Wootton Robyn E, Dack Kyle, Jones Hannah J, Riglin Lucy, Madley-Dowd Paul, Borges Carolina, Pagoni Panagiota, Roth Christine, Brantsæter Anne Lise, Corfield Elizabeth C, Stoltenberg Camilla, Øyen Anne-Siri, Davey Smith George, Ask Helga, Thapar Anita, Stergiakouli Evie, Havdahl Alexandra
Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
MRC (Medical Research Council) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Psychol Med. 2024 Sep 9;54(12):1-11. doi: 10.1017/S0033291724001466.
Maternal vitamin-D and omega-3 fatty acid (DHA) deficiencies during pregnancy have previously been associated with offspring neurodevelopmental traits. However, observational study designs cannot distinguish causal effects from confounding.
First, we conducted Mendelian randomisation (MR) using genetic instruments for vitamin-D and DHA identified in independent genome-wide association studies (GWAS). Outcomes were (1) GWAS for traits related to autism and ADHD, generated in the Norwegian mother, father, and child cohort study (MoBa) from 3 to 8 years, (2) autism and ADHD diagnoses. Second, we used mother-father-child trio-MR in MoBa (1) to test causal effects through maternal nutrient levels, (2) to test effects of child nutrient levels, and (3) as a paternal negative control.
Associations between higher maternal vitamin-D levels on lower ADHD related traits at age 5 did not remain after controlling for familial genetic predisposition using trio-MR. Furthermore, we did not find evidence for causal maternal effects of vitamin-D/DHA levels on other offspring traits or diagnoses. In the reverse direction, there was evidence for a causal effect of autism genetic predisposition on lower vitamin-D levels and of ADHD genetic predisposition on lower DHA levels.
Triangulating across study designs, we did not find evidence for maternal effects. We add to a growing body of evidence that suggests that previous observational associations are likely biased by genetic confounding. Consequently, maternal supplementation is unlikely to influence these offspring neurodevelopmental traits. Notably, genetic predisposition to ADHD and autism was associated with lower DHA and vitamin-D levels respectively, suggesting previous associations might have been due to reverse causation.
先前研究表明，孕期母亲维生素D和ω-3脂肪酸（DHA）缺乏与后代神经发育特征有关。然而，观察性研究设计无法区分因果效应和混杂因素。
首先，我们利用在独立全基因组关联研究（GWAS）中确定的维生素D和DHA的基因工具进行孟德尔随机化（MR）。研究结果包括：（1）在挪威母婴队列研究（MoBa）中，对3至8岁儿童的自闭症和注意力缺陷多动障碍（ADHD）相关特征进行GWAS分析；（2）自闭症和ADHD诊断。其次，我们在MoBa中使用母婴三联体MR：（1）通过母亲营养水平测试因果效应；（2）测试儿童营养水平的影响；（3）作为父亲的阴性对照。
在使用三联体MR控制家族遗传易感性后，母亲维生素D水平较高与5岁时较低的ADHD相关特征之间的关联不再显著。此外，我们没有发现证据表明维生素D/DHA水平对其他后代特征或诊断有因果性的母亲效应。相反，有证据表明自闭症遗传易感性对较低的维生素D水平有因果效应，ADHD遗传易感性对较低的DHA水平有因果效应。
综合各项研究设计，我们没有发现母亲效应的证据。我们补充了越来越多的证据，表明先前的观察性关联可能受到遗传混杂因素的影响。因此，母亲补充营养不太可能影响这些后代的神经发育特征。值得注意的是，ADHD和自闭症的遗传易感性分别与较低的DHA和维生素D水平相关，这表明先前的关联可能是由于反向因果关系。
