Genetic instrumental variable studies of maternal risk behaviors for oral clefts

描述（由申请人提供）：唇裂和/或腭裂（CL/P）是常见且负担沉重的出生缺陷，具有遗传、行为和环境因素的复杂病因学。CL/P对受影响的个人和家庭的健康、生活质量和经济造成重大负担。一些研究表明，母亲在怀孕期间的风险行为，如吸烟，饮酒和肥胖在CL/P的病因学中发挥作用。然而，这些研究没有考虑可能影响母亲自我选择风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承受能力以及母亲对健康风险的看法。这些因素导致了一些孕产妇风险和健康行为之间的相关性，并且本身与生物、环境和孕产妇健康风险因素相关。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。忽略这些未观察到的相关因素可能会混淆母体风险行为对CL/P影响的估计，包括平均影响和与遗传风险因素的交互影响的估计。准确估计产妇的危险行为的影响是需要制定有效的咨询和预防计划CL/P。本研究的目的是估计产妇的危险行为在怀孕期间，包括吸烟，饮酒和肥胖CL/P风险的影响，使用遗传工具变量（IV）模型，占未观察到的混杂因素。IV模型将使用遗传变异（工具）预测的风险行为变异估计这些效应，遗传变异与这些风险行为显著相关，但通过未观察到的混杂因素与CL/P无关。使用适当的工具，IV模型将提供一致的（渐近无偏）估计这些风险行为对CL/P的“因果”影响。该研究将包括一个独特的大型国际财团的人口水平样本约8917母亲的儿童CL/P和母亲的未受影响的儿童。本研究将选择作为研究母体风险行为工具的强候选遗传变异并对其进行基因分型，评价这些变异作为工具的效用，并使用具有适合IV条件的遗传工具的IV模型估计母体风险行为对CL/P的影响。所采用的IV模型将估计这些危险行为对CL/P的平均影响以及与CL/P遗传危险因素的交互作用。该研究将提供一致的估计主要孕产妇危险行为对CL/P的“因果”影响，这对于制定有效和具有成本效益的方案预防CL/P和咨询高危妇女是非常必要的。此外，该研究利用了一种新的分析方法，可用于研究孕产妇风险行为对其他出生缺陷和围产期结局的影响，并有可能显著推进这一研究领域。 公共卫生相关性：该项目将有助于确定怀孕期间的几种产妇风险行为，包括吸烟、酗酒和肥胖对唇腭裂风险的影响，唇腭裂是常见的和负担沉重的出生缺陷。准确估计这些风险行为的影响，需要制定有效的干预措施和政策，以防止唇腭裂。

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.