Importance Several maternal exposures during pregnancy are considered predisposing factors for offspring neurodevelopmental conditions. However, many of these exposures may be noncausal and biased by maternal genetic liability. Objective To assess whether pregnancy-related predisposing factors for offspring neurodevelopmental conditions are associated with maternal genetic liability for attention-deficit/hyperactivity disorder (ADHD), autism, and schizophrenia and to compare associations for maternal genetic liability with those for paternal genetic liability, which could indicate that paternal exposures are not suitable negative controls for maternal exposures. Design, Setting, and Participants The Norwegian Mother, Father and Child Cohort Study (MoBa) is a population-based pregnancy cohort that recruited parents from June 1999 to December 2008. Polygenic scores (PGS) for ADHD, autism, and schizophrenia were derived in mothers and fathers. The associations between maternal PGS and 37 pregnancy-related measures were estimated, and these results were compared with those from paternal PGS predicting paternal measures during the mother's pregnancy. Analysis took place between March 2021 and March 2022. Exposures PGS for ADHD, autism, and schizophrenia, calculated (using discovery effect size estimates and threshold of P < .05) from the largest available genome-wide association studies. Main Outcomes and Measures Self-reported pregnancy-related measures capturing lifestyle behaviors, metabolism, infectious and autoimmune diseases, other physical health conditions, and medication use. Results Data were available for up to 14 539 mothers (mean [SD] age, 30.00 [4.45] years) and 14 897 fathers (mean [SD] age, 32.46 [5.13] years) of European ancestry. Modest but robust associations were observed between specific pregnancy-related measures and maternal PGS, including ADHD PGS with asthma (odds ratio [OR], 1.15 [95% CI, 1.06-1.25]), smoking (OR, 1.26 [95% CI, 1.19-1.33]), prepregnancy body mass index (β, 0.25 [95% CI, 0.18-0.31]), pregnancy weight gain (β, 0.20 [95% CI, 0.10-0.30]), taking folate (OR, 0.92 [95% CI, 0.88-0.96]), and not taking supplements (OR, 1.09 [95% CI, 1.04-1.14]). Schizophrenia PGS was associated with coffee consumption (OR, 1.09 [95% CI, 1.05-1.12]), smoking (OR, 1.12 [95% CI, 1.06-1.19]), prepregnancy body mass index (β, -0.18 [95% CI, -0.25 to -0.11]), and pregnancy weight gain (β, 0.17 [95% CI, 0.07-0.27]). All 3 PGSs associated with symptoms of depression/anxiety (ADHD: OR, 1.15 [95% CI, 1.09-1.22]; autism: OR, 1.13 [95% CI, 1.06-1.19]; schizophrenia: OR, 1.13 [95% CI, 1.07-1.20]). Associations were largely consistent for maternal and paternal PGS, except ADHD PGS and smoking (fathers: OR, 1.13 [95% CI, 1.09-1.17]). Conclusions and Relevance In this study, genetic liability to neurodevelopmental conditions that is passed from mothers to children was associated with several pregnancy-related factors and may therefore confound associations between these pregnancy-related factors and offspring neurodevelopment that have previously been thought to be causal. It is crucial that future study designs account for genetic confounding to obtain valid causal inferences so that accurate advice can be given to pregnant individuals.

中文翻译：

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后代神经发育状况的妊娠相关诱发因素与父母对注意力缺陷/多动症、自闭症和精神分裂症的遗传责任之间的关联：挪威母亲、父亲和儿童队列研究 (MoBa)。


重要性 母亲在怀孕期间的几种暴露被认为是后代神经发育状况的诱发因素。然而，许多这些暴露可能是非因果性的，并且受到母亲遗传倾向的影响。目的 评估与妊娠相关的后代神经发育状况的诱发因素是否与注意力缺陷/多动障碍（ADHD）、自闭症和精神分裂症的母亲遗传倾向相关，并比较母亲遗传倾向与父亲遗传倾向的关联。可能表明父亲的暴露不适合作为母亲暴露的阴性对照。设母亲和父亲。评估了母亲 PGS 与 37 项妊娠相关指标之间的关联，并将这些结果与父亲 PGS 的结果进行比较，预测母亲怀孕期间父亲的指标。分析于 2021 年 3 月至 2022 年 3 月期间进行。ADHD、自闭症和精神分裂症的暴露 PGS 根据最大​​的可用全基因组关联研究计算（使用发现效应大小估计和 P < .05 的阈值）。主要成果和措施自我报告的与妊娠相关的措施，包括生活方式、新陈代谢、传染病和自身免疫性疾病、其他身体健康状况以及药物使用。结果 可获得多达 14 539 名欧洲血统母亲（平均 [SD] 年龄，30.00 [4.45] 岁）和 14 897 名父亲（平均 [SD] 年龄，32.46 [5.13] 岁）的数据。 在特定的妊娠相关指标和孕产妇 PGS 之间观察到适度但强有力的关联，包括 ADHD PGS 与哮喘（比值比 [OR]，1.15 [95% CI，1.06-1.25]）、吸烟（OR，1.26 [95% CI， 1.19-1.33]）、孕前体重指数（β，0.25 [95% CI，0.18-0.31]）、孕期体重增加（β，0.20 [95% CI，0.10-0.30]）、服用叶酸（OR，0.92 [ 95% CI, 0.88-0.96]），并且不服用补充剂（OR, 1.09 [95% CI, 1.04-1.14]）。精神分裂症 PGS 与咖啡摄入量（OR，1.09 [95% CI，1.05-1.12]）、吸烟（OR，1.12 [95% CI，1.06-1.19]）、孕前体重指数（β，-0.18 [95%]）相关。 CI，-0.25 至 -0.11]）和妊娠期体重增加（β，0.17 [95% CI，0.07-0.27]）。所有 3 个 PGS 均与抑郁/焦虑症状相关（ADHD：OR, 1.15 [95% CI, 1.09-1.22]；自闭症：OR, 1.13 [95% CI, 1.06-1.19]；精神分裂症：OR, 1.13 [95% CI, 1.09-1.22] ，1.07-1.20]）。除 ADHD PGS 和吸烟外，母亲和父亲 PGS 的关联基本一致（父亲：OR，1.13 [95% CI，1.09-1.17]）。结论和相关性在这项研究中，从母亲传给孩子的神经发育状况的遗传倾向与多种妊娠相关因素有关，因此可能会混淆这些妊娠相关因素与后代神经发育之间的关联，而此前这些因素被认为是因果关系。未来的研究设计必须考虑遗传混杂因素，以获得有效的因果推论，以便为怀孕个体提供准确的建议。