Testing intrauterine effects of vitamin-d and omega-3 levels on offspring neurodevelopmental traits in the norwegian mother, father and child cohort study

Maternal vitamin-D and omega-3 fatty acid (DHA) deficiencies during pregnancy have previously been associated with offspring neurodevelopmental traits. Observational study designs cannot distinguish causal intrauterine effects from unmeasured 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 autism and ADHD traits, generated in the Norwegian Mother, Father and Child cohort study (MoBa) from 3-8 years, 2) PGC GWAS of autism and ADHD diagnoses. Second, we used mother-father-child trio-MR in MoBa 1) to estimate causal effects through maternal intrauterine exposure, 2) to estimate effects of child nutrient levels, and 3) as a paternal negative control. Using MR, our findings did not support causal intrauterine effects of vitamin-D or DHA levels on offspring traits nor diagnoses. In the reverse direction, there was evidence for a causal effect of autism genetic liability on lower Vitamin-D levels and of ADHD genetic liability on lower DHA levels. In trio-MR, there was evidence for an effect of higher maternal Vitamin-D levels on reduced ADHD traits at age 5. However, these effects attenuated after controlling for familial polygenic risk, suggesting that these associations are unlikely intrauterine. Triangulating across study designs, we did not find evidence for intrauterine effects. We add to a growing body of evidence which suggests that previous observational associations are likely biased by genetic confounding. Consequently, supplementation in pregnancy is unlikely to influence the neurodevelopmental traits included in this study.