HIGH THROUGHPUT GENOTYPING AND DNA SEQUENCING FOR STUDYING THE GENETIC CONTRIBUTIONS TO HUMAN HEALTH AND DISEASE: Whole Genome Sequencing of Bilateral Cleft Lip and Palate families from Africa

用于研究对人类健康和疾病的遗传贡献的高通量基因分型和 DNA 测序：非洲双侧唇裂和腭裂家族的全基因组测序

• 批准号: 10498645
• 负责人: KIM DOHENY
• 金额: $ 103.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-09 至 2023-09-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10498645
• 关键词: Accounting; Adult; Affect; Africa; African; Asia; BCL1 Oncogene; Bilateral; Biological; Biological Markers; Birth; Candidate Disease Gene; Caring; Cleft Lip; Cleft Palate; Cleft lip with or without cleft palate; Clinical; Complex; Congenital Abnormality; Craniofacial Abnormalities; DNA sequencing; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Ethnic group; Etiology; European; Experimental Designs; Family; FarGo; Folic Acid; Funding; Gene Frequency; Genetic; Genetic Heterogeneity; Genetic Variation; Genetic study; Genomics; Genotype; Geographic Locations; Goals; Health; Health Benefit; Human; Individual; Infant; Infrastructure; Investigation; Knowledge; Lead; Link; Medical; Meta-Analysis; Minor; Molecular; Mutation; National Human Genome Research Institute; Oral; Outcome; Parents; Pathogenesis; Pathway interactions; Pediatric Research; Phenotype; Population; Prevalence; Prevention; Principal Investigator; Public Health; Publishing; Race; Reporting; Research; Resources; Risk; Sampling; Severities; Testing; Translating; Triad Acrylic Resin; United States; Universities; Variant; Work; base; catalyst; cleft lip and palate; clinical practice; cohort; comparative; cost; craniofacial; craniofacial development; de novo mutation; effective intervention; exome; experience; genetic risk factor; genetic variant; genome sequencing; genome wide association study; geographic difference; high risk; improved; insight; loss of function mutation; multi-ethnic; novel; orofacial cleft; programs; psychologic; public health relevance; racial and ethnic; racial difference; risk variant; trait; whole genome

Orofacial clefts (OFCs) affects one out of every 700 infants born worldwide and are some of the most common birth defects in humans. Investigations into the genetic and molecular etiology of OFC is an essential pre- requisite for prevention and will have a huge impact on financial, educational, medical, psychological, and cultural problems associated with OFCs—leading to significant public health benefits. We have made reasonable progress in human OFC genetics through seven Genome Wide Association Studies (GWAS) for CL/P, three meta-analyses for CL/P, three GWAS for cleft palate only (CPO), and two Whole Genome Sequencing (WGS) study identifying over 60 risk loci and several de novo variants. The proposed specific aims will allow us to identify and test both common and rare genetic variants that elevate risk for CL/P, and to identify genetic variants associated with specific OFC phenotypes in the population that has accumulated the greatest genetic variation in the human race. The use of whole-genome sequencing to identify rare functional variants is expected to substantially expand the findings from the few exome studies of OFC that have been conducted. We hypothesize that bilateral complete cleft lip and palate(BCLP), the most clinically severe form of OFC, is associated with a higher mutation load than less severe forms and focusing on BCLP will facilitate the discovery of novel risk variants. This approach is robust in that we are using a clinically homogeneous cohort in order to minimize genetic heterogeneity and increases the likelihood of discovering genetic factors for BCLP. This application will be led by Dr Butali as Principal Investigator. He will collaborate with Dr. Taub at John Hopkins University and Dr. Adeyemo at the NHGRI. Collectively, the experimental design and approach, the PI and co-Is, and the environment outlined in this proposal provide the catalyst to improve oral and craniofacial health.

口面裂口（OFC）会影响全球每700名婴儿中的一个，并且是人类最常见的先天缺陷。对OFC的遗传和分子病因的调查是预防的基本先决条件，将对与OFC相关的财务，教育，医学，心理，心理和文化问题产生巨大影响，这是对重大公共卫生益处的领域。我们通过七个基因组遗传学研究（GWAS）在人类OFC遗传学方面取得了合理的进步，Cl/p的三个荟萃分析，仅用于cl裂的三个GWA（CPO）（CPO）（CPO）和两个整个基因组测序（WGS）研究，鉴定了60多个风险位置和几个变种。提出的特定目的将使我们能够识别和测试升高Cl/p风险的常见和稀有遗传变异，并鉴定与人群中与特定OFC表型相关的遗传变异，这些变异已积累了人类中最大的遗传变异。全基因组测序鉴定稀有功能变体的使用有望大大扩展从已进行的OFC的少数外显子组研究中扩大发现。我们假设双边完全裂口唇和pa（BCLP）是OFC的最严重形式，它与更高的突变负荷相比，与不太严重的形式相比，关注BCLP将有助于发现新型风险变体。这种方法是可靠的，因为我们使用临床上均匀的队列来最大程度地减少遗传异质性并增加了发现BCLP遗传因素的可能性。该申请将由Butali博士担任首席研究员。他将与John Hopkins大学的Taub博士和NHGRI的Adeyemo博士合作。总的来说，该提案中概述的实验设计和方法，PI和CO-IS以及环境为改善口服和颅面健康的催化剂提供了催化剂。