Assembly and re-alignment of HLA genomic region and its implication for fine-mapping suicidality in African descent population

HLA基因组区域的组装和重新排列及其对非洲人后裔自杀倾向精细定位的意义

• 批准号: 10797122
• 负责人: Hongsheng Gui
• 金额: $ 15.7万
• 依托单位: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797122
• 关键词: Address; African; African American population; African ancestry; All of Us Research Program; Alleles; Amino Acids; Antigenic Variation; Antigens; Area; Autoantigens; Autoimmune Diseases; Behavior; Bipolar Disorder; Black race; COVID-19 impact; Cessation of life; Chromosomes; Chronic; Code; Data; Data Set; Diagnostic and Statistical Manual of Mental Disorders; Diploidy; Disease; Disease Pathway; Disease susceptibility; European; Evaluation; Feeling suicidal; Genes; Genetic; Genetic Code; Genetic Predisposition to Disease; Genetic Structures; Genetic study; Genomic Segment; Genomics; Genotype; Goals; Graft Rejection; Grain; HLA Antigens; Haplotypes; Health; Host Defense; Human; Human Genetics; Hybrids; Immune System Diseases; Immune response; Immunologics; Individual; Inflammatory; Inflammatory Response; International; Knowledge; Link; Linkage Disequilibrium; Longitudinal cohort; Major Depressive Disorder; Major Histocompatibility Complex; Maps; Measurable; Mediating; Medical; Mental Health; Mental disorders; Minority Groups; Not Hispanic or Latino; Participant; Pattern; Phase; Phenotype; Population; Population Group; Population Heterogeneity; Process; Proteins; Public Health; Reduce health disparities; Reporting; Research; Research Personnel; Resolution; Resources; Risk Factors; Role; Sampling; Schizophrenia; Shotgun Sequencing; Single Nucleotide Polymorphism; Suicide; Suicide attempt; Technology; Transplantation; United States; Variant; Virus Diseases; adaptive immune response; arm; biobank; burden of illness; causal variant; clinical care; comorbidity; data mining; disability; genetic architecture; genome resource; genome sequencing; genome wide association study; genomic data; improved; inflammatory marker; innovation; mortality; neuroinflammation; neuropsychiatric disorder; novel sequencing technology; phenome; phenomics; phenotypic data; physical conditioning; post-transplant; precision medicine; risk variant; severe mental illness; social determinants; suicidal; suicidal behavior; whole genome

PROJECT SUMMARY/ABSTRACT Technology is rapidly expanding our knowledge of the human genetic code and the alterations which predispose to disease; however, minority populations (e.g., African Americans) are rarely included in the discovery arms of genomic studies. As a particular genomic region, the major histocompatibility complex (MHC) that encompasses the human leukocyte antigen (HLA) genes and variations are critically important for their role in presenting foreign antigens and initiating adaptive immune responses. However, previous MHC genomic resource and relevant disease gene findings were mostly enriched for non-Hispanic White individuals. This area has been intractably difficult to decipher even with the most commonly used short-read shotgun sequencing. This impedes the process for identification of functional HLA variants underlying immunologically relevant mental health conditions in diverse populations. New sequencing technology (long-read) and population-scale African samples are needed to address this knowledge gap. Recently we have gained access to All of US (AoU) controlled tier data (e.g., long- and short-read whole-genome sequencing, WGS) and UK Biobank (UKB) WGS data, consisting of >24,000 participants of African descent. Our overall goal is to identify HLA long haplotypes and create the most detailed reference map of the MHC region for individuals of African descent, and to leverage this new knowledge for fine-mapping HLA locus for suicidality phenotypes. In the first aim, we hypothesize that a hybrid assembly approach with both short- and long-read sequencing data provides a solution to the phasing ambiguity problem. We will generate African-specific HLA haplotype assembly, then call, impute, and phase HLA variants and haplotypes for all African/Black samples in AoU and UKB. In the second aim, we assume both direct and indirect HLA genetic effects are present in suicidal thoughts and behaviors (STB). In addition to discover HLA variations and genes associated with STB and its related inflammatory markers in AoU, we will further replicate top associations in UKB and annotate HLA functional units by integrative omics approaches. More fully characterizing HLA variation in African populations is both a significant and important innovation, and its implication for suicide genomics has never been done before at such a resolution. The cloud-tailored analytical pipeline and MHC resources generated is expected to support large projects in the AoU Researcher workbench that incorporates HLA effects in precision medicine. In addition to our intended research goal of fine-mapping variants and genes which contribute to STB, identifying HLA alleles that are exclusive to individuals of African descent also has the tangible benefit of improving clinical care for transplantation and serious mental illness.

项目总结/摘要 技术正在迅速扩大我们对人类遗传密码和改变的了解， 易患疾病;然而，少数人群（例如，非洲裔美国人）很少被包括在 基因组研究的发现武器。主要组织相容性复合体作为一个特殊的基因组区域， (MHC)包括人类白细胞抗原（HLA）基因和变异的基因对于 它们在呈递外源抗原和启动适应性免疫应答中的作用。然而，以前的MHC 基因组资源和相关疾病基因发现主要富集于非西班牙裔白色个体。 这一领域一直难以破译，即使是最常用的短读猎枪 测序这阻碍了识别免疫学上潜在的功能性HLA变体的过程。 不同人群的相关心理健康状况。新的测序技术（长读）和 需要非洲人口规模的样本来弥补这一知识差距。最近，我们获得了 访问所有US（AoU）控制的层数据（例如，长读和短读全基因组测序，WGS）和 UK Biobank（UKB）WGS数据，包括> 24，000名非洲裔参与者。我们的总体目标是 确定HLA长单倍型，并为以下个体创建最详细的MHC区域参考图谱： 非洲血统，并利用这一新的知识精细定位自杀表型的HLA基因座。在 第一个目标，我们假设一个混合组装方法与短和长阅读测序数据， 提供了一种解决定相模糊问题的方法。我们将产生非洲特异性HLA单倍型 组装，然后调用，插补，并对AoU中所有非洲人/黑人样本的HLA变体和单倍型进行定相， UKB。在第二个目标中，我们假设自杀者中存在直接和间接的HLA遗传效应。 思想和行为（STB）。除了发现与STB及其相关的HLA变异和基因外， 相关炎症标志物，我们将进一步复制UKB中的顶级关联，并注释HLA 功能单位的整合组学方法。更全面地描述非洲人群中的HLA变异 是一项重大而重要的创新，它对自杀基因组学的影响从未被研究过。 在这样的决议之前。预计云定制的分析管道和生成的MHC资源 支持AoU研究员工作台中的大型项目，该工作台将HLA效应精确地结合起来 药除了我们预期的研究目标，即精细定位有助于 STB，鉴定非洲血统个体独有的HLA等位基因也有明显的好处， 改善移植和严重精神疾病的临床护理。