Genetic modifiers of orofacial cleft subtypes in families

家族中口面裂亚型的遗传修饰

基本信息

批准号：
10681239
负责人：
Sarah Whelan Curtis
金额：
$ 7.73万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681239
关键词：
Affect Architecture Biological Birth Case/Control Studies Chromosome Mapping Cleft Lip Complex Congenital Abnormality Counseling Data Data Set Development Disease Educational process of instructing Environmental Risk Factor Epidemiologist Epigenetic Process Face Family Family member First Degree Relative Genes Genetic Genetic Risk Genetic Variation Genetic study Genome Genotype Goals Growth Hearing problem Heritability Human Individual Learning Life Lip structure Live Birth Mediating Mentors Methods Molecular Odds Ratio Operative Surgical Procedures Palate Persons Phenotype Predisposing Factor Prevention Public Health Recording of previous events Recurrence Research Research Personnel Risk Risk Assessment Risk Estimate Sample Size Speech Technology Testing Training Variant analytical method case control cleft lip and palate cost estimate disorder risk experience genetic analysis genetic approach genetic architecture genetic epidemiology genetic pedigree genetic risk factor genetic variant genome sequencing genome-wide human disease improved innovation large datasets multi-ethnic orofacial cleft polygenic risk score psychosocial rare variant repaired risk variant segregation skills trait transmission process variant detection whole genome

项目摘要

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.

项目摘要口面裂（OFC）是最常见的先天缺陷之一，影响了700个分娩中的大约1个在全球范围内，在表型上是可变的，包括唇裂（CL），paprate（CP）以及唇彩和口感（CLP）。尽管大多数OFC案件是零星的，但在受影响个体的亲属中，OFC的复发风险比是实质性的，突出了这一组疾病的强大遗传成分。尽管如此，尽管如此大量证据表明OFC是可遗传的，过去一个世纪的各种OFC的遗传研究已经然而，要确定解释这种遗传力的大多数的遗传因素。一种可能的解释是一些遗传变异只会增加OFC的某些亚型的风险，因此这些变体被遗漏标准分析将亚型结合在一起以增强样本量表面上，以提高功率基因映射。该提议的总体假设是，这种高复发风险是OFC的亚型家庭是由稀有和普通亚型特异性遗传风险变异的继承而引起的，许多仍然未知。为了更好地研究引起OFC的稀有遗传变异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因果的强大方法分离变体。此外，该提议的独特之处在于，主要目标不仅是识别和有可能在功能上测试这些变体，但要了解这些风险变体如何在家庭中隔离和与已知的环境风险因素相互作用，从而更好地了解亚型特异性OFC风险。该提案的中心假设将以两个独立的目的进行测试：首先，测试稀有遗传变异 OFC家族的传播，利用全基因组测序数据和基因分型数据，以及其次，开发亚型特异性多基因风险评分（PR），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，以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·爱泼斯坦博士和合作者 Mary Marazita博士，Terri Beaty博士和Robert Cornell博士。拟议的项目和培训计划是量身定制的提供统计遗传学，测序和基于家庭的分析方法的培训。学习这些新遗传学方法和技术将增加我在环境表观遗传学方面的现有技能，并将促进我的成长成为独立的遗传流行病学家。