Integrative approaches to understand systemic lupus erythematosus etiology in trans-ancestry genetic studies

跨祖先遗传学研究中了解系统性红斑狼疮病因的综合方法

• 批准号: 10577502
• 负责人: Laura Carrel
• 金额: $ 68.26万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577502
• 关键词: Address; Affect; Antinuclear Antibodies; Autoimmune Diseases; Biological Assay; Clinical; Complement; Computer software; Data; Data Set; Diagnosis; Disease; Disease Progression; Early Diagnosis; Early treatment; Enhancers; Environmental Exposure; Etiology; European; Exanthema; Feedback; Female; Frequencies; Gene Frequency; Genetic; Genetic Heterogeneity; Genetic Models; Genetic Risk; Genetic study; Genotype; Heritability; Heterogeneity; Human; Individual; Lead; Linkage Disequilibrium; Logistics; Lupus; Maps; Meta-Analysis; Methods; Modeling; Multiple Organ Failure; Organ; Phenotype; Population; Quality of life; Reporter; Research; Signal Transduction; Statistical Methods; Symptoms; Systemic Lupus Erythematosus; Testing; Validation; Variant; base; causal model; causal variant; cost effective; disorder risk; experimental study; genetic architecture; genetic variant; genome wide association study; genome-wide; improved; interest; method development; multiple datasets; prevent; public health relevance; risk prediction; simulation; statistics; success; trait

ABSTRACT Systemic lupus erythematosus (SLE) is a heritable autoimmune disease that primarily affects young females. SLE symptoms can be very heterogeneous, which posts great challenges in early diagnosis. In its advanced stages, SLE can lead to multiple organ failures and even fatality. Early diagnosis is critical for controlling and mitigating the symptoms and improving the quality of life. Genome-wide association studies of SLE to date have identified >150 loci. Yet, the causal variants remain elusive for most loci. There is great interest to integrate datasets from diverse human populations to further empower discovery, refine causal variants, and improve the risk prediction accuracy. In this proposal, we seek to aggregate available GWAS summary statistics from a myriad of autoimmune diseases. We will develop improved meta-analysis methods that effectively integrate data from multiple traits and ancestries. We will also develop better fine-mapping methods that can integrate statistical approaches and experimental validations. Finally, we will develop more accurate genetic risk scores using datasets from multiple ancestries and traits, and combine them with commonly used lab values for improved disease risk predictions. We will release useful software packages implementing these methods to benefit studies of other traits and maximize the impact of the proposed research.

摘要 系统性红斑狼疮（SLE）是一种遗传性自身免疫性疾病，主要影响年轻女性。 SLE的症状可以是非常异质性的，这给早期诊断带来了很大的挑战。在其先进的 在不同的阶段，SLE可导致多器官衰竭，甚至死亡。早期诊断对于控制和 减轻症状，提高生活质量。迄今为止的SLE全基因组关联研究 已识别>150个位点。然而，大多数基因座的致病变异仍然难以捉摸。有很大的兴趣去整合 数据集从不同的人群，以进一步授权发现，完善因果变异，并提高 风险预测的准确性。在本提案中，我们试图从一个 各种自身免疫性疾病我们将开发改进的荟萃分析方法， 来自多个特征和祖先的数据。我们还将开发更好的精细映射方法， 统计方法和实验验证。最后，我们将开发更准确的遗传风险评分 使用来自多个祖先和性状的数据集，并将它们与常用的实验室值联合收割机结合， 改善疾病风险预测。我们将发布实现这些方法的有用软件包， 有利于其他性状的研究，并最大限度地发挥拟议研究的影响。