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）是美国最常见的恶性肿瘤， 在年轻人中越来越常见。与BCC相关的沉重公共卫生负担 强调了有效管理和预防工作的重要性， 恶性肿瘤，特别是针对高危人群。我们最近发表了一个大的全基因组 相关性研究（GWAS），包括17，187例病例和287，054例对照。我们得到一个31个位点的列表， 进一步研究以阐明真正的致病变异和特定基因或DNA功能元件 遗传变异通过这些机制发挥作用。在本申请中，我们的目标是执行第一个 对BCC进行定位良好的GWAS后调查，以整合互补战略，包括精细的 定位和全转录组关联研究（TWAS），针对潜在的因果变异， 功能相关基因我们提出以下具体目标：（1）执行经验贝叶斯精细- 使用ProbabilityAnnotationINTEGratOR（PAINTOR）软件进行映射，以预测因果单一 核苷酸多态性（SNP）。PAINTOR将总结GWAS数据，有关本地联系的信息 不平衡（LD）模式，以及来自公开可获得的SNP的功能注释。 数据库（例如ENCODE、表观基因组路线图、GTEx和代谢组学GWAS服务器）。(2)执行 TWAS分析，它将BCC上的当前GWAS元数据与来自表达的数据相结合 数量性状基因座（eQTL）研究，以确定基因的表达水平显着 与BCC风险有关。我们的TWAS将使用几种新的和新兴的鲁棒方法 （包括我们开发的多效性稳健MR-Egger回归的扩展），以减少 由于这些混杂因素导致的假阳性风险。我们将进行一系列TWAS分析， 来自血液样品和皮肤组织样品的eQTL数据，以区分具有皮肤特异性eQTL的SNP 影响和跨组织影响。这项研究不仅将大大推进我们对 BCC发病机制的研究，也为开发临床有用的遗传学提供了坚实的科学基础。 风险预测模型，精准防范。此外，这项拟议的研究可能会指出一些 治疗干预和风险降低的潜在/可操作目标。