Genetic modifiers of orofacial cleft subtypes in families

家族中口面裂亚型的遗传修饰

• 批准号: 10536295
• 负责人: Sarah Whelan Curtis
• 金额: $ 7.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10536295
• 关键词: Affect; Architecture; Biological; Birth; Case-Control Studies; Chromosome Mapping; Cleft Lip; Cleft Palate; Complex; Congenital Abnormality; Counseling; Data; Data Set; Development; Disease; 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; Lead; 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; Training Support; Variant; analytical method; base; 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; skills; trait; transmission process; whole genome

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）是最常见的出生缺陷之一，大约每700名新生儿中就有1名受到影响 在全球范围内，并且是表型可变的，包括唇裂（CL）、腭裂（CP）和唇腭裂（CLP）。 虽然大多数OFC病例是散发性的，但受影响个体的亲属中OFC复发的风险比是 大量的，突出了一个强大的遗传组成部分，这组疾病。然而，尽管 尽管有大量证据表明OFC是可遗传的，但在过去的世纪里， 还没有确定解释这种遗传性的遗传因素。一种可能的解释是， 遗传变异只会增加某些OFC亚型的风险，因此这些变异在 标准分析将联合收割机亚型结合在一起以增加样本量，表面上是为了提高 基因定位这一建议的总体假设是，OFC亚型的高复发风险， 家族遗传是由罕见和常见的亚型特异性遗传风险变异引起的，许多 目前还不清楚为了更好地研究导致OFC的罕见和常见遗传变异， 我们将使用基于家族的遗传学方法，因为它们是鉴定潜在因果关系的有力方法， 分离变体。此外，该提案的独特之处在于，其主要目标不仅是确定和 潜在的功能测试这些变异，但要了解这些风险变异如何在家庭中分离， 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。 这项建议的中心假设将在两个独立的目标进行测试：第一，测试罕见的遗传变异 利用全基因组测序数据和基因分型数据， 第二，开发一个亚型特异性多基因风险评分（PRS），并测试受影响和 不受影响的家庭成员。我已经组建了一个指导小组，提供必要的培训和支持 完成拟议的研究：赞助商伊丽莎白·莱斯利博士和迈克尔·爱泼斯坦博士和合作者 博士玛丽·马拉齐塔，特丽·贝蒂医生和罗伯特·康奈尔医生。拟议的项目和培训计划是量身定制的 提供统计遗传学、测序和基于家族的分析方法方面的培训。学习这些新 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， 帮助我成长为独立的遗传流行病学家