University Mental Health Research Institute, Athens, Greece.
Schizophr Bull. 2013 Mar;39(2):349-57. doi: 10.1093/schbul/sbr169. Epub 2011 Nov 24.
Prior genetic and functional evidence established ERBB4 as a probable schizophrenia susceptibility gene that may confer risk via modulating brain information processing dependent on the integrity of frontotemporal brain circuitry. Utilizing retrospective data drawn from the cross-sectional population-based Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS) (n = 1127), we attempted to independently replicate and further extend previous findings by examining the effects of ERBB4 gene variants on 3 broad population-based psychosis-related phenotypes: verbal working memory (VWM), trait schizotypy, and stress-induced subclinical psychotic experiences (PE). Three common ERBB4 single nucleotide polymorphisms that were previously associated with schizophrenia and impaired frontotemporal-related information processing (rs7598440, rs839523, and rs707284), their haplotypes, and corresponding diplotypes were tested. VWM performance was significantly associated with rs839523 and rs707284 markers even after correction for multiple testing, thus validating reported findings that have implicated ERBB4 gene variation on working memory. No associations were detected between these ERBB4 variants and trait schizotypy. However, we were able to detect a significant effect of rs7598440 marker on PE expressed under stressful environmental conditions. Combined haplotype analysis of the above 3 markers, identified a "yin-yang" pattern of association, confirmed at the diplotype level. While GGG haplotype homozygotes were associated with "protective" effects on VWM performance and PE, AAA "risk" haplotype carriers were associated with worse VWM performance and simultaneously exhibited significantly elevated PE. This dual, possibly pleiotropic, impact on frontotemporal circuitry and increased sensitivity to psychosocial stress may represent subtle manifestations of ERBB4-related vulnerability to psychosis, expressed at the population level.
先前的遗传和功能证据表明 ERBB4 是一种可能的精神分裂症易感基因，它可能通过调节依赖于额颞叶脑回路完整性的大脑信息处理来产生风险。利用来自横断面人群为基础的雅典精神分裂症易感性和发病率研究（ASPIS）（n=1127）的回顾性数据，我们试图通过检查 ERBB4 基因变异对 3 种广泛的基于人群的精神病相关表型的影响，独立复制并进一步扩展先前的发现：言语工作记忆（VWM）、特质精神分裂症样和应激诱导的亚临床精神病体验（PE）。先前与精神分裂症和额颞叶相关信息处理受损相关的三种常见 ERBB4 单核苷酸多态性（rs7598440、rs839523 和 rs707284）、它们的单倍型及其相应的二倍型进行了测试。即使在进行多次测试校正后，VWM 表现仍与 rs839523 和 rs707284 标志物显著相关，从而验证了先前报道的 ERBB4 基因变异对工作记忆有影响的发现。在这些 ERBB4 变体和特质精神分裂症样之间没有检测到关联。然而，我们能够检测到 rs7598440 标志物在应激环境下表达的 PE 中的显著影响。上述 3 个标志物的联合单倍型分析确定了一种“阴阳”关联模式，并在二倍型水平上得到证实。当 GGG 单倍型纯合子与 VWM 表现和 PE 的“保护”作用相关联时，AAA“风险”单倍型携带者与较差的 VWM 表现相关联，同时表现出明显升高的 PE。这种对额颞叶电路的双重、可能是多效性影响，以及对心理社会应激的敏感性增加，可能代表 ERBB4 相关易感性对精神病的细微表现，在人群水平上表现出来。
