Statistical Models of Maternal and Offspring Genetic Effects For Risk of Disease

母亲和后代遗传效应对疾病风险的统计模型

• 批准号: 7849557
• 负责人: Erica Joy Childs
• 金额: $ 1.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849557
• 关键词: Affect; Alleles; Biological; Blood typing procedure; Candidate Disease Gene; Code; Communities; Complex; Computer software; Development; Disease; Environment; Environmental Exposure; Extended Family; Family; Fetus; Generations; Genes; Genetic; Genotype; Joints; Knowledge; Life; Macaca mulatta; Mentors; Methodology; Methods; Modeling; Mothers; Nuclear Family; Outcome; Parents; Population; Predisposition; Problem Solving; Process; Public Health; Relative Risks; Research; Research Personnel; Rheumatoid Arthritis; Risk; Risk Factors; Schizophrenia; Siblings; Statistical Methods; Statistical Models; Susceptibility Gene; Testing; Work; base; blood group; design; disorder risk; family structure; fetal; genetic analysis; genetic risk factor; human leukocyte antigen gene; offspring; public health relevance; sex; software development; trait

DESCRIPTION (provided by applicant): The development of statistical methods to detect complex biological or genetic mechanisms is very important to the furthering of our knowledge of the etymology of complex diseases. One example where genes operate through complex biological mechanisms to increase disease risk is through an interaction between maternal and offspring genes termed maternal-fetal genotype (MFC) incompatibility. MFC incompatibility arises from maternal-fetal genotype combinations that predispose for maternal immunological processes that adversely affect the developing fetus, and thereby increase susceptibility to disease. Although the adverse environment takes place early in life, the effects of it can be studied decades later because of its genetic origins. Using population designs that collect only offspring and their mothers, interactions between mothers and offspring gene effects are confounded with the effects of a susceptibility risk allele in the offspring or the mother. To solve this problem, my research group developed the original MFG test to estimate MFC interaction effects by adapting the log-linear method for estimating genotypic relative risks for trios (parents and affected offspring). However, there are still some fundamental limitations to the current version of the MFG test that must be overcome. The current test is limited to 2-generation families, it can not handle all forms of MFG incompatibility and it can not be used with quantitative outcomes. This proposed work will expand upon existing statistical methodology (the MFG Test) that estimates disease relative risk for MFG incompatible offspring. Specifically this research will (1) Develop an extended MFG test (EMFG Test) to accommodate arbitrary family structures, (2) Generalize the EMFG test so that one statistical method can be used to fit a variety of MFG incompatibility models, (3) Allow for interactions between specific covariates and MFG incompatibility in the arbitrary family setting, (4) Extend the EMFG test for use with quantitative traits. PUBLIC HEALTH RELEVANCE: This proposed work is relevant to public health because it will provide new statistical methods that can be used by others to test for the joint effects of maternal and offspring genes in a wide range of diseases. Ultimately it will help the scientific community better understand the mechanisms by which environmental and genetic risk factors interact to increase risk to disease.

描述（由申请人提供）：检测复杂生物学或遗传机制的统计方法的开发对于进一步了解复杂疾病词源的知识非常重要。基因通过复杂的生物学机制运行以增加疾病风险的一个例子是通过孕产妇和后代基因之间的相互作用，称为母亲 - 狂欢基因型（MFC）不兼容。 MFC不兼容是由母亲 - 狂热的基因型组合产生的，这些组合对母体免疫学过程产生了不利影响，从而对发育中的胎儿产生了不利影响，从而增加了对疾病的易感性。尽管不利的环境发生在生命的早期，但由于其遗传起源，它可以在数十年后进行研究。使用只收集后代及其母亲的人群设计，母亲与后代基因效应之间的相互作用与后代或母亲的易感性风险等位基因的影响混淆。为了解决这个问题，我的研究小组开发了原始的MFG测试，以通过调整对数线性方法来估计三重奏（父母和受影响后代）的基因型相对风险来估计MFC相互作用效应。但是，必须克服当前版本的MFG测试仍然存在一些基本限制。当前的测试仅限于2代家族，无法处理所有形式的MFG不相容性，也不能与定量结果一起使用。这项提出的工作将扩大现有的统计方法（MFG检验），该方法估计了MFG不相容后代的疾病风险。具体而言，这项研究将（1）开发一个延长的MFG测试（EMFG测试）以适应任意家庭结构，（2）将EMFG测试推广，以便可以使用一种统计方法来拟合各种MFG不相容模型，（3）允许在特定的协方差和MFG不合时宜的情况下进行相互作用，并在特定的家族设置中使用量化量，以扩展量化量的量级，（4）扩展EMF。公共卫生相关性：这项拟议的工作与公共卫生有关，因为它将提供新的统计方法，而其他人可以使用这些方法来测试各种疾病中孕产妇和后代基因的共同影响。最终，它将帮助科学界更好地了解环境和遗传危险因素相互作用以增加疾病风险的机制。