Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.
J Alzheimers Dis. 2013;35(2):403-12. doi: 10.3233/JAD-122257.
The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632-0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males.
神经连接素和神经黏连蛋白之间的相互作用促进了功能性突触结构的形成。最近有报道称，神经连接素和神经黏连蛋白在突触处被早老素进行蛋白水解加工。基于这种相互作用以及早老素在家族性阿尔茨海默病（AD）中的作用，我们假设神经黏连蛋白-神经连接素途径的功能障碍可能与 AD 有关。为了探索这一假设，我们对包含 NRXN1、NRXN2、NRXN3 和 NLGN1 基因中的 1256 个 SNP 的 5 项全基因组关联研究（GWAS）进行了荟萃分析（3009 例病例和 3006 例对照个体）。我们在 NRXN3 基因中发现了一个标记物（rs17757879），该标记在所有 GWAS 中均表现出一致的保护作用，然而，所获得的统计学意义并未抵抗多重测试校正（OR=0.851，p=0.002）。尽管如此，性别分析表明，这种效应仅限于男性。对前 5 项 GWAS 的联合荟萃分析以及包括 1785 例病例和 1634 例对照的西班牙复制样本证实了这一观察结果（rs17757879，OR=0.742，95%CI=0.632-0.872，p=0.00028，最终荟萃分析）。我们得出结论，NRXN3 可能在男性 AD 易感性中起作用。
