Cleft Lip Genetics: A Multi Center International Consortium

唇裂遗传学：多中心国际联盟

基本信息

批准号：
7664988
负责人：
Andrew C Lidral
金额：
$ 60.3万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664988
关键词：
11p12 12q13 14q24-q31 16q22 17q12 1p22 1p36 3q26 6p23 9q22 Address Admixture Affect African American Indians Candidate Disease Gene Child Cleaved cell Cleft Lip Cleft Palate Cleft lip with or without cleft palate Clinic Collaborations Colombia Complex Congenital Abnormality Data Analyses Defect Development Disease Embryo Etiology Extended Family Face Facial Expression Family Funding Future Gene Expression Genes Genetic Genome Scan Genotype Goals Grant Heterogeneity Human Human Genetics Individual Inherited Iowa Linkage Disequilibrium Lip structure MSX1 gene Maps Medical Methods Mission Modeling Mus Mutation Native Americans Ohio Operative Surgical Procedures Parents Pathway interactions Pattern Phase Phenotype Pilot Projects Population Population Study Prevention strategy Recruitment Activity Research Scanning Screening procedure Smiling Testing Time Universities Vertebral column Washington Work base cost density gene discovery gene interaction genetic analysis genetic variant genome-wide linkage international center novel orofacial tool trait

项目摘要

DESCRIPTION (provided by applicant): The goal of this competitive renewal is to identify the genetic basis in humans for cleft lip with or without cleft palate (CL/P), which is a common and genetically complex birth defect. We have accomplished all 3 of the specific aims of the initial grant, including: 1) Recruitment of more than 130 extended families and 500 affected child/parent trios. 2) Genetic analysis of candidate genes, which revealed positive results in both Colombian and Ohio families. These loci will be used as covariates in gene-gene interaction tests. 3) Completion of a genome wide linkage scan which identified additional positive loci, including a previously unidentified major locus at 9q22-33. A genome scan, accomplished by the successful application to the Center for Inherited Disease Research (CIDR: Lidral PI) in collaboration with Drs. Arcos-Burgos, Marazita and Murray to evaluate over 600 CL/P families from 7 different populations, revealed a highly significant result to 9q22-33 (combined LOD=6.6) in 4 of these populations with the Colombian families yielding the most significant results. The specific focus of the renewal is to positionally clone the 9q CL/P locus which has an 18cM 2-LOD interval. The initial fine-mapping will be accomplished by genotyping an Illumina panel of 1536 SNPs on the same 600 families to narrow the region by linkage and to screen for association. The genotyping will be performed by CIDR as part of a successful pilot project application (Lidral PI). For greater power we have established collaborations with another center in Colombia that is a unique admixed population of Native American Indians, Spaniards and Africans. This admixture likely results in a powerful pattern of linkage disequilibrium that permits association studies at a much lower marker density. We propose to explore whether this exists in our study population and if so apply emerging admixture methods. All total, we will be able to recruit a total of more than 300 extended and 2000 trio families that will be the basis for replication and for future studies to fine-map the other positive loci and identify gene-gene interactions. To aid in prioritizing which genes should be sequenced, we propose to determine in a mouse CL/P model the embryonic facial expression of uncharacterized genes within the critical region. Through the use of complimentary mouse and human genetics this project will identify genes and pathways essential for normal facial development, such that preventive strategies for CL/P can be developed.

描述（由申请人提供）：这种竞争性更新的目的是确定人类中有或没有left裂（Cl/p）的人类的遗传基础，这是一种常见且遗传上复杂的先天性缺陷。我们已经完成了最初赠款的所有特定目标，包括：1）招募130多个大家庭和500个受影响的儿童/家长三重奏。 2）对候选基因的遗传分析，该分析揭示了哥伦比亚和俄亥俄州家族的积极结果。这些基因座将用作基因 - 基因相互作用测试中的协变量。 3）完成基因组宽连接扫描，该扫描确定了额外的阳性基因座，包括以前未知的主要基因座，位于9q22-33。通过成功应用于遗传性疾病研究中心（CIDR：LIDRAR PI）与DRS合作的基因组扫描。 Arcos-Burgos，Marazita和Murray评估来自7个不同人群的600多个Cl/p家族，在其中4个人口中，哥伦比亚家庭中有4个人口揭示了9q22-33（合并的LOD = 6.6）的非常重要的结果，产生了最重要的结果。续订的特定焦点是将具有18cm 2-lod间隔的9Q Cl/p基因座定位。最初的精细映射将通过在同一600个家庭上的1536个SNP的Illumina面板来完成，以通过连锁和筛选关联来缩小该区域的范围。基因分型将由CIDR作为成功的试点项目应用程序（Lidral PI）进行。为了获得更大的权力，我们与哥伦比亚的另一个中心建立了合作，该中心是美国印第安人，西班牙人和非洲人的独特混合人群。这种混合可能会导致链接不平衡的强大模式，从而使关联研究以低得多的标记密度研究。我们建议探讨这是否存在于我们的研究人群中，如果这样，则采用了新兴的混合方法。总的来说，我们将能够招募总共300多个扩展和2000个三重奏家族，这将是复制的基础和将来的研究，以对其他阳性基因座进行绘制并确定基因 - 基因的相互作用。为了确定应该测序哪些基因的优先级，我们建议在小鼠CL/P中确定临界区域内未表征基因的胚胎面部表达。通过使用免费小鼠和人类遗传学，该项目将确定对正常面部发育必不可少的基因和途径，从而可以制定CL/P的预防策略。