No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: Implications for psychiatric genetics
No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: Implications for psychiatric genetics
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DOI：
10.1176/appi.ajp.2007.07101573
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发表时间：
2008-04-01
影响因子：
17.7
通讯作者：
Gejman, Pablo V.
中科院分区：
文献类型：
--
作者：
Sanders, Alan R.;Duan, Jubao;Gejman, Pablo V.
目的：对14个精神分裂症候选基因（RGS4、DISC1、DTNBP1、STX7、TAAR6、PPP3CC、NRG1、DRD2、HTR2A、DAOA、AKT1、CHRNA7、COMT、ARVCF）进行遗传关联研究。本研究使用迄今为止最大的样本，通过统一的临床方法和每个基因中最全面的单核苷酸多态性集，测试了精神分裂症与这些基因中常见单核苷酸多态性（snp）相关的假设。方法：样本包括1870例（精神分裂症和分裂情感性障碍）和2002例筛选的对照受试者（即对照组），均为欧洲血统，根据祖先信息标记分析排除了祖先异常值。作者对789个snp进行了基因分型，包括每个基因中最常见snp的标签，先前报道的相关snp，以及位于基因功能域的snp，如启动子，编码外显子（包括非同义snp）， 3'非翻译区和保守的非编码序列。经过大量的数据清理，分析了648个snp与单倍型的关联。结果：在初级单snp分析、单倍型的二级分析或其他常见HapMap snp的输入基因型分析中，均未观察到实验范围内或基因范围内的统计学意义。先前报道的与精神分裂症相关的snp结果与机会预期一致，COMT、DRD2和HTR2A中的四个功能多态性并没有产生名义上的显著证据来支持先前的关联证据。结论：这些基因中常见的snp不太可能占精神分裂症遗传风险的很大比例，尽管不能排除小的影响。
Objective: The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene.Method: The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes.Results: Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association.Conclusions: It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out.