High Throughput Genotyping and DNA Sequencing for Studying the Genetic Contributions to Human Disease: Genotyping of the ZOE 2.0 Pediatric Oral Health Cohort Study (Divaris)

用于研究人类疾病遗传贡献的高通量基因分型和 DNA 测序：ZOE 2.0 儿科口腔健康队列研究的基因分型 (Divaris)

• 批准号: 10023840
• 负责人: KIM DOHENY
• 金额: $ 80.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2022-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023840
• 关键词: 12 year old; 4 year old; Address; Adult; Affect; Age; Alleles; Behavioral; Biological; Caring; Child; Childhood; Chronic; Chronic Disease; Clinical; Cohort Studies; Collaborations; Communities; Community Health Systems; Confidence Intervals; DNA; DNA sequencing; Data; Dental; Dental Records; Dental caries; Diagnosis; Diagnostic; Disease; Enrollment; Ethnic group; Etiology; European; Family; Follow-Up Studies; Funding; Future; Gene Frequency; General Anesthesia; Genes; Genetic; Genetic Structures; Genetic study; Genomics; Genotype; Head Start Program; Health; Healthcare; Heritability; Human; Individual; Infrastructure; International; Investigation; Knowledge; Lead; Light; Measurement; Meta-Analysis; Methods; Microbial Biofilms; Minor; National Institute of Dental and Craniofacial Research; North Carolina; Nursery Schools; Odds Ratio; Oral; Oral health; Participant; Pathway interactions; Pattern; Personal Satisfaction; Phenotype; Population; Positioning Attribute; Preschool Child; Prevalence; Primary Dentition; Public Health; Publishing; Questionnaires; Regulatory Element; Reporting; Request for Proposals; Research; Research Personnel; Resources; Risk; Risk Factors; Saliva; Sampling; Sedation procedure; Services; Severities; Signal Transduction; Smiling; Social Impacts; Sum; Tooth Demineralization; Tooth structure; Training; United States National Institutes of Health; Variant; Visual system structure; age group; base; burden of illness; cohort; deciduous tooth; density; design; dysbiosis; early childhood; early onset; economic cost; economic impact; experience; genetic analysis; genetic epidemiology; genetic variant; genome wide association study; genome-wide; human disease; improved; interest; knowledge base; microbiome analysis; novel; population based; programs; racial and ethnic; response; risk variant; sex; sociodemographics; tooth surface; trait; virtual

Early childhood caries (ECC) is the most common chronic disease of childhood and a persistent clinical and public health problem. The prevalence of ECC in the US increased by 15% during the last 2 decades, and according to the most recent national data 28% of children ages 2-5 are affected. ECC can have severe sequelae for children's general health and well-being and confers important social and economic impacts on their families, communities, and the health system. Caries is a multifactorial disease with a substantial genetic component, which is estimated between 40-60% (43% using our own pilot data), but little is known regarding specific genetic factors. To-date, a GWAS of the traditional definition of ECC (including tooth surfaces affected, restored or missing due to dental caries in children younger than 72 months) has not been done. The first GWAS of childhood caries was conducted among 1,300 3-12-year-old European-ancestry children—that study did not identify any significant signals but nominated 7 genes, 2 of which showed evidence of association in follow-up studies among children and adults. A recent GWAS meta-analysis identified one significant locus for childhood caries, among 17,033 children of European ancestry. Here, we propose to conduct a large-scale GWAS of ECC involving a multi-ethnic community-based sample of 6,000 children ages 3 to 5. Under NIH/NIDCR U01-DE025046, we have undertaken comprehensive clinical dental characterization of a community-based sample of over 6,000 children enrolled in Head Start programs in North Carolina. We have obtained tooth-surface level data of dental caries experience using the latest International Caries Diagnosis System (ICDAS) visual diagnostic criteria to define ECC traits. We have obtained saliva samples from virtually all examined participants and have been extracting more-than-adequate DNA yields from them. A wealth of additional behavioral risk factor and socio-demographic information of interest has been collected. Supragingival plaque samples have also been collected and stored to be used in future microbiome analyses that will be funded separately. To identify genetic variants that are associated with ECC, we propose to conduct a trans-ethnic GWAS of ECC and related traits, utilizing high- density genotyping and subsequent imputation to the most current reference panels. We will use advanced statistical approaches to leverage differences in genetic structure between racial/ethnic groups. Subsequently, we will utilize publicly available GWAS data of early childhood and adult caries, to determine the racial/ethnic and age-group generalization/transferability of loci, genes, and gene sets/pathways identified in our study. Our group's experience in conducting genetic epidemiologic studies, ongoing collaboration among the investigators' team and the breadth and quality of the already-collected information, create a unique opportunity to carry out this important investigation and advance the knowledge base of genomics of dental caries. The study will improve our understanding of ECC's genomic etiology, key knowledge to reduce the burden of disease in populations of young children, including those underrepresented in research.

幼儿龋病是儿童期最常见的慢性疾病，也是一个长期存在的临床和公共卫生问题。在过去的20年里，美国ECC的患病率增加了15%，根据最新的国家数据，28%的2-5岁儿童受到影响。幼儿保育会对儿童的一般健康和福祉产生严重的后遗症，并对其家庭、社区和卫生系统产生重要的社会和经济影响。龋齿是一种多因素疾病，具有大量的遗传成分，估计在40-60%之间（使用我们自己的试点数据为43%），但对特定的遗传因素知之甚少。迄今为止，尚未进行传统ECC定义的GWAS（包括年龄小于72个月的儿童因龋齿而受影响、修复或缺失的牙齿表面）。第一个儿童龋齿的GWAS在1,300名3-12岁的欧洲血统儿童中进行，该研究没有发现任何显著的信号，但提名了7个基因，其中2个在儿童和成人的后续研究中显示出相关性的证据。最近的一项GWAS荟萃分析在17,033名欧洲血统的儿童中确定了一个儿童龋齿的重要位点。在这里，我们建议进行一个大规模的GWAS的ECC涉及一个多种族的社区为基础的样本的6,000名儿童3至5岁。根据NIH/NIDCR U 01-DE 025046，我们对北卡罗来纳州参加学前教育项目的6,000多名儿童进行了全面的临床牙科表征。我们已经获得了牙齿表面水平的数据龋齿的经验，使用最新的国际龋齿诊断系统（ICDAS）的视觉诊断标准，以定义ECC性状。我们已经从几乎所有接受检查的参与者那里获得了唾液样本，并从他们身上提取了足够的DNA。已经收集了大量的其他行为风险因素和感兴趣的社会人口统计学信息。还收集并储存了龈上菌斑样本，以用于未来的微生物组分析，这些分析将单独资助。为了鉴定与ECC相关的遗传变异，我们建议进行ECC和相关性状的跨种族GWAS，利用高密度基因分型和随后对最新参考组的插补。我们将使用先进的统计方法来利用种族/族裔群体之间的遗传结构差异。随后，我们将利用公开的儿童早期和成人龋齿的GWAS数据，以确定在我们的研究中确定的位点，基因和基因集/途径的种族/民族和年龄组的泛化/可转移性。我们小组在进行遗传流行病学研究方面的经验，研究人员团队之间的持续合作以及已经收集的信息的广度和质量，为开展这项重要的调查和推进龋齿基因组学的知识基础创造了独特的机会。这项研究将提高我们对ECC基因组病因学的理解，这是减少幼儿人群疾病负担的关键知识，包括那些在研究中代表性不足的人群。