Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease
Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease
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DOI：
10.1093/hmg/ddq264
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发表时间：
2010-09-01
影响因子：
3.5
通讯作者：
Weersma, Rinse K.
中科院分区：
文献类型：
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作者：
Fransen, Karin;Visschedijk, Marijn C.;Weersma, Rinse K.
克罗恩病 (CD) 的全基因组关联研究 (GWAS) 已确定了与 20% 的克罗恩病总遗传风险相似的基因座。其他遗传风险位点的一部分可能部分隐藏在 GWAS 数据分析所需的多重测试校正所丢弃的信号中。寻找这些隐藏基因座的策略需要大量的复制队列，并且执行成本高昂。我们采用了选择 SNP 进行后续跟踪的策略，该策略显示与基因表达 [顺式表达数量性状位点 (eQTL)] 相关，因为这些已被证明更有可能与性状相关。首先，我们表明在已知的 CD 相关基因座中存在过多的顺式 eQTL。然后通过从 CD GWAS 数据集中筛选前 500 个 SNP 命中来选择 SNP 进行后续研究。我们鉴定了 10 个 cis-eQTL SNP。在荷兰 CD 患者 (1539) 和健康对照 (2648) 的两个独立队列中测试了这 10 个 SNP 与 CD 的关联性。在综合分析中，我们鉴定了两个与UBE2L3中的CD rs2298428 (P = 5.22 x 10(-5))和BCL3中的rs2927488 (P = 2.94 x 10(-4))相关的顺式-eQTL SNP。添加先前报道的荟萃分析中的其他公开数据后，与 rs2298428 的关联几乎达到全基因组显着性（P = 2.40 x 10(-7)），并且与 rs2927488 的关联得到证实（P = 6.46 x 10(-4)）。我们已确定 UBE2L3 和 BCL3 可能是 CD 的新风险基因。 UBE2L3 还与其他免疫介导的疾病相关。这些结果表明，基于 eQTL 的后续预选择是从中等规模的 GWAS 中识别风险位点的有用方法。
Genome-wide association studies (GWAS) for Crohn's disease (CD) have identified loci explaining similar to 20% of the total genetic risk of CD. Part of the other genetic risk loci is probably partly hidden among signals discarded by the multiple testing correction needed in the analysis of GWAS data. Strategies for finding these hidden loci require large replication cohorts and are costly to perform. We adopted a strategy of selecting SNPs for follow-up that showed a correlation to gene expression [cis-expression quantitative trait loci (eQTLs)] since these have been shown more likely to be trait-associated. First we show that there is an overrepresentation of cis-eQTLs in the known CD-associated loci. Then SNPs were selected for follow-up by screening the top 500 SNP hits from a CD GWAS data set. We identified 10 cis-eQTL SNPs. These 10 SNPs were tested for association with CD in two independent cohorts of Dutch CD patients (1539) and healthy controls (2648). In a combined analysis, we identified two cis-eQTL SNPs that were associated with CD rs2298428 in UBE2L3 (P = 5.22 x 10(-5)) and rs2927488 in BCL3 (P = 2.94 x 10(-4)). After adding additional publicly available data from a previously reported meta-analysis, the association with rs2298428 almost reached genome-wide significance (P = 2.40 x 10(-7)) and the association with rs2927488 was corroborated (P = 6.46 x 10(-4)). We have identified UBE2L3 and BCL3 as likely novel risk genes for CD. UBE2L3 is also associated with other immune-mediated diseases. These results show that eQTL-based pre-selection for follow-up is a useful approach for identifying risk loci from a moderately sized GWAS.