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

描述（由申请人提供）：发展用于检测复杂生物或遗传机制的统计方法对于进一步了解复杂疾病的词源学非常重要。基因通过复杂的生物学机制起作用以增加疾病风险的一个例子是通过称为母胎基因型（MFC）不相容的母体和后代基因之间的相互作用。MFC不相容源于母胎基因型组合，这种组合易导致母体免疫过程对发育中的胎儿产生不利影响，从而增加对疾病的易感性。尽管不利环境发生在生命早期，但由于其遗传起源，其影响可以在几十年后研究。使用只收集后代及其母亲的种群设计，母亲和后代之间的相互作用基因效应与后代或母亲的易感性风险等位基因的影响相混淆。为了解决这个问题，我的研究小组开发了最初的MFG测试，通过采用对数线性方法来估计三人组（父母和受影响的后代）的基因型相对风险，以估计MFC相互作用的影响。然而，当前版本的MFG测试仍然存在一些必须克服的基本限制。目前的测试仅限于2代家庭，它不能处理所有形式的MFG不相容，也不能用于定量结果。这项拟议的工作将扩展现有的统计方法（MFG测试），估计MFG不相容后代的疾病相对风险。具体来说，本研究将(1)开发一个扩展的MFG测试（EMFG测试）来适应任意的家庭结构，(2)推广EMFG测试，以便一种统计方法可以用来拟合各种MFG不相容模型，(3)允许特定协变量与任意家庭设置中的MFG不相容之间的相互作用，(4)扩展EMFG测试用于定量特征。公共卫生相关性：这项拟议的工作与公共卫生相关，因为它将提供新的统计方法，其他人可以使用这些方法来测试母亲和后代基因在各种疾病中的共同影响。最终，它将帮助科学界更好地了解环境和遗传风险因素相互作用增加疾病风险的机制。

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.