Benzel Isabel, Bansal Aruna, Browning Brian L, Galwey Nicholas W, Maycox Peter R, McGinnis Ralph, Smart Devi, St Clair David, Yates Phillip, Purvis Ian
Psychiatry CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW Harlow, Essex, UK.
Behav Brain Funct. 2007 Jun 28;3:31. doi: 10.1186/1744-9081-3-31.
Evidence of genetic association between the NRG1 (Neuregulin-1) gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and single-nucleotide polymorphisms (SNPs) in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia.
Eight genes from the ERBB and NRG families were tested for association to schizophrenia using a collection of 396 cases and 1,342 blood bank controls ascertained from Aberdeen, UK. A total of 365 SNPs were tested. Association testing of both alleles and genotypes was carried out using the fast Fisher's Exact Test (FET). To understand better the nature of the associations, all pairs of SNPs separated by >or= 0.5 cM with at least nominal evidence of association (P < 0.10) were tested for evidence of pairwise interaction by logistic regression analysis.
42 out of 365 tested SNPs in the eight genes from the ERBB and NRG gene families were significantly associated with schizophrenia (P < 0.05). Associated SNPs were located in ERBB4 and NRG1, confirming earlier reports. However, novel associations were also seen in NRG2, NRG3 and EGFR. In pairwise interaction tests, clear evidence of gene-gene interaction was detected for NRG1-NRG2, NRG1-NRG3 and EGFR-NRG2, and suggestive evidence was also seen for ERBB4-NRG1, ERBB4-NRG2, ERBB4-NRG3 and ERBB4-ERBB2. Evidence of intragenic interaction was seen for SNPs in ERBB4.
These new findings suggest that observed associations between NRG1 and schizophrenia may be mediated through functional interaction not just with ERBB4, but with other members of the NRG and ERBB families. There is evidence that genetic interaction among these loci may increase susceptibility to schizophrenia.
NRG1(神经调节蛋白-1)基因与精神分裂症之间的遗传关联证据现已充分记载。此外,最近的几份报告表明精神分裂症与神经调节蛋白-1的受体之一ERBB4中的单核苷酸多态性(SNP)之间存在关联。在本研究中,我们通过调查ERBB和NRG家族的所有八个基因与精神分裂症的关联,扩展了先前发表的关联研究。
使用从英国阿伯丁确定的396例病例和1342例血库对照样本,对ERBB和NRG家族中的八个基因与精神分裂症的关联进行测试。共测试了365个SNP。使用快速Fisher精确检验(FET)对等位基因和基因型进行关联测试。为了更好地理解关联的性质,对所有间距≥0.5 cM且至少有名义关联证据(P < 0.10)的SNP对进行逻辑回归分析,以检验成对相互作用的证据。
ERBB和NRG基因家族的八个基因中,365个测试SNP中有42个与精神分裂症显著相关(P < 0.05)。相关SNP位于ERBB4和NRG1中,证实了早期报告。然而,在NRG2、NRG3和EGFR中也发现了新的关联。在成对相互作用测试中,检测到NRG1-NRG2、NRG1-NRG3和EGFR-NRG2存在明确的基因-基因相互作用证据,ERBB4-NRG1、ERBB4-NRG2、ERBB4-NRG3和ERBB4-ERBB2也有提示性证据。在ERBB4的SNP中发现了基因内相互作用的证据。
这些新发现表明,观察到的NRG1与精神分裂症之间的关联可能不仅通过与ERBB4,还通过与NRG和ERBB家族的其他成员的功能相互作用来介导。有证据表明这些基因座之间的遗传相互作用可能增加对精神分裂症的易感性。