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（GWAS）已成功鉴定出许多单核苷酸 与黑色素瘤风险相关的多态性（SNP）然而，传统的 GWAS 仅关注边缘。 单个标记的影响，并且仅在识别稳健后才纳入外部功能信息 统计关联通常缺乏检测大多数遗传变异所带来的相对较小影响的能力。 基于途径的方法，评估生物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病因学中的生物途径 正如传统途径方法中所使用的，将 SNP 分配给它们的物理途径。 位置可能会因对非功能性 SNP 的多次测试和漏检而引入许多假阳性关联。 注释远距离调节基因表达的 SNP，而是定义表达数量性状。 位点（eQTL）并将它们分配到它们调节的基因中可能有助于对 SNP 进行功能注释并增加 通路分析中功能变异的富集 在 GWAS 中关联较弱的众多 SNP 中， 通过使用整合基因遗传学的途径分析从已识别的途径中选择那些 表达和用于复制的 GWAS 数据可能会比偶然增加靶向真实信号的可能性。 将肝脏和脂肪组织的 eQTL 整合到 2 型糖尿病 GWAS 的通路分析中 最近，成功鉴定了几种新的疾病相关途径。 皮肤的 eQTL 已系统生成，但尚未进行路径分析。 当前提案的目标是系统地评估生物学与黑色素瘤的关联。 通过在发现阶段将这种新方法应用于黑色素瘤 GWAS 来了解黑色素瘤风险的途径，并 验证复制阶段已确定的途径中与黑色素瘤风险相关的特定位点。 还将对潜在的中间表型进行分析，以调查其病因学贡献 我们计划对 420 例黑色素瘤病例进行巢式黑色素瘤病例对照研究，并 护士健康研究 (NHS) 和健康研究这两个大型、特征明确的队列中的 2,284 名对照者 发现阶段的专业人员追踪研究 (HPFS)，并使用 1,804 名黑色素瘤病例对照研究 MD 安德森癌症中心的黑色素瘤病例和 1,026 例对照处于复制阶段。 和对照之前已在 Illumina 芯片上进行了基因分型。预先存在的 GWAS 基因型数据为我们提供了一个数据。 我们提出的研究将是第一个将新方法应用于黑色素瘤研究的具有成本效益的机会。 将基因表达遗传学和基因功能分类结合起来作为黑色素瘤的先验信息 这项研究的结果将从 GWAS 数据中找出影响不大的遗传变异，这将 更大程度地利用 GWAS 数据，为黑色素瘤的病因学提供新的见解。