Genetic instrumental variable studies of maternal risk behaviors for oral clefts

描述(由申请人提供)：唇腭裂(CL/P)是常见的、负担沉重的出生缺陷，其病因复杂，有遗传、行为和环境因素。CL/P对受影响的个人、个人和家庭的健康、生活质量和经济造成重大负担。一些研究表明，孕期母亲的危险行为，如吸烟、饮酒和肥胖，在CL/P的病因中发挥了作用。然而，这些研究没有考虑到可能影响母亲自我选择进入危险行为的未观察或未测量的因素，但与CL/P风险有关，如母亲对健康的偏好和风险容忍度以及母亲对健康风险的看法。这些因素导致几种母亲风险与健康行为之间的相关性，并本身与生物、环境和母亲健康风险因素相关。在现有的数据样本中，几乎不可能观察到所有相关的行为和风险因素。忽视这些未观察到的相关因素可能会混淆母亲危险行为对CL/P的影响的估计，包括平均影响和与遗传危险因素的交互影响的估计。为了制定有效的CL/P咨询和预防计划，需要对母亲危险行为的影响进行准确的估计。本研究的目的是使用一个解释未观察到的混杂因素的遗传工具变量(IV)模型来估计怀孕期间母亲危险行为(包括吸烟、酒精和肥胖)对CL/P风险的影响。IV模型将使用危险行为的变异来估计这些影响，这些变异是由与这些危险行为显著相关但通过未观察到的混杂因素与CL/P无关的遗传变异(工具)预测的。使用适当的工具，IV模型将对这些危险行为对CL/P的“因果”影响提供一致的(渐近无偏的)估计。这项研究将包括一个由大约8917名CL/P儿童的母亲和未受影响儿童的母亲组成的独特的大型国际人群联合样本。本研究将选择最适合作为研究工具的遗传变异，评估这些变异作为工具的实用性，并使用符合IV条件的遗传工具，使用IV模型估计母亲风险行为对CL/P的影响。所采用的IV模型将估计这些危险行为对CL/P的平均影响，以及它们与CL/P的遗传危险因素的交互作用。这项研究将对主要母亲危险行为对CL/P的“因果”影响提供一致的估计，这对于开发有效和经济高效的CL/P预防计划和高危妇女咨询是非常必要的。此外，这项研究使用了一种新的分析方法，可以应用于研究母亲危险行为对其他出生缺陷和围产儿结局的影响，并有可能显著推进这一研究领域。 公共卫生相关性：该项目将帮助确定怀孕期间几种母亲危险行为的影响，包括吸烟、酗酒和肥胖对唇裂和/或腭裂风险的影响，唇裂和/或腭裂是常见的、负担沉重的出生缺陷。需要对这些危险行为的影响进行准确的估计，以制定有效的干预措施和政策来预防唇裂和/或腭裂。

DESCRIPTION (provided by applicant): Cleft lip and/or palate (CL/P) are common and burdensome birth defects with a complex etiology of genetic, behavioral and environmental contributors. CL/P impose significant burden on the health, quality of life and economics of affected individuals individual and families. Several studies have suggested that maternal risk behaviors during pregnancy such as smoking, alcohol use, and obesity play a role in the etiology of CL/P. However, these studies that do not account for unobserved or unmeasured factors that may influence maternal self-selection into risk behaviors but are related to CL/P risks, such as maternal preferences for health and risk tolerance and maternal perceptions of health risks. These factors induce correlations between several maternal risk and health behaviors and are themselves correlated with biologic, environmental and maternal health risk factors. It is virtually impossible to observe all relevant behaviors and risk factors in available data samples. Ignoring these unobserved yet relevant factors may confound the estimates of the effects of maternal risk behaviors on CL/P, including estimates of average effects and interactive effects with genetic risk factors. Accurate estimation of the effects of maternal risk behaviors is needed for developing effective counseling and prevention programs for CL/P. The objective of this study is to estimate the effects of maternal risk behaviors during pregnancy including smoking, alcohol, and obesity on CL/P risks using a genetic instrumental variable (IV) model that accounts for unobserved confounders. The IV model will estimate these effects using variation in the risk behaviors that is predicted by genetic variants (instruments) that are significantly correlated with these risk behaviors but are otherwise unrelated to CL/P through unobserved confounders. Using appropriate instruments, the IV model will provide consistent (asymptotically unbiased) estimates of the "causal" effects of these risk behaviors on CL/P. The study will include a unique and large international consortium of population-level samples of about 8917 mothers of children with CL/P and mothers of unaffected children. The study will select and genotype genetic variants that are strong candidates for use as instruments for the study maternal risk behaviors, evaluate the utility of these variants as instruments, and estimate the effects of the maternal risk behaviors on CL/P using an IV model with the genetic instruments that fit the IV conditions. The employed IV model will estimate the average effects of these risk behaviors on CL/P as well as their interactive effects with genetic risk factors for CL/P. The study will provide consistent estimates of the "causal" effects of major maternal risk behaviors on CL/P which are highly needed for developing effective and cost-effective programs for prevention of CL/P and counseling at risk women. Further, the study utilizes a novel analytical approach that can be applied to study the effects of maternal risk behaviors on other birth defects and perinatal outcomes and has the potential for advancing this research field significantly. PUBLIC HEALTH RELEVANCE: This project will help to identify the effects of several maternal risk behaviors during pregnancy including smoking, alcohol and obesity on the risks of cleft lip and/or palate, which are common and burdensome birth defects. Accurate estimates of the effects of these risk behaviors are needed for developing effective interventions and policies to prevent cleft lip and/or palate.