MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
Mol Psychiatry. 2012 Feb;17(2):193-201. doi: 10.1038/mp.2011.11. Epub 2011 Feb 22.
It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. As 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 single-nucleotide polymorphisms (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 expression quantitative trait loci (eQTLs), should carry more true association signals compared with SNPs that are not marginally associated. To test this, we identified marginally associated (P<0.5) SNPs from two of the largest available schizophrenia GWAS data sets. We assigned eQTL status to those SNPs based upon an eQTL data set 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.
人们普遍认为，影响常见疾病（包括精神分裂症）易感性的等位基因通常通过对基因表达的影响来实现。由于精神分裂症的遗传变异只有一小部分归因于特定的基因座，因此这仍然是一个未经证实的假设。国际精神分裂症联盟（ISC）最近报告称，该疾病存在大量的多基因贡献，并且精神分裂症风险等位基因在单核苷酸多态性（SNP）中富集，这些 SNP 是从全基因组关联研究（GWAS）中选择的具有边缘关联证据（P<0.5）。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，那么那些边缘关联的 SNP（也是表达数量性状基因座（eQTL））与那些非边缘关联的 SNP 相比，应该携带更多的真实关联信号。为了验证这一点，我们从两个最大的可用精神分裂症 GWAS 数据集之一中确定了边缘关联的（P<0.5）SNP。我们根据来自成人大脑的 eQTL 数据集为这些 SNP 分配了 eQTL 状态。使用 ISC 报告的多基因评分分析方法，我们观察并复制了这样的观察结果，即更高概率的顺式 eQTL 比那些具有较低概率的顺式 eQTL 更好地预测精神分裂症。我们的数据支持这样一种假设，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具有发育起源，但对成人脑组织的研究原则上可以识别相关的易感性 eQTL。
