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: 10342388
• 负责人: Harrison Brand
• 金额: $ 79.62万
• 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/10342388
• 关键词: 3-Dimensional; Accounting; African; American; Bayesian Method; Bioinformatics; Biology; Case-Control Studies; 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 group; European; Face; Family; Generations; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genotype; Goals; Heritability; Individual; Life; Lip structure; 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; base; care burden; case control; 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.

抽象的 嘴唇和/或腭的口面裂 (OFC) 是一种常见的先天性畸形，具有复杂的遗传因素 由常见和罕见的遗传变异驱动的病因学。 OFC 由三种主要亚型组成： 单纯唇裂 (CL)、唇裂伴腭裂 (CLP) 和单纯腭裂 (CP)，遗传研究表明两者都有 影响每个亚型的共同因素和独特因素。在发现方面取得了显着的成功 使用全基因组关联研究 (GWAS) 与 OFC 相关的遗传位点；但相对较弱的 每个个体位点对总体疾病易感性的贡献限制了量化个体疾病易感性的努力 OFC 的遗传风险。在过去的十年中，已经开发出新的方法来提供更好的测量 通过将许多微妙的常见遗传效应聚合成一个单一的、 多基因风险评分（PRS）。将 PRS 应用于 OFC 案例将极大地有助于确定可遗传的基础 更多案例，但两个基本挑战限制了其当前的使用：1）大多数 OFC 数据 来自不同的人群，这与传统的 PRS 方法相混淆； 2) PRS的评估是 通常在病例/对照研究设计中进行，并且没有针对大多数 OFC 中的家族数据进行优化 研究。在这项研究中，我们将采用创新的统计技术来克服以前的这些限制 PRS 生成并探索大型 OFC 队列中的 OFC 遗传易感性（n = 24,195；7,896 例） 由 5 个不同的民族组成（非洲、美洲混血、欧洲、东亚、中亚/南亚） （目标 1）。此外，为了对 OFC 的遗传责任提供更强有力的衡量标准，我们将检查 我们的 OFC 队列中 59 个与 OFC 相关的 3D 面部特征的影响，目的是了解这些特征如何 可能会相互作用增加 OFC 风险。这些分析中的每一个都将 OFC 视为一个单一群体 独立考虑每个单独的亚型。在目标 2 中，我们将应用复杂的变异检测 探索稀有结构和短期变异对 OFC 的贡献的技术。这将使我们能够利用 我们的大型聚合 OFC 数据集通过整合罕见和常见遗传来执行新基因发现 信号。最后，我们将目标 1 中生成的 PRS 与目标 2 中发现的罕见突变进行分层，以 更好地了解它们如何相互作用以赋予 OFC 风险。该分析将进一步扩展 开发 OFC 综合遗传风险评分，通过将 OFC PRS 直接与罕见疾病相结合而创建 变异风险评分，提供更全面的 OFC 遗传责任测量。综合起来，这些 目标是极大地扩展我们对不同类型 OFC 遗传风险因素的理解 群体并发现与 OFC 相关的新基因。总体而言，这项研究将产生变革性影响 OFC 研究界在产前筛查、遗传咨询和 对这种疾病的治疗。