Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility
Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility
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DOI：
10.1016/j.jpsychires.2015.04.013
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发表时间：
2015-07-01
影响因子：
4.8
通讯作者：
Costas, Javier
中科院分区：
文献类型：
--
作者：
Javier Suarez-Rama, Jose;Arrojo, Manuel;Costas, Javier
患精神分裂症的遗传风险中有一小部分可能是由于低频变异。这项多步骤研究试图找到11个精神分裂症易感基因编码区的高效低频变异，这些基因是由全基因组关联研究(Gwas)支持的，以及DISCI交互作用组(DISCI Interactome)的9个基因。在发现步骤中，对来自西班牙西北部加利西亚的153名精神分裂症患者和153名对照的每个样本总共125kb进行了重新测序，并通过负荷和基于方差的测试分析了低频变异在基因或DISCI基因集中的累积作用。相关结果在有适当数据的情况下进行荟萃分析。此外，在另外419例病例和398名对照中，仅对假定的破坏性变异进行了基因分型。发现步骤揭示了NRXN1罕见错义变异的保护作用，这一结果得到了Meta分析的支持(基于6项研究的3848名患者和3896名对照，OR=0.67，95%CI：0.47~0.94，P=0.021)。基于仅病例推定的破坏性变异的后续步骤揭示了AKAP9的一个有希望的风险变异。这个变种K873R在从数据库中纳入240个额外的西班牙对照后达到了名义上的意义。该变异体位于ADCY2结合区，在大型公共数据库中缺失。有趣的是，GWAS揭示了常见的ADCY2变异与双相情感障碍之间的关联，双相情感障碍是一种与精神分裂症有相当大遗传重叠的障碍。这些数据表明，NRXN1和AKAP9上罕见的错义变异在精神分裂症易感性中的作用，可能与兴奋性/抑制性突触平衡的改变有关，值得进一步研究。(C)2015爱思唯尔有限公司。保留所有权利。
A fraction of genetic risk to develop schizophrenia may be due to low-frequency variants. This multistep study attempted to find low-frequency variants of high effect at coding regions of eleven schizophrenia susceptibility genes supported by genome-wide association studies (GWAS) and nine genes for the DISCI interactome, a susceptibility gene-set. During the discovery step, a total of 125 kb per sample were resequenced in 153 schizophrenia patients and 153 controls from Galicia (NW Spain), and the cumulative role of low-frequency variants at a gene or at the DISCI gene-set were analyzed by burden and variance-based tests. Relevant results were meta-analyzed when appropriate data were available. In addition, case-only putative damaging variants were genotyped in a further 419 cases and 398 controls. The discovery step revealed a protective effect of rare missense variants at NRXN1, a result supported by meta-analysis (OR = 0.67, 95% Cl: 0.47-0.94, P = 0.021, based on 3848 patients and 3896 controls from six studies). The follow-up step based on case-only putative damaging variants revealed a promising risk variant at AKAP9. This variant, K873R, reached nominal significance after inclusion of 240 additional Spanish controls from databases. The variant, located in an ADCY2 binding region, is absent from large public databases. Interestingly, GWAS revealed an association between common ADCY2 variants and bipolar disorder, a disorder with considerable genetic overlap with schizophrenia. These data suggest a role of rare missense variants at NRXN1 and AKAP9 in schizophrenia susceptibility, probably related to alteration of the excitatory/inhibitory synaptic balance, deserving further investigation. (C) 2015 Elsevier Ltd. All rights reserved.