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Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis.
Molecular Psychiatry ( IF 11.0 ) Pub Date : 2018-May-01 , DOI: 10.1038/mp.2017.154


Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10-7; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10-6; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10-6; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ⩾40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.

中文翻译:

使用荟萃分析揭示强迫症的复杂遗传结构。

独立的强迫症协会,国际强迫症基金会遗传学合作组织(IOCDF-GC)和强迫症患者遗传学联合会研究(OCGAS)已发表了两项强迫症(OCD)全基因组关联研究(GWAS),但仅一项研究支持了许多排名最高的信号。因此,我们从这两个财团进行了荟萃分析,共调查了2688名欧洲血统的强迫症患者和7037个基因组匹配的对照。没有单核苷酸多态性(SNPs)达到全基因组意义。但是,与两个单独的GWAS相比,P值的分布向显着性转移。顶部单倍型区标记为rs4733767(P = 7.1×10 -7; 比值比(OR)= 1.21;置信区间(CI):1.12-1.31,CASC8 / CASC11),rs1030757(P = 1.1×10 -6 ; OR = 1.18; CI:1.10-1.26,GRID2)和rs12504244(P = 1.6×10 -6; 或= 1.18; CI:1.11-1.27,KIT)。位于连锁峰和原始GWAS中的,位于基因ASB13,RSPO4,DLGAP1,PTPRD,GRIK2,FAIM2和CDH20中或附近的变体是最高信号。每个单独研究的多基因风险评分分别通过解释OCGAS和欧洲IOCDF-GC目标样本的表型变异的0.9%(P = 0.003)和0.3%(P = 0.0009)来预测病例对照状态。合并的OCGAS和IOCDF-GC样品中常见的SNP遗传力估计为0.28(se = 0.04)。令人惊讶的是,OCGAS样本中约65%的基于SNP的遗传力是由等位基因频率⩾40%的SNP引起的。这项联合分析构成了迄今为止最大的单个OCD全基因组研究,代表了阐明OCD遗传原因的主要整合步骤。
更新日期:2018-05-07
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