Integration of polygenic risk and facial morphometrics to decipher the genetic susceptibility of orofacial clefting

整合多基因风险和面部形态测量来破译口颌裂的遗传易感性

• 批准号: 10539314
• 负责人: Harrison Brand
• 金额: $ 77.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539314
• 关键词: 3-Dimensional; Accounting; African; American; Bayesian Method; Bioinformatics; Biology; Case/Control Studies; Categories; Child; Cleft Lip; Cleft Palate; Cleft lip with or without cleft palate; Communities; Complex; Congenital Abnormality; Copy Number Polymorphism; Data; Data Set; Development; Disease; East Asian; Ensure; Ethnic Population; European; Face; Family; Generations; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genotype; Goals; Heritability; Individual; Life; Lip structure; Maps; Measures; Methods; Modeling; Mutation; Nasal cavity; Operative Surgical Procedures; Oral cavity; Palate; Parents; Pathogenicity; Pathway interactions; Patients; Persons; Population Control; Population Heterogeneity; Population Study; Research; Research Design; Risk; Risk Estimate; SNP array; Sampling; Scoring Method; Series; Shapes; Signal Transduction; South Asian; Statistical Methods; Structure; Techniques; Testing; Variant; care burden; cohort; craniofacial; design; detection method; diagnostic screening; disorder subtype; ethnic diversity; family structure; gene discovery; genetic architecture; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genomic locus; improved; innovation; notch protein; novel; orofacial cleft; orofacial development; polygenic risk score; prenatal; prenatal testing; rare variant; success; trait; transmission process; variant detection; whole genome

Abstract Orofacial clefts (OFCs) of the lip and/or palate are a prevalent congenital malformation with a complex genetic etiology driven by both common and rare genetic variants. OFCs are comprised of three major subtypes: cleft lip alone (CL), cleft lip with cleft palate (CLP) and cleft palate alone (CP) with genetic studies indicating both shared and unique factors contributing to each subtype. There has been remarkable success in discovering genetic loci associated with OFCs using genome wide association studies (GWAS); however, the relatively weak contribution of each individual locus toward overall disease liability has limited efforts to quantify an individual’s genetic risk for OFC. Over the past decade, novel methods have been developed to provide better measures of genetic liability for complex disorders by aggregating many subtle common genetic effects into a single, polygenic risk score (PRS). Application of a PRS to OFC cases would greatly aid in defining the heritable basis of many more cases, but two fundamental challenges have limited its current use: 1) the majority of OFC data has come from diverse populations, which confounds traditional PRS approaches; 2) assessments of PRS are typically performed on case/control study designs and aren’t optimized for the familial data found in most OFC studies. In this study we will perform innovative statistical techniques to overcome these previous limitations in PRS generation and explore OFC genetic susceptibility in a large OFC cohort (n = 24,195; 7,896 cases) comprised of 5 distinct ethnic groups (African, Admixed American, European, East Asian, Central /South Asian) (Aim 1). Moreover, to provide an even more robust measure of genetic liability for OFCs, we will examine the influence of 59 OFC-related 3D facial features in our OFC cohort with the goal of understanding how these traits may interact to increase OFC risk. Each of these analyses will both consider OFCs as a singular group as well as consider each of the individual subtypes independently. In Aim 2, we will apply sophisticated variant detection techniques to explore the contribution of rare structural and short variation on OFCs. This will allow us to leverage our large, aggregated OFC dataset to perform novel gene discovery by integrating rare and common genetic signals. Finally, we will stratify the PRSs generated in Aim 1 against the rare mutations discovered in Aim 2 to better understand how they may interact to confer OFC risk. This analysis will be further expanded by the development of an OFC composite genetic risk score, created by integrating the OFC PRSs directly with a rare variation risk score, to provide a more comprehensive measure of OFC genetic liability. Taken together, these aims are poised to greatly expand our understanding of the genetic risk factors for OFC across diverse populations and discover new genes associated with OFCs. Overall, this study will have a transformative impact on the OFC research community with potential applications in prenatal screening, genetic counseling, and treatments for the disorder.

摘要 唇腭裂是一种常见的先天性畸形，遗传因素复杂。 由常见和罕见的遗传变异驱动的病因学。离岸金融中心由三个主要亚型组成：裂隙 单独唇裂(CL)、唇裂合并腭裂(CLP)和单纯腭裂(CP)，基因研究表明两者都有 构成每个亚型的共同和独特的因素。已经取得了显著的成功发现 用全基因组关联研究(GWAS)研究与OFC相关的遗传位点；然而，相对较弱的 每个个体基因座对总体疾病责任的贡献有限，无法量化个人的 OFC的遗传风险。在过去的十年里，已经开发了新的方法来提供更好的测量 复杂疾病的遗传易感性通过将许多微妙的共同遗传效应聚集到一个单一的、 多基因风险评分(Prs)。在OFC病例中应用PRS将极大地帮助确定可遗传基础 但有两个基本挑战限制了它目前的使用：1)大多数OFC数据 来自不同的人群，这混淆了传统的PR方法；2)PR的评估是 通常在病例/对照研究设计中执行，并且没有针对大多数OFC中的家族数据进行优化 学习。在这项研究中，我们将执行创新的统计技术，以克服这些以前在 在一个大的OFC队列中研究OFC的遗传易感性(n=24,195；7,896例) 由5个不同的民族组成(非洲人、美国人、欧洲人、东亚人、中亚人/南亚人) (目标1)。此外，为了更有力地衡量离岸金融中心的遗传责任，我们将研究 59个OFC相关3D面部特征在我们的OFC队列中的影响，目的是了解这些特征是如何 可能会相互作用，增加OFC的风险。这两种分析都会将离岸金融中心视为一个单独的群体。 正如单独考虑每个单独的子类型一样。在目标2中，我们将应用复杂的变异检测 探索罕见的结构和短变异对OFCs的贡献的技术。这将使我们能够利用 我们的大型聚合OFC数据集通过整合稀有和常见基因来执行新的基因发现 信号。最后，我们将目标1中产生的PRS与目标2中发现的罕见突变进行分层，以 更好地了解它们可能如何相互作用来赋予OFC风险。这一分析将通过 OFC综合遗传风险评分的开发，通过直接将OFC PRSS与罕见的 变异风险评分，为OFC遗传易感性提供更全面的衡量标准。这些加在一起， AIMS准备极大地扩展我们对OFC的遗传风险因素的了解 并发现与OFCs相关的新基因。总体而言，这项研究将产生革命性的影响 OFC研究社区在产前筛查、遗传咨询和 治疗这种疾病的方法。