Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Hum Mol Genet. 2013 Jun 1;22(11):2293-302. doi: 10.1093/hmg/ddt063. Epub 2013 Feb 11.
We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.
我们先前已经确定了影响神经胶质瘤风险的 8q24.21 标签 SNP。我们试图使用来自四个全基因组关联研究的数据对该关联的功能基础进行精细定位，该研究共包括 4147 例神经胶质瘤病例和 7435 例对照。为了提高 700 kb 区域内的标记密度，我们使用 1000 基因组计划数据和 253 个人的高覆盖率测序数据进行了基因型推断。分析显示，一个推断的低频 SNP rs55705857（P = 2.24 × 10(-38)）足以完全捕获 8q24.21 关联。按神经胶质瘤亚型分析表明，rs55705857 与非胶质母细胞瘤多形性（非 GBM）肿瘤的关联仅限于非 GBM 肿瘤（P = 1.07 × 10(-67)）。在另外三个数据集（625 例非 GBM 病例，2412 例对照；P = 1.41 × 10(-28)）中验证了非 GBM 关联。在汇总分析中，rs55705857 与低级别神经胶质瘤相关的优势比为 4.3（P = 2.31 × 10(-94)）。rs55705857 映射到长非编码 RNA CCDC26 内高度进化保守的序列，这增加了其直接功能的可能性。这些数据为神经胶质瘤发病机制的病因学基础提供了更多的见解。
