Genetic modifiers of orofacial cleft subtypes in families

项目总结 口裂是最常见的出生缺陷之一，大约每700名新生儿中就有1名受到影响。 包括唇裂(CL)、腭裂(CP)和唇腭裂(CLP)。 虽然大多数OFCS病例是零星的，但受影响个人亲属中OFCS的复发风险比为 大量的，突出了这组疾病的强烈遗传成分。然而，尽管 相当多的证据表明OFC是可遗传的，过去一个世纪对OFC的各种基因研究已经 然而，还没有确定解释这种遗传性的大部分遗传因素。一种可能的解释是有些人 基因变异只会增加某些亚型OFCs的风险，因此这些变异在 标准分析将亚型结合在一起以支持样本量，表面上是为了提高 基因图谱。这项建议的总体假设是，这种高复发风险的离岸中心亚型 家族性遗传是由罕见和常见的亚型特有遗传风险变异引起的，许多 还不知道是什么。为了更好地研究导致OFC的罕见和常见的遗传变异， 我们将使用基于家庭的遗传方法，因为它们是识别潜在原因的强大方法， 分离变种。此外，这项建议的独特之处在于，其主要目标不仅是确定和 潜在地测试这些变异的功能，但要了解这些风险变异是如何在家族和 与已知的环境风险因素相互作用，从而更好地了解特定亚型的OFC风险。 这项提议的核心假设将在两个独立的目标中得到检验：第一，检测罕见的基因变异 利用全基因组测序数据和基因分型数据在有OFCS的家庭中传播，以及 第二，开发特定亚型的多基因风险评分(PRS)，并测试受影响和 未受影响的家庭成员。我已经组建了一个指导团队，提供必要的培训和支持 为了完成拟议的研究：赞助伊丽莎白·莱斯利博士和迈克尔·爱泼斯坦博士及其合作者 玛丽·马拉齐塔博士、特里·比蒂博士和罗伯特·康奈尔博士。建议的项目和培训计划是量身定做的 提供统计遗传学、测序和基于家族的分析方法方面的培训。学习这些新知识 遗传学的方法和技术将增加我在环境表观遗传学方面的现有技能，并将 帮助我成长为一名独立的遗传流行病学家。

PROJECT SUMMARY Orofacial clefts (OFCs) are one of the most common birth defects, affecting approximately 1 in 700 births globally, and are phenotypically variable, including clefts of the lip (CL), palate (CP), and lip and palate (CLP). While most cases of OFCs are sporadic, recurrence risk ratios of OFCs in relatives of affected individuals are substantial, highlighting a strong genetic component to this group of disorders. Nevertheless, despite considerable evidence that OFCs are heritable, a variety of genetic studies of OFCs over the past century have yet to identify genetic factors that explain the majority of this heritability. One possible explanation is that some genetic variants only increase risk for certain subtypes of OFCs and thus these variants have been missed in standard analyses that combine subtypes together to bolster sample size ostensibly for improved power in gene mapping. The overall hypothesis of this proposal is that this high recurrence risk for subtypes of OFCs in families is caused by inheritance of both rare and common subtype-specific genetic risk variants, many of which are still unknown. In order to better investigate both rare and common genetic variants that cause OFCs, we will use family-based genetic approaches since they are powerful methods to identify potentially causal, segregating variants. Additionally, this proposal is unique in that the primary goal is not just to identify and potentially test these variants functionally, but to understand how these risk variants segregate in families and interact with known environmental risk factors, leading to a better understanding of subtype-specific OFC risk. The central hypothesis of this proposal will be tested in two independent aims: first, testing rare genetic variant transmission in families with OFCs, leveraging both whole-genome sequencing data and genotyping data, and second, developing a subtype-specific polygenic risk score (PRS) and testing the genetic risk in affected and unaffected family members. I have assembled a mentoring team to provide the necessary training and support to accomplish the proposed research: sponsors Dr. Elizabeth Leslie and Dr. Michael Epstein and collaborators Dr. Mary Marazita, Dr. Terri Beaty, and Dr. Robert Cornell. The proposed project and training plan are tailored to provide training in statistical genetics, sequencing, and family-based analytic methods. Learning these new methods and technologies in genetics will add to my existing skills in environmental epigenetics and will facilitate my growth into an independent genetic epidemiologist.