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BACKGROUND

Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children's obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment.

METHODS

We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5-11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level.

RESULTS

We observed that E1 was defined by the combination of low dairy consumption, non-smokers' cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (OR = 0.070, P = 2.59 × 10). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (OR = 0.42, P = 0.047) and working memory (OR = 0.31, P = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0.

CONCLUSIONS

The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk.

背景

肥胖和神经发育迟缓是复杂的特征，它们经常同时发生，并在男孩和女孩之间存在差异。人们认为产前暴露会影响儿童肥胖，但尚不清楚孕妇的暴露是否会导致性别之间肥胖风险的差异，以及它们是否会影响神经发育。

方法

我们分析了来自 HELIX 项目的 1044 名儿童的数据，其中包括 93 项怀孕期间的暴露，以及儿童时期（5-11 岁）的临床、神经心理学和甲基化数据。使用暴露组全基因组交互分析，我们确定了在肥胖风险方面具有最高性别二态性的产前暴露，这些暴露被用来创建一个多暴露谱。我们应用因果随机森林将个体分类为两个环境：E1 和 E0。E1 由一组暴露水平组成，与 E0 相比，女孩患肥胖症的风险显著降低，E0 由其余的暴露水平组合组成。我们研究了性别和神经发育迟缓之间的关联是否也在 E0 和 E1 之间存在差异。我们使用甲基化数据在环境之间进行全基因组关联研究，以了解在分子水平上属于 E1 或 E0 的影响。

结果

我们发现，E1 由怀孕期间低乳制品摄入量、非吸烟者血液中的可替宁水平、低设施丰富度和存在绿地的组合定义（OR=0.070，P=2.59×10）。E1 也与女孩神经发育迟缓的风险降低相关，基于非言语智力（OR=0.42，P=0.047）和工作记忆（OR=0.31，P=0.02）的神经心理学测试。与此一致的是，E1 和 E0 之间的显著差异甲基化探针中富集了几个神经发育功能。