Integrative functional characterization of genetic loci for cutaneous basal cell carcinoma

皮肤基底细胞癌遗传位点的综合功能特征

• 批准号: 10046682
• 负责人: JIALI HAN
• 金额: $ 17.35万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046682
• 关键词: 1p36; Address; Affect; Animal Model; Area; Basal cell carcinoma; Biological; Blood specimen; Candidate Disease Gene; Clinical; Computer software; Cutaneous; DNA; Data; Databases; Development; Diagnosis; Elements; Enhancers; FOXP1 gene; Funding; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genotype-Tissue Expression Project; HLA-B Antigens; Human; IRF4 gene; Individual; Intuition; Investigation; Light; Link; Linkage Disequilibrium; Malignant Neoplasms; Metadata; Monophenol Monooxygenase; Natural regeneration; Pathogenesis; Pathway interactions; Pattern; Pigmentation physiologic function; Positioning Attribute; Prevention; Probability; Public Health; Publishing; Quantitative Trait Loci; Reporting; Review Literature; Risk; Risk Reduction; Series; Single Nucleotide Polymorphism; Skin; Skin Tissue; Specific qualifier value; Susceptibility Gene; TFAP2A gene; TP53 gene; Telomere Maintenance; Therapeutic Intervention; Tissue Model; Tissue Sample; Tissues; Validation; Variant; Work; carcinogenesis; causal variant; epigenome; genetic predictors; genetic variant; genome wide association study; genome-wide; genomic locus; high risk population; immunoregulation; individualized prevention; innovation; large datasets; metabolomics; novel; pleiotropism; risk prediction model; targeted treatment; tool; transcriptome; tumor progression

Cutaneous basal cell carcinoma (BCC) is the most common malignancy diagnosed in the USA and is becoming more frequent in younger individuals. The heavy public health burden associated with BCC underscores the importance of efficient management and prevention efforts directed toward this malignancy, especially targeting the high-risk population. We recently published a large genome-wide association study (GWAS) on BCC with 17,187 cases and 287,054 controls. We yield a list of 31 loci for further investigation to elucidate true causal variants and the specific genes or DNA functional elements through which the genetic variants exert their effects. In this application, we aim to carry out the first well-positioned post-GWAS investigation of BCC to integrate complementary strategies including fine- mapping and transcriptome-wide association study (TWAS), targeting potentially causal variants and functionally relevant genes. We propose the following specific aims: (1) Perform empirical Bayes fine- mapping using the Probabilistic Annotation INTegratOR (PAINTOR) software to predict causal single- nucleotide polymorphisms (SNPs). PAINTOR will summarize GWAS data, information on local linkage disequilibrium (LD) patterns, as well as functional annotations for SNPs from publicly available databases (e.g. ENCODE, Epigenome Roadmap, GTEx, and Metabolomic GWAS Server). (2) Perform TWAS analysis, which integrates current GWAS-meta data on BCC with data from expression quantitative trait loci (eQTL) studies to identify genes whose expression levels are significantly associated with BCC risk. Several novel and emerging robust approaches will be used in our TWAS (including an extension of pleiotropy-robust MR-Egger regression that we have developed) to reduce the risk of false positives due to these confounders. We will conduct a series of TWAS analyses using eQTL data from blood samples and skin tissue samples to distinguish SNPs with skin-specific eQTL effects and those with cross-tissue effects. This study will not only greatly advance our understanding of BCC pathogenesis, but also provide a robust scientific basis for developing clinically useful genetic risk prediction model for precision prevention. Moreover, this proposed study may pinpoint some potential/actionable targets for therapeutic intervention and risk reduction.

皮肤基底细胞癌（BCC）是美国诊断出的最常见的恶性肿瘤，是 在年轻人中变得越来越频繁。与BCC相关的沉重公共卫生负担 强调了有效管理和预防努力的重要性 恶性肿瘤，尤其是针对高风险人群的。我们最近发表了全基因组的大型 协会研究（GWAS）在BCC上具有17,187例病例和287,054例对照。我们产生31个基因座的清单 进一步研究以阐明真实因果变异和特定基因或DNA功能元素 遗传变异的作用。在此应用程序中，我们旨在执行第一个 BCC的GWAS调查良好，以整合互补策略，包括精细的策略 映射和转录组整个关联研究（TWA），针对潜在的因果变体和 功能相关的基因。我们提出以下具体目的：（1）执行经验贝叶斯精细 - 使用概率注释积分器（Paintor）软件进行映射，以预测因果关系 核苷酸多态性（SNP）。 Paintor将总结GWAS数据，有关本地链接的信息 不平衡（LD）模式，以及SNP的功能注释，可公开可用 数据库（例如编码，表观基因组路线图，GTEX和代谢组GWAS服务器）。 （2）执行 TWA分析，将BCC上的当前GWAS-META数据与来自表达的数据集成 定量性状基因座（EQTL）研究以鉴定其表达水平显着的基因 与BCC风险相关。我们的两种小说和新兴的强大方法将使用 （包括我们已经开发的多效性射击MR-EGGER回归的扩展）以减少 由于这些混杂因素而引起的误报风险。我们将使用 来自血液样品和皮肤组织样品的EQTL数据，可通过皮肤特异性EQTL区分SNP 效果和具有跨组织效应的效果。这项研究不仅会大大提高我们的理解 BCC发病机理的作用，但也为发展临床上有用的遗传提供了强大的科学基础 预防精度的风险预测模型。此外，这项拟议的研究可能会指出一些 用于治疗干预和降低风险的潜在/可行目标。