Cleft Lip Genetics: A Multicenter International Consorti

唇裂遗传学：多中心国际联盟

• 批准号: 6765089
• 负责人: Andrew C Lidral
• 金额: $ 42.36万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765089
• 关键词: American; Colombia; Scandinavian country; child (0-11); cleft lip; cleft palate; clinical research; cooperative study; family genetics; gene environment interaction; gene mutation; genetic screening; genome; genotype; human subject; international health /scientific organization; linkage disequilibriums; linkage mapping; parents

Cleft lip with or without cleft palate (CL/P) is a common birth defect. Previous studies have indicated that CL/P is a complex trait that is caused by a combination of genetic and environmental factors. This complexity has limited studies, such that disease mutations have only been identified in one unique family. It is also unlikely that all disease loci have been identified. The overall objective of this project is to identify disease genes involved in nonsyndromic CL/P by applying new multistaged linkage and linkage disequilibrium (LD) strategies to affected relative pairs and extended pedigrees. This multistage approach, which has not yet been applied to CL/P, is very powerful in that no prior knowledge about the involved genetic or biological processes is needed. Hypotheses to be tested: Nonsyndromic CL/P is caused by Genetic Variants at one or more loci. To test this hypothesis, CL/P families with both multiple affected members and mother/father and affected child trios will be recruited from a variety of clinical centers including: Columbus, OH; Medellin, Colombia SA; Seattle, WA; Pittsburgh; and Finland as well as smaller centers including Cleveland (Dr. Nat Robin); San Francisco (Dr. Ed Lammer) and San Diego (Dr. Marilyn Jones). The multiplex families will be the basis for initially evaluating candidate genes to test the above hypothesis using the genetic tools of linkage and linkage disequilibrium to reject (exclude) or provide evidence for support (i.e. linkage) the hypotheses. A 10 cM genome-wide screen will also be performed to find additional loci. Positive loci will be further evaluated by a combination of multipoint, multi-locus and TDT/association analyses using more densely spaced markers. The heritage of the Colombia and Finland populations have led to unique population structures that are advantageous for finding disease genes for complex traits. Comparison of these populations to the outbred US population will provide important information regarding the genetic diversity leading to CL/P. The power initially (will be sufficient to identify loci of moderate or major risk (relative risks greater than 2.0) and during the project, power will increase to be able to identify minor loci (relative risks greater than 1.5). It will be through multi- center projects such as this one, in which worldwide collaborations have been established to apply a combination of complimentary genetic strategies, that disease loci for CL/P will be identified. Ultimately, this will further the understanding of normal and abnormal craniofacial development, such that therapies to prevent CL/P can be developed and implemented.

带有或没有裂口的唇唇（Cl/p）是常见的先天缺陷。 先前的研究表明，Cl/P是由遗传因素和环境因素组合引起的复杂特征。 这种复杂性的研究有限，因此仅在一个独特的家庭中发现了疾病突变。 所有疾病基因座也不太可能被发现。 该项目的总体目的是通过将新的多链接连接和连锁不平衡（LD）策略应用于受影响的相对对和扩展的谱系中，以识别非疾病CL/P的疾病基因。 这种多阶段方法尚未应用于Cl/P，非常有力，因为不需要关于涉及的遗传或生物过程的先验知识。要测试的假设：非综合征Cl/p是由一个或多个基因座的遗传变异引起的。为了检验这一假设，将从各种临床中心招募CL/P家族，并具有多个受影响的成员以及母亲/父亲和受影响的孩子三人。麦德林，哥伦比亚SA；华盛顿州西雅图；匹兹堡；和芬兰以及包括克利夫兰（Cleveland）（Nat Robin博士）在内的较小中心；旧金山（Ed Lammer博士）和圣地亚哥（玛丽莲·琼斯博士）。 多重家族将是最初评估候选基因的基础，该基因使用链接和连锁的遗传工具不平衡（排除）或提供支持（即联系）的证据（即链接）。 还将进行10厘米全基因组屏幕以找到其他位点。 通过使用更密集的分布标记，将通过多点，多核和TDT/关联分析的组合进一步评估阳性基因座。哥伦比亚和芬兰人口的遗产导致了独特的人口结构，这对于为复杂性状寻找疾病基因而言是有利的。 这些人群与美国人口的比较将提供有关导致Cl/p的遗传多样性的重要信息。 The power initially (will be sufficient to identify loci of moderate or major risk (relative risks greater than 2.0) and during the project, power will increase to be able to identify minor loci (relative risks greater than 1.5). It will be through multi- center projects such as this one, in which worldwide collaborations have been established to apply a combination of complimentary genetic strategies, that disease loci for CL/P will be identified. Ultimately, this will further the understanding of normal and异常的颅面发展，可以开发和实施预防CL/P的疗法。