Large-Scale East-Asian eQTL Mapping Reveals Novel Candidate Genes for LD Mapping and the Genomic Landscape of Transcriptional Effects of Sequence Variants
Large-Scale East-Asian eQTL Mapping Reveals Novel Candidate Genes for LD Mapping and the Genomic Landscape of Transcriptional Effects of Sequence Variants
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DOI：
10.1371/journal.pone.0100924
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发表时间：
2014-06-23
期刊：
影响因子：
3.7
通讯作者：
Yamada, Ryo
中科院分区：
文献类型：
--
作者：
Narahara, Maiko;Higasa, Koichiro;Yamada, Ryo
影响基因转录的序列变异概况对于理解影响表型变异和疾病易感性的机制非常重要。利用从 298 个日本人的外周血细胞中获得的 140 万个 SNP 的基因型以及 15,454 个编码基因和 6,113 个 lincRNA 基因的综合转录谱，我们绘制了表达数量性状基因座 (eQTL) 的图谱。我们鉴定了 3,804 个顺式 eQTL（距目标基因 500 kb 以内）和 165 个反式 eQTL（距目标基因 > 500 kb 或位于不同染色体上）。顺式 eQTL 通常位于基因的转录区域或邻近区域；在这些区域中，59个非翻译区域和59个侧翼区域的影响最大。公共数据库中积累的调控潜力的表观遗传证据解释了我们的 eQTL 的影响程度。顺式 eQTL 通常位于各自的目标基因附近（即使不在基因内）。当 eQTL 靠近目标基因时，观察到较大的效应大小，并且随着 eQTL 与基因距离的增加，效应大小明显减弱。使用非常严格的显着性阈值，我们鉴定了 165 个大效应反式 eQTL。我们使用 eQTL 图谱评估了 1,436 项全基因组关联研究 (GWAS) 中发现的 8,069 个与疾病相关的 SNP。我们鉴定出了可能真正致病的基因，但 GWAS 可能未能鉴定出 GWAS 鉴定的 SNP 中的 148 个；例如，TUFM (P = 3.3E-48) 被确定用于治疗炎症性肠病（早发型）； ZFP90 (P = 4.4E-34) 用于溃疡性结肠炎； IDUA (P = 2.2E-11) 治疗帕金森病。我们鉴定了四个基因（P
Profiles of sequence variants that influence gene transcription are very important for understanding mechanisms that affect phenotypic variation and disease susceptibility. Using genotypes at 1.4 million SNPs and a comprehensive transcriptional profile of 15,454 coding genes and 6,113 lincRNA genes obtained from peripheral blood cells of 298 Japanese individuals, we mapped expression quantitative trait loci (eQTLs). We identified 3,804 cis-eQTLs (within 500 kb from target genes) and 165 trans-eQTLs (>500 kb away or on different chromosomes). Cis-eQTLs were often located in transcribed or adjacent regions of genes; among these regions, 59 untranslated regions and 59 flanking regions had the largest effects. Epigenetic evidence for regulatory potential accumulated in public databases explained the magnitude of the effects of our eQTLs. Cis-eQTLs were often located near the respective target genes, if not within genes. Large effect sizes were observed with eQTLs near target genes, and effect sizes were obviously attenuated as the eQTL distance from the gene increased. Using a very stringent significance threshold, we identified 165 large-effect trans-eQTLs. We used our eQTL map to assess 8,069 disease-associated SNPs identified in 1,436 genome-wide association studies (GWAS). We identified genes that might be truly causative, but GWAS might have failed to identify for 148 out of the GWAS-identified SNPs; for example, TUFM (P = 3.3E-48) was identified for inflammatory bowel disease (early onset); ZFP90 (P = 4.4E-34) for ulcerative colitis; and IDUA (P = 2.2E-11) for Parkinson's disease. We identified four genes (P