Integrating Genetics of Gene Expression into Pathway Analysis for Melanoma GWAS

将基因表达遗传学整合到黑色素瘤 GWAS 的通路分析中

• 批准号: 8879567
• 负责人: JIALI HAN
• 金额: $ 7.89万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879567
• 关键词: Integrating; Genetics; Gene; Expression; into

The genome-wide association studies (GWASs) have successfully identified a number of single nucleotide polymorphisms (SNPs) associated with melanoma risk. However, the traditional GWASs focus only on marginal effects of individual markers and have incorporated external functional information only after identifying robust statistical associations. It is often lack power to detect relatively small effects conferred by most genetic variants. The pathway-based approaches, which evaluate the cumulative contribution of the genes within biological pathways, may help collect the modest signals contained in the GWAS data and identify biological pathways in the etiology of disease on a pathway level. As used in the traditional pathway approaches, assigning SNPs to their physical location may introduce many false positive associations from multiple testing on non-functional SNPs and miss- annotate SNPs that regulate the expression of genes in distance. Instead, defining the expression quantitative trait loci (eQTLs) and assigning them into the genes they regulate may help functionally annotate SNPs and increase the enrichment of functional variants in the pathway analysis. Among numerous SNPs with weak associations in GWAS, the selection of those from the identified pathways by using the pathway analysis integrating the genetics of gene expression and the GWAS data for replication may increase the likelihood of targeting true signals than by chance. The integration of eQTLs of liver and adipose tissues into the pathway analysis for the GWAS of type 2 diabetes has successfully identified several novel disease-related pathways. More recently, a GWAS on global gene expression of the skin have systematically generated skin eQTLs. However, no pathway analysis has been conducted for melanoma GWAS. The goal of the current proposal is to systematically assess the associations of biological pathways with melanoma risk by applying this new approach to melanoma GWAS in the discovery stage and to validate specific loci associated with melanoma risk within the identified pathways in the replication stage. Mediation analysis on potentially intermediate phenotypes will also be conducted to investigate the etiological contribution of the identified pathways/SNPs. We plan to use a nested melanoma case-control study of 420 melanoma cases and 2,284 controls in two large, well-characterized cohorts, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) in the discovery stage, and use a melanoma case-control study of 1,804 melanoma cases and 1,026 controls from the MD Anderson Cancer Center in the replication stage. All the cases and controls have been previously genotyped on Illumina chips. The pre-existing GWAS genotype data gives us a cost-effective opportunity to apply the new approach to melanoma research. Our proposed study would be the first to combine the genetics of gene expression and functional classification of genes as prior information to melanoma GWAS. Findings from this study will pick up the genetic variants with modest effects from the GWAS data, which will utilize the GWAS data to a greater extent and provide new insights into the etiology of melanoma.

全基因组关联研究（GWASS）成功鉴定了许多单核苷酸 与黑色素瘤风险相关的多态性（SNP）。但是，传统的gwass仅关注边际 单个标记的效果，仅在识别强大后才合并出外部功能信息 统计关联。通常缺乏检测大多数遗传变异赋予的相对较小效应的能力。 基于途径的方法评估了生物学途径中基因的累积贡献 可能有助于收集GWAS数据中包含的适度信号，并确定在病因中的生物学途径 途径水平的疾病。如传统途径方法中所使用的那样，将SNP分配给其物理 位置可能会引入许多关于非功能SNP和MISS-多次测试的假阳性关联 注释SNP，调节距离基因的表达。相反，定义表达定量性状 基因座（EQTL）并将其分配到它们调节的基因中可能有助于在功能上注释SNP并增加 途径分析中功能变体的富集。在GWAS的众多SNP中， 通过使用整合基因基因的途径分析，从识别途径中选择那些。 与偶然相比，用于复制的GWAS数据可能会增加靶向真实信号的可能性。 将肝脏和脂肪时序的EQTL集成到2型糖尿病的GWA的途径分析中 成功鉴定了几种与疾病相关的新途径。最近，关于全球基因表达的GWA 皮肤有系统地产生的皮肤eqtl。但是，尚未进行途径分析 黑色素瘤GWAS。当前建议的目的是系统地评估生物学的关联 通过在发现阶段将这种新方法应用于黑色素瘤GWA和 在复制阶段验证与黑色素瘤风险相关的特定位置。调解 还将对潜在中间表型进行分析，以研究研究的病因贡献 已确定的途径/SNP。我们计划使用420例黑色素瘤病例和 2,284个对照，有两个大型，良好的人群，护士健康研究（NHS）和健康 在发现阶段的专业人士后续研究（HPFS），并使用1,804的黑色素瘤病例对照研究 在复制阶段，来自MD Anderson癌症中心的黑色素瘤病例和1,026例对照。所有情况 并以前已经在Illumina芯片上进行了基因分型。现有的GWAS基因型数据为我们提供了 具有成本效益的机会，将新方法应用于黑色素瘤研究。我们提出的研究将是第一个 结合基因表达基因和基因的功能分类作为对黑色素瘤的先验信息 GWAS。这项研究的结果将拾取具有GWAS数据中适度效果的遗传变异，这将是 在更大程度上利用GWAS数据，并提供有关黑色素瘤病因的新见解。