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

摘要 唇和/或腭的口面裂（OFC）是一种常见的先天性畸形，具有复杂的遗传学特征。 病因学由常见和罕见的遗传变异驱动。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存在 每个亚型都有共同的独特因素。人类已经成功地发现了 使用全基因组关联研究（GWAS）与OFC相关的遗传位点;然而， 每个个体基因座对整体疾病易感性的贡献限制了量化个体的努力。 OFC的遗传风险。在过去的十年中，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，将许多微妙的共同遗传效应聚集成一个单一的， 多基因风险评分（PRS）。将PRS应用于OFC病例将大大有助于确定遗传基础 但有两个基本的挑战限制了它目前的用途：1）大多数OFC数据 来自不同的人群，这与传统的减贫战略方法相混淆; 2）减贫战略的评估是 通常在病例/对照研究设计中进行，并没有针对大多数OFC中发现的家族数据进行优化 问题研究在这项研究中，我们将进行创新的统计技术，以克服这些以前的限制， 在大型OFC队列中生成PRS并探索OFC遗传易感性（n = 24，195; 7，896例病例） 由5个不同的族裔群体组成（非洲人、美洲混血儿、欧洲人、东亚人、中亚/南亚人） (Aim 1）。此外，为了提供一个更可靠的测量OFC的遗传易感性，我们将研究 我们的OFC队列中59个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的风险。这些分析都将OFC视为一个单一的群体，以及 就像独立地考虑每个单独的亚型一样。在目标2中，我们将应用复杂的变体检测 技术来探索罕见的结构和短的变化对OFCs的贡献。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的遗传基因， 信号.最后，我们将针对目标2中发现的罕见突变对目标1中产生的PRS进行分层， 更好地了解它们如何相互作用以产生OFC风险。这一分析将进一步扩大， 开发OFC综合遗传风险评分，通过将OFC PRS直接与罕见的 变异风险评分，以提供更全面的衡量OFC遗传易感性。综上所述各项 我们的目标是大大扩展我们对OFC遗传风险因素的理解， 并发现与OFC相关的新基因。总的来说，这项研究将产生变革性的影响， OFC研究社区在产前筛查，遗传咨询和 治疗方法

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.