Testing Maternal Effects of Vitamin-D and Omega-3 levels on Offspring Neurodevelopmental Traits in the Norwegian Mother, Father and Child Cohort Study

Background.
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.

Methods.
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 related traits, generated in the Norwegian Mother, Father and Child cohort study (MoBa) from 3-8 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.

Results.
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 nor 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.

Conclusions.
Triangulating across study designs, we did not find evidence for maternal effects. We add to a growing body of evidence which 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 causality