Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC.
Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC.
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DOI：
10.1038/mp.2012.67
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发表时间：
2013-06
影响因子：
11
通讯作者：
O'Donovan MC
中科院分区：
文献类型：
--
作者：
Hamshere ML;Walters JT;Smith R;Richards AL;Green E;Grozeva D;Jones I;Forty L;Jones L;Gordon-Smith K;Riley B;O'Neill FA;Kendler KS;Sklar P;Purcell S;Kranz J;Schizophrenia Psychiatric Genome-wide Association Study Consortium;Wellcome Trust Case Control Consortium+;Wellcome Trust Case Control Consortium 2;Morris D;Gill M;Holmans P;Craddock N;Corvin A;Owen MJ;O'Donovan MC
精神分裂症全基因组协会联合会(PGC)强调了81个单核苷酸多态(SNPs)，这些SNPs有中等证据表明与精神分裂症有关。在对独立样本进行跟踪后，有7个基因座获得了全基因组意义(GWS)，但多个基因座测试表明，一些没有做到这一点的SNPs代表了真正的关联。我们检测了在氯氮平诊所(CLOZUK)就诊的2640名临床诊断为精神分裂症的患者(CLOZUK)、2504名研究诊断为双相情感障碍的患者和2878名对照组的81个SNPs中的78个。在CLOZUK，我们获得了不少于37个(47%)SNP的PGC相关等位基因的显著复制，包括许多先前的GWS MHC SNP以及我们有数据被PGC报告为GWS的3/6个非MHC SNP。在将新的精神分裂症数据与PGC的数据结合后，三个基因座(ITIH3/4、CACNA1C和SDCCAG8)上以前没有在精神分裂症中出现过GW的变异获得了这种支持。在双相情感障碍中，我们还获得了与PGC中与精神分裂症相关的21%的等位基因相关的重要证据。我们的研究独立地确认了与先前报道的3个GWS基因座在精神分裂症中的关联，并确定了精神分裂症中另外3个GWS基因座的第一个GWS证据。考虑到独立重复的数量和我们样本的力量，我们估计原始78个SNP中的98%(C.I.78-100%)代表了真正的关联。我们还为精神分裂症和双相情感障碍之间的遗传风险重叠提供了强有力的证据。
The Schizophrenia Psychiatric Genome-Wide Association Consortium (PGC) highlighted 81 single nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow up in independent samples, 7 loci attained genome wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS MHC SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to 3 loci previously reported to be GWS in schizophrenia and identifies the first GWS evidence in schizophrenia for a further 3 loci. Given the number of independent replications and the power of our sample, we estimate 98% (C.I. 78–100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.