phenotype - highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.
感觉运动门控由声起始反应（ASR）的前脉冲抑制（PPI）来衡量，它被认为是精神分裂症最有前途的电生理内表型之一。在过去的十年中，许多出版物报告了精神分裂症患者和健康志愿者样本中遗传多态性与 PPI 之间的显著关联。然而，迄今为止，尚未发表对这些结果的稳健性进行全面评估。因此，我们对发表和未发表的与 ASR 的 PPI 相关的基因多态性进行了首次荟萃分析。未发表的与遗传多态性和 PPI 相关的关联来自三个独立的样本。总共包括来自 16 个独立样本的 120 个单观测值，这些样本有 2660 名研究参与者和 43 个多态性。基于错误发现率进行了多次测试校正，并考虑了分析的多态性数量后，四个变体显示出显著关联，尽管没有一个关联在全基因组校正后存活下来（P<5∗10）。这些结果表明，PPI 可能由四个基因型调节 - COMT rs4680（主要在男性中），GRIK3 rs1027599，TCF4 rs9960767 和 PRODH rs385440 - 表明这些基因变异在精神分裂症早期信息处理缺陷的发展中起作用。然而，单个基因对 PPI 的总体影响仍然相当小，这表明 PPI 与疾病表型一样，是高度多基因的。具有大样本量的全基因组分析研究将增强我们对 PPI 遗传结构的理解。
