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）是一种常见和沉重的出生缺陷，具有遗传，行为和环境因素的复杂病因。艾滋病毒/艾滋病对受影响个人和家庭的健康、生活质量和经济造成重大负担。一些研究表明，怀孕期间的产妇危险行为，如吸烟、饮酒和肥胖，在CL/P的病因中起作用。然而，这些研究没有考虑到未观察或未测量的因素，这些因素可能会影响产妇自我选择风险行为，但与CL/P风险有关，例如产妇对健康和风险承受能力的偏好以及产妇对健康风险的看法。这些因素导致了几种孕产妇风险与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。忽略这些未观察到但相关的因素可能会混淆孕产妇危险行为对CL/P影响的估计，包括对平均影响和与遗传风险因素相互作用影响的估计。需要准确估计孕产妇危险行为的影响，以制定有效的CL/P咨询和预防方案。本研究的目的是利用考虑未观察到的混杂因素的遗传工具变量（IV）模型，估计怀孕期间孕产妇危险行为（包括吸烟、饮酒和肥胖）对CL/P风险的影响。IV模型将使用与这些风险行为显著相关的遗传变异（工具）预测的风险行为的变化来估计这些影响，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模型将提供这些风险行为对CL/P的“因果”影响的一致（渐近无偏）估计。这项研究将包括一个独特的、大型的国际联盟，由大约8917名患有CL/P儿童的母亲和未受影响儿童的母亲组成的人口水平样本。该研究将选择和基因型的遗传变异是强有力的候选者用于研究产妇风险行为的工具，评估这些变异作为工具的效用，并估计产妇风险行为对CL/P的影响，使用符合IV条件的遗传工具的IV模型。所采用的IV模型将估计这些风险行为对CL/P的平均影响，以及它们与CL/P遗传风险因素的交互影响。该研究将对主要孕产妇风险行为对CL/P的“因果”影响提供一致的估计，这对于制定有效和具有成本效益的CL/P预防计划和高危妇女咨询是非常需要的。此外，该研究采用了一种新的分析方法，可以应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。

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.