Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain.
Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain.
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DOI：
10.1038/mp.2011.11
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发表时间：
2012-02
影响因子：
11
通讯作者：
O'Donovan MC
中科院分区：
文献类型：
--
作者：
Richards AL;Jones L;Moskvina V;Kirov G;Gejman PV;Levinson DF;Sanders AR;Molecular Genetics of Schizophrenia Collaboration (MGS);International Schizophrenia Consortium (ISC);Purcell S;Visscher PM;Craddock N;Owen MJ;Holmans P;O'Donovan MC
人们普遍认为，影响对常见疾病（包括精神分裂症）易感性的等位基因通常会通过影响基因表达来实现这一点。由于只有一小部分精神分裂症的遗传变异归因于特定的基因座，这仍然是一个未经证实的假设。国际精神分裂症联盟（ISC）最近报道了该疾病的实质性多基因贡献，并且精神分裂症风险等位基因在从全基因组关联研究（GWAS）中选择的关联边缘证据（p<0.5）的SNP中富集。因此，如果精神分裂症易感性等位基因富集了那些影响基因表达的等位基因，那么那些边缘相关的SNP（也是eQTL）与那些不是的SNP相比，应该携带更多真实的关联信号。为了验证这一点，我们从两个最大的精神分裂症GWAS数据集中鉴定了边缘相关（p<0.5）的SNP。我们基于来自成人大脑的eQTL数据集将eQTL状态分配给这些SNP。使用ISC报告的多基因评分分析方法，我们观察并重复了这样的观察结果，即高概率的顺式eQTL比低概率的顺式eQTL更好地预测精神分裂症。我们的数据支持这样的假设，即赋予精神分裂症风险的等位基因在影响基因表达的等位基因中富集。此外，我们的数据表明，尽管精神分裂症可能的发育起源，成人脑组织的研究可以在原则上允许相关的易感性eQTL被确定。
It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. Since only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among SNPs selected for marginal evidence for association (p<0.5) from genome wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs which are also eQTLs should carry more true association signals compared with SNPs which are not. To test this, we identified marginally associated (p<0.5) SNPs from two of the largest available schizophrenia GWAS datasets. We assigned eQTL status to those SNPs based upon an eQTL dataset derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can in principle allow relevant susceptibility eQTLs to be identified.