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.

抽象的 嘴唇和/或pa的口面裂（OFC）是一种普遍的先天性畸形，具有复杂的遗传 由常见和稀有遗传变异驱动的病因。 OFC由三个主要亚型组成：裂口 单独嘴唇（Cl），唇裂（CLP）和单独的left裂（CP），遗传研究都表明 共享和独特的因素有助于每个亚型。在发现方面取得了巨大的成功 使用基因组广泛关联研究（GWAS）与OFC相关的遗传位置；但是，相对弱 每个单独的基因座对整体疾病责任的贡献有限于量化个人的努力 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 通过将许多微妙的共同遗传效应汇总到单个，单一的， 多基因风险评分（PRS）。将PRS应用于OFC案件将极大地有助于定义可遗传的基础 在更多案例中，但是两个基本挑战限制了目前的用途：1）大多数OFC数据 来自潜水员人群，这种种群混淆了传统的公关方法。 2）PR的评估是 通常在案例/对照研究设计上执行，并且未针对大多数OFC中的家庭数据进行优化 研究。在这项研究中，我们将执行创新的统计技术来克服以前的限制 PRS生成并探索大量OFC队列中的OFC遗传敏感性（n = 24,195; 7,896例） 由5个不同的种族组成（非洲，混合美国，欧洲，东亚，中亚 /南亚） （目标1）。此外，为了为OFC提供更强大的遗传负债测量，我们将检查 我们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 可以相互作用以增加风险。这些分析中的每一个都将OFC也将其视为一个单数组 如独立考虑每个个体亚型。在AIM 2中，我们将应用复杂的变体检测 探索罕见结构和短变化对OFC的贡献的技术。这将使我们能够利用 我们通过整合稀有和常见的遗传来执行新的，汇总的OFC数据集，以执行新的基因发现 信号。最后，我们将对目标1中在AIM 2中发现的罕见突变中产生的PRS进行分类 更好地了解它们如何相互作用以赋予OFC风险。该分析将由 开发OFC复合遗传风险评分，通过将OFC PRS与罕见 变异风险评分，以提供OFC遗传责任的更全面的测量。总的来说，这些 目的是中毒的，以大大扩展我们对OFC遗传危险因素的理解 人群并发现与OFC相关的新基因。总体而言，这项研究将产生变革性的影响 在OFC研究社区中，在产前筛查，遗传咨询和 治疗疾病。