A comprehensive family-based replication study of schizophrenia genes.
A comprehensive family-based replication study of schizophrenia genes.
复制标题
DOI：
10.1001/jamapsychiatry.2013.288
复制
发表时间：
2013-06
期刊：
影响因子：
25.8
通讯作者：
van den Oord EJ
中科院分区：
文献类型：
--
作者：
Aberg KA;Liu Y;Bukszár J;McClay JL;Khachane AN;Andreassen OA;Blackwood D;Corvin A;Djurovic S;Gurling H;Ophoff R;Pato CN;Pato MT;Riley B;Webb T;Kendler K;O'Donovan M;Craddock N;Kirov G;Owen M;Rujescu D;St Clair D;Werge T;Hultman CM;Delisi LE;Sullivan P;van den Oord EJ
精神分裂症(SCZ)是一种毁灭性的精神疾病。确定增加对SCZ易感性的特定遗传变异和途径对于增进对疾病的了解和解决对新药靶点的迫切需求至关重要。鉴定SCZ易感基因。我们综合了18项全基因组关联研究(GWAS)的荟萃分析结果，这些研究涉及1085772个单核苷酸多态(SNPs)和6个数据库，这些数据库显示了SCZ的重要信息量。然后，在一项基于家庭的独立复制研究中，对9380个最有希望的SNPs进行了特定的基因分型，经过质量控制，该研究由8107个SNPs组成。连锁荟萃分析、脑转录组荟萃分析、候选基因数据库、OMIM、相关小鼠研究和表达数量性状基因座数据库。我们收集了6个数据库中的11 185例病例和10768例对照对象，经质量控制后，来自1811个核心家庭的6298人(包括3286例)。SCZ的病例对照状态。复制结果显示，P值较小的SNPs有极显著的富集性。在复制值为P<；01的SNP中，与GWASMeta分析中的效应方向相同的SNP在联合血统组(符号检验，P<；2.20×10−16)中为%，在仅有欧洲血统的受试者中为93%(P<；2.20×10−16)。我们的结果支持主要组织相容性复合体区域，表明在欧洲血统的受试者中，P<；.01的复制值总体上丰富了3.7倍。我们在TCF4(P=2.53×10−10)和NOTCH4(P=3.16×10−7)中复制了SNP，这是最可靠的SCZ发现之一。新发现包括POM121L2(P=3.51×10−7)、AS3MT(P=9.01×10−7)、CNNM2(P=6.07×10−7)和NT5C2(P=4.09×10−7)。为了探索许多小的影响，我们进行了路径分析。最重要的通路涉及神经元功能(轴突引导、神经系统和L1细胞黏附分子相互作用)和免疫系统(抗原处理、与T细胞相关的细胞黏附分子和移位到免疫突触)。我们复制了新的SCZ病基因和致病途径。更好地了解与精神分裂症有关的分子和生物机制可能会改善疾病管理，并可能确定新的药物靶点。
Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. To identify SCZ susceptibility genes. We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. Case-control status for SCZ. Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P<.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P<2.20×10−16) and 93% in subjects of European ancestry only (P<2.20×10−16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P<.01 in subjects from European ancestry. We replicated SNPs in TCF4 (P=2.53×10−10) and NOTCH4 (P=3.16×10−7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P=3.51×10−7), AS3MT (P=9.01×10−7), CNNM2 (P=6.07×10−7), and NT5C2 (P=4.09×10−7). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.